Eye Meds Now

None listed in package insert.

None listed in package insert.

• Warnings for patients:
  • Liver warning: This product contains acetaminophen. The maximum daily dose of this product is 10 tablets (3,250 mg) in 24 hours for adults or 5 tablets (1,625 mg) in 24 hours for children. Severe liver damage may occur if:
    • Adult takes more than 4,000 mg of acetaminophen in 24 hours.
    • Child takes more than 5 doses in 24 hours, which is the maximum daily amount.
    • Taken with other drugs containing acetaminophen.
    • Adult has 3 or more alcoholic drinks every day while using this product.
  • Allergy alert:
    • Acetaminophen may cause severe skin reactions. Symptoms may include:
      • Skin reddening.
      • Blisters.
      • Rash.
    • If a skin reaction occurs, stop use and seek medical help right away.
  • Do not use with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.
  • Do not use if you are allergic to acetaminophen or any of the inactive ingredients in this product.
  • Ask a doctor before use if you have liver disease.
  • Ask a doctor or pharmacist before use if you are taking the blood thinning drug warfarin.
  • Stop use and ask a doctor if you experience any of the following, which could be signs of a serious condition:
    • Pain gets worse or lasts more than 10 days in adults.
    • Pain gets worse or lasts more than 5 days in children under 12 years.
    • Fever gets worse or lasts more than 3 days.
    • New symptoms occur.
    • Redness or swelling is present.
  • Keep out of reach of children.
  • Overdose warning:
    • In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222).
    • Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms.

None listed in package insert.

TYLENOL^® with Codeine is contraindicated for:

• All children younger than 12 years of age (See WARNINGS in package insert).
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (See WARNINGS in package insert).

TYLENOL^® with Codeine is contraindicated in patients with:

• Significant respiratory depression (See WARNINGS in package insert).
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (See WARNINGS in package insert).
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (See WARNINGS in package insert).
• Known or suspected gastrointestinal obstruction, including paralytic ileus (See WARNINGS in package insert).
• Hypersensitivity to codeine, acetaminophen, or any of the formulation excipients (e.g., anaphylaxis) (See WARNINGS in package insert).

• The following serious adverse reactions are described, or described in greater detail, in other sections: 
  • Addiction, abuse, and misuse [See WARNINGS in package insert].
  • Life-threatening respiratory depression [See WARNINGS in package insert].
  • Ultra-rapid metabolism of codeine and other risk factors for Life-threatening respiratory depression in children [See WARNINGS in package insert].
  • Neonatal opioid withdrawal syndrome [See WARNINGS in package insert].
  • Interactions with CNS depressants [See WARNINGS in package insert].
  • Severe hypotension [See WARNINGS in package insert].
  • Gastrointestinal adverse reactions [See WARNINGS in package insert].
  • Seizures [See WARNINGS in package insert].
  • Withdrawal [See WARNINGS in package insert].
• The following adverse reactions have been identified during post-approval use of TYLENOL with Codeine tablets. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
  • Serious adverse reactions associated with codeine are respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
  • The most frequently observed adverse reactions with codeine administration include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.
  • Other adverse reactions include allergic reactions, euphoria, dysphoria, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis.
• Other less frequently observed adverse reactions expected from opioid analgesics, including TYLENOL^® with Codeine:
  • Cardiovascular system: faintness, flushing, hypotension, palpitations, syncope.
  • Digestive system: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis.
  • Nervous system: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness.
  • Skin and appendages: rash, sweating, urticarial.
• Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
• Anaphylaxis: Anaphylaxis has been reported with ingredients contained in TYLENOL with Codeine.
• Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (See CLINICAL PHARMACOLOGY in package insert).
• Consult package insert for additional information.

• Addiction, abuse, and misuse:
  • TYLENOL^® with Codeine contains codeine. Codeine in combination with acetaminophen, is a Schedule III controlled substance. As an opioid, TYLENOL^® with Codeine tablets expose users to the risks of addiction, abuse, and misuse (See DRUG ABUSE and DEPENDENCE in package insert).
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed TYLENOL^® with Codeine tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
  • Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing TYLENOL^® with Codeine tablets, and monitor all patients receiving TYLENOL^® with Codeine tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as TYLENOL^® with Codeine tablets, but use in such patients necessitates intensive counseling about the risks and proper use of TYLENOL^® with Codeine tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing TYLENOL^® with Codeine. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug (See PRECAUTIONS; Information for Patients/Caregivers in package insert). Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
• Opioid analgesic Risk Evaluation and Mitigation Strategy (REMS):
  • To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
    • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
    • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCDG.
    • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
    • Consider using other tools to improve patient, household, and community safety, such as patientprescriber agreements that reinforce patient-prescriber responsibilities.
  • To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at: www.fda.gov/OpioidAnalgesicREMSBlueprint.
• Life-threatening respiratory depression:
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status (See OVERDOSAGE in package insert). Carbon dioxide (CO₂ ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
  • While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of TYLENOL^® with Codeine, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 – 72 hours of initiating therapy with and following dosage increases of TYLENOL^® with Codeine.
  • To reduce the risk of respiratory depression, proper dosing and titration of TYLENOL^® with Codeine are essential (See DOSAGE AND ADMINISTRATION in package insert). Overestimating the TYLENOL^® with Codeine dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
  • Accidental ingestion of TYLENOL^® with Codeine, especially by children, can result in respiratory depression and death due to an overdose of codeine.
  • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper (See DOSAGE AND ADMINISTRATION in package insert).
• Ultra-rapid metabolism of Codeine and other risk factors for life-threatening respiratory depression in children:
  • Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below in package insert), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years of age appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effects. Because of the risk of life-threatening respiratory depression and death:
    • TYLENOL^® with Codeine tablets are contraindicated for all children younger than 12 years of age (See CONTRAINDICATIONS in package insert).
    • TYLENOL^® with Codeine tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy (See CONTRAINDICATIONS in package insert).
    • Avoid the use of TYLENOL^® with Codeine tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression (See WARNINGS in packag insert).
    • As with adults, when prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these 2 risks and the signs of morphine overdose (See OVERDOSAGE in package insert).
• Nursing mothers: At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with TYLENOL^® with Codeine tablets.
• CYP2D6 genetic variability: Ultra-rapid metabolizers: Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1×N or *1/*2×N). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1% to 10% for Whites (European, North American), 3% to 4% for Blacks (African Americans), 1% to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have lifethreatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (See OVERDOSAGE in package insert). Therefore, individuals who are ultra-rapid metabolizers should not use TYLENOL^® with Codeine tablets.
• Neonatal opioid withdrawal syndrome: Prolonged use of TYLENOL^® with Codeine tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (See PRECAUTIONS, Information for Patients/Caregivers, Pregnancy in package insert).
• Interactions with drugs affecting Cytochrome P450 Isoenzymes:
  • The effects of concomitant use or discontinuation of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with codeine are complex. Use of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with TYLENOL^® with Codeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.
  • CYP3A4 Interaction:
    • The concomitant use of TYLENOL^® with Codeine with all CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a CYP3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
    • The concomitant use of TYLENOL^® with Codeine with all CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.
    • Follow patients receiving TYLENOL^® with Codeine and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when TYLENOL^® with Codeine are used in conjunction with inhibitors and inducers of CYP3A4 (See WARNINGS, Drug Interactions in package insert).
    • If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of TYLENOL^® with Codeine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
    • If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the TYLENOL^® with Codeine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal (See PRECAUTIONS, Drug Interactions in package insert).
  • Risks of concomitant use or discontinuation of CYP2D6 Inhibitors:
    • The concomitant use of TYLENOL^® with Codeine with all CYP2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.
    • Discontinuation of a concomitantly used CYP2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
    • Follow patients receiving TYLENOL^® with Codeine and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when TYLENOL^® with Codeine tablets are used in conjunction with inhibitors of CYP2D6.
    • If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the TYLENOL^® with Codeine dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the TYLENOL^® with Codeine dosage and follow the patient for signs and symptoms of respiratory depression or sedation (See PRECAUTIONS, Drug Interactions in package insert).
• Hepatotoxicity:
  • Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.
  • The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
  • Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.
• Risks from concomitant use with benzodiazepines or other CNS depressants:
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of TYLENOL^® with Codeine tablets with benzodiazepines and/or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (See PRECAUTIONS; Drug Interactions in package insert).
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when TYLENOL^® with Codeine tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (See PRECAUTIONS; Drug Interactions, Information for Patients/Caregivers in package insert).
• Life-threatening respiratory depression in patients with chronic pulmonary disease or elderly, cachectic, or debilitated patients:
  • The use of TYLENOL^® with Codeine tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
  • Patients with chronic pulmonary disease: TYLENOL^® with Codeine-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of TYLENOL^® with Codeine tablets (See WARNINGS; LifeThreatening Respiratory Depression in package insert).
  • Elderly, cachectic, or debilitated patients:
    • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, including clearance, compared to younger, healthier patients (See WARNINGS; Life-Threatening Respiratory Depression in package insert).
    • Monitor such patients closely, particularly when initiating and titrating TYLENOL with Codeine tablets and when TYLENOL^® with Codeine tablets are given concomitantly with other drugs that depress respiration (See WARNINGS; Life-Threatening Respiratory Depression in package insert). Alternatively, consider the use of non-opioid analgesics in these patients.
• Interaction with monoamine oxidase inhibitors: Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine's active metabolite, including respiratory depression, coma, and confusion. TYLENOL^® with Codeine tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
• Severe hypotension: TYLENOL^® with Codeine may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (See PRECAUTIONS; Drug Interactions in package insert). Monitor these patients for signs of hypotension after initiating or titrating the dosage of TYLENOL^® with Codeine. In patients with circulatory shock TYLENOL^® with Codeine tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of TYLENOL^® with Codeine tablets with circulatory shock.
• Serious skin reactions: Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
• Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness:
  • In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), TYLENOL^® with Codeine tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with TYLENOL^® with Codeine tablets.
  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of TYLENOL with Codeine tablets in patients with impaired consciousness or coma.
• Hypersensitivity/anaphylaxis: There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue TYLENOL^® with Codeine immediately and seek medical care if they experience these symptoms. Do not prescribe TYLENOL^® with Codeine tablets for patients with acetaminophen allergy (See PRECAUTIONS;Information for Patients/Caregivers in package insert).
• Risks of use in patients with gastrointestinal conditions:
  • TYLENOL^® with Codeine tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
  • The administration of TYLENOL^® with Codeine tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
  • TYLENOL^® with Codeine tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
• Sulfite sensitivity: TYLENOL^® with Codeine tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
• Increased risk of seizures in patients with seizure disorders: The codeine in TYLENOL^® with Codeine tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during TYLENOL^® with Codeine tablets therapy.
• Withdrawal:
  • Do not abruptly discontinue TYLENOL with Codeine tablets in a patient physically dependent on opioids. When discontinuing TYLENOL with Codeine tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of TYLENOL with Codeine tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain (See DOSAGE and ADMINISTRATION, DRUG ABUSE and DEPENDENCE in package insert).
  • Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including TYLENOL with Codeine tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms (See PRECAUTIONS; Drug Interactions in package insert).
• TYLENOL^® with Codeine (acetaminophen and codeine phosphate) tablets should be prescribed with caution in certain special-risk patients with severe impairment of renal or hepatic function, convulsive disorders, obstructive airways disease, acute abdominal conditions such as obstructive bowel disorders (See WARNINGS - Risks of Use in Patients with Gastrointestinal Conditions in package insert), hypothyroidism, urethral stricture, Addison’s disease, or prostatic hypertrophy.
• Risks of driving and operating machinery: TYLENOL^® with Codeine tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of TYLENOL^® with Codeine tablets and know how they will react to the medication (See PRECAUTIONS; Information for Patients/Caregivers in package insert).
• Information for patients/caregivers:
  • Advise the patient to read the FDA-approved patient labeling (Medication Guide):
  • Storage and disposal:
    • Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store TYLENOL^® with Codeine tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home (See WARNINGS, DRUG ABUSE AND DEPENDENCE in package insert). Inform patients that leaving TYLENOL^® with Codeine tablets unsecured can pose a deadly risk to others in the home.
    • Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that drug take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or Drug Enforcement Administration (DEA)-registered collectors are available, instruct patients to dispose of TYLENOL^® with Codeine tablets by following these four steps:
      • Mix TYLENOL^® with Codeine tablets (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds;
      • Place the mixture in a container such as a sealed plastic bag;
      • Throw the container in the household trash;
      • Delete all personal information on the prescription label of the empty bottle.
    • Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.
  • ​​​​​Addiction, abuse and misuse: Inform patients that the use of TYLENOL^® with Codeine tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (See WARNINGS in package insert). Instruct patients not to share TYLENOL^® with Codeine tablets with others and to take steps to protect TYLENOL^® with Codeine tablets from theft or misuse.
  • Life-threatening respiratory depression: Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting TYLENOL^® with Codeine tablets or when the dosage is increased, and that it can occur even at recommended dosages (See WARNINGS in package insert). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
  • Accidental ingestion:
    • Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (See WARNINGS in package insert). Instruct patients to take steps to store TYLENOL^® with Codeine tablets securely. Advise patients to properly dispose of TYLENOL^® with Codeine tablets in accordance with local state guidelines and/or regulations.
  • Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children:
    • Advise caregivers that TYLENOL^® with Codeine is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
    • Advise caregivers of children 12 to 18 years of age receiving TYLENOL^® with Codeine to monitor for signs of respiratory depression (See WARNINGS in package insert).
  • Interactions with benzodiazepines and other CNS depressants: Inform patients and caregivers that potentially fatal additive effects may occur if TYLENOL^® with Codeine is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these drugs concomitantly unless supervised by a healthcare provider (See WARNINGS, PRECAUTIONS; Drug Interactions in package insert).
  • Serotonin syndrome:
    • Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome and to seek medical attention right away if symptoms develop.
    • Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications (See PRECAUTIONS; Drug Interactions in package insert).
  • MAOI interaction: Inform patients not to take TYLENOL^® with Codeine tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TYLENOL with Codeine tablets (See WARNINGS, Drug Interactions in package insert).
  • Adrenal insufficiency: Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms (See WARNINGS in package insert).
  • Important administration instructions: Instruct patients how to properly take TYLENOL^® with Codeine tablets (See DOSAGE AND ADMINISTRATION in package insert):
    • Advise patients not to adjust the dose of TYLENOL^® with Codeine without consulting a physician or other healthcare professional.
    • Important discontinuation instructions: In order to avoid developing withdrawal symptoms, instruct patients not to discontinue TYLENOL^® with Codeine tablets without first discussing a tapering plan with the prescriber (See DOSAGE AND ADMINISTRATION in package insert).
  • Maximum daily dose of acetaminophen: Inform patients not to take more than 4,000 milligrams of acetaminophen per day. Advise patients to call their healthcare provider if they have taken more than the recommended dose.
  • Hypotension: Inform patients that TYLENOL^® with Codeine may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) (See WARNINGS; Hypotension in package insert).
  • Anaphylaxis: Inform patients that anaphylaxis has been reported with ingredients contained in TYLENOL^® with Codeine. Advise patients how to recognize such a reaction, and if they develop signs of allergy such as a rash or difficulty breathing to stop taking TYLENOL^® with Codeine and seek medical attention. (see CONTRAINDICATIONS, ADVERSE REACTIONS in package insert).
  • Pregnancy:
    • Neonatal opioid withdrawal syndrome: Inform female patients of reproductive potential that prolonged use of TYLENOL^® with Codeine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (See WARNINGS, Pregnancy in package insert).
    • Embryo-fetal toxicity: Inform female patients of reproductive potential that TYLENOL^® with Codeine can cause fetal harm and to inform the prescriber of a known or suspected pregnancy (See PRECAUTIONS; Pregnancy in package insert).
  • Lactation: Advise women that breastfeeding is not recommended during treatment with TYLENOL^® with Codeine tablets (See PRECAUTIONS; Nursing Mothers in package insert).
  • Infertility: Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.
  • Driving or operating heavy machinery: Inform patients that TYLENOL^® with Codeine tablets may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery and to avoid such tasks while taking this product, until they know how they will react to the medication.
  • Constipation: Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (See ADVERSE REACTIONS, CLINICAL PHARMACOLOGY in package insert).
• Consult package insert for additional information.

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; HEPATOTOXICITY; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse and Misuse

TYLENOL^®  with Codeine exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing TYLENOL^®  with Codeine tablets, and monitor all patients regularly for the development of these behaviors and conditions (See WARNINGS in package insert).

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products (See WARNINGS in package insert). Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to:

• complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
• consider other tools to improve patient, household, and community safety

Life-Threatening Respiratory Depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of TYLENOL^®  with Codeine tablets. Monitor for respiratory depression, especially during initiation of TYLENOL^®  with Codeine tablets or following a dose increase (See WARNINGS in package insert).

Accidental Ingestion: 

Accidental ingestion of TYLENOL^®  with Codeine tablets, especially by children, can result in a fatal overdose of TYLENOL^®  with Codeine tablets (See WARNINGS in package insert).

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being ultra-rapid metabolizers of codeine due to a cytochrome P450 (CYP) 2D6 polymorphism (See WARNINGS, PRECAUTIONS; Information for Patients/Caregivers, Nursing Mothers in package insert). TYLENOL^®  with Codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (See CONTRAINDICATIONS in package insert). Avoid the use of TYLENOL^®  with Codeine tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine (See WARNINGS, PRECAUTIONS in package insert).

Neonatal Opioid Withdrawal Syndrome

Prolonged use of TYLENOL^®  with Codeine tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (See WARNINGS, PRECAUTIONS in package insert).

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with codeine are complex. Use of CYP3A4 inducers, CYP3A4 inhibitors, or CYP2D6 inhibitors with TYLENOL with Codeine tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine (See WARNINGS, PRECAUTIONS: Drug Interactions in package insert).

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product (See WARNINGS in package insert).

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (See WARNINGS, Drug Interactions in package insert).

• Reserve concomitant prescribing of TYLENOL^®  with Codeine tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Contraindicated for:

• All children younger than 12 years of age [See Warnings and Precautions (5.4) in package insert].
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [See Warnings and Precautions (5.4) in package insert].

ULTRACET is also contraindicated in patients with:

• Significant respiratory depression [See Warnings and Precautions (5.3) in package insert].
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [See Warnings and Precautions (5.13) in package insert].
• Patients with known or suspected gastrointestinal obstruction, including paralytic ileus [See Warnings and Precautions (5.17) in package insert].
• Previous hypersensitivity to tramadol, acetaminophen, any other component of this product, or opioids [See Warnings and Precautions (5.18) in package insert].
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [See Drug Interactions (7) in package insert].

• The incidence rate of treatment-emergent adverse events over 5 days of ULTRACET^® use in clinical trials (subjects took an average of at least 6 tablets per day):
  • Gastrointestinal system disorders:
    • Constipation 6%. 
    • Diarrhea 3%.
    • Nausea 3%. 
    • Dry mouth 2%.
  • Psychiatric disorders:
    • Somnolence 6%.
    • Anorexia 3%. 
    • Insomnia 2%.
  • Central & peripheral nervous system:
    • Dizziness 3%.
  • Skin and appendages:
    • Sweating increased 4%. 
    • Pruritus 2%.
  • Reproductive disorders, male:  
    • Prostatic disorder 2%.
• The following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of ULTRACET^®:
  • Body as a whole: Asthenia, fatigue, hot flushes.
  • Central and peripheral nervous system: Dizziness, headache, tremor.
  • Gastrointestinal system: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting.
  • Psychiatric disorders: Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence.
  • Skin and appendages: Pruritus, rash, increased sweating.
• The following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in ULTRACET^® clinical trials:
  • Body as a whole: Chest pain, rigors, syncope, withdrawal syndrome.
  • Cardiovascular disorders: Hypertension, aggravated hypertension, hypotension.
  • Central and peripheral nervous system: Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo.
  • Gastrointestinal system: Dysphagia, melena, tongue edema.
  • Hearing and vestibular disorders: Tinnitus.
  • Heart rate and rhythm disorders: Arrhythmia, palpitation, tachycardia.
  • Liver and biliary system: Hepatic function abnorma.
  • Metabolic and nutritional disorders: Weight decrease.
  • Psychiatric disorders: Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking.
  • Red blood cell disorders: Anemia.
  • Respiratory system: Dyspnea.
  • Urinary system: Albuminuria, micturition disorder, oliguria, urinary retention.
  • Vision disorders: Abnormal vision. 
• Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis liver failure and gastrointestinal bleeding. Reported laboratory abnormalities included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.
• Consult package insert for additional information.

• Addiction, abuse and misuse:
  • ULTRACET contains tramadol, a Schedule IV controlled substance. As an opioid, ULTRACET exposes users to the risks of addiction, abuse, and misuse [See Drug Abuse and Dependence (9) in package insert].
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ULTRACET. Addiction can occur at recommended dosages and if the drug is misused or abused.
  • Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing ULTRACET, and monitor all patients receiving ULTRACET for the development of these behaviors and conditions.
  • Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as ULTRACET, but use in such patients necessitates intensive counseling about the risks and proper use of ULTRACET along with intensive monitoring for signs of addiction, abuse, and misuse.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ULTRACET. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [See Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
• Opioid analgesic risk evaluation and mitigation strategy (REMS):
  • To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
    • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
    • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
    • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
    • Consider using other tools to improve patient, household, and community safety, such as patient- prescriber agreements that reinforce patient-prescriber responsibilities.
  • To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
• Life-threatening respiratory depression:
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [See Overdosage (10) in package insert]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
  • While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ULTRACET, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of ULTRACET.
  • To reduce the risk of respiratory depression, proper dosing and titration of ULTRACET are essential [See Dosage and Administration (2) in package insert]. Overestimating the ULTRACET dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
  • Accidental ingestion of even one dose of ULTRACET, especially by children, can result in respiratory depression and death due to an overdose of tramadol.
  • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [See Dosage and Administration (2.4) in package insert].
• Ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children:
  • Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
    • ULTRACET is contraindicated for all children younger than 12 years of age [See Contraindications (4) in package insert].
    • ULTRACET is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [See Contraindications (4) in package insert].
    • Avoid the use of ULTRACET in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
    • As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [See Use in Specific Populations (8.4), Overdosage (10) in package insert].
  • Nursing mothers: Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of O-desmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra- rapid metabolizer mother taking ULTRACET could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with ULTRACET [See Use in Specific Populations (8.2) in package insert].
  • CYP2D6 genetic variability: ultra-rapid metabolizer: Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1×N or *1/*2×N). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [See Overdosage (10) in package insert]. Therefore, individuals who are ultra-rapid metabolizers should not use ULTRACET.
• Neonatal opioid withdrawal syndrome: Prolonged use of ULTRACET during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [See Use in Specific Populations (8.1) and Patient Counseling Information (17) in package insert].
• Risks of interactions with drugs affecting cytochrome P450 isoenzymes:
  • The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from ULTRACET are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRACET requires careful consideration of the effects on the parent drug, tramadol, which is a weak serotonin and norepinephrine reuptake inhibitor and μ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in μ- opioid receptor binding [See Drug Interactions (7) in package insert].
  • Risks of concomitant use or discontinuation of cytochrome P450 2D6 inhibitors:
    • The concomitant use of ULTRACET with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome.
    • Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression.
    • Follow patients receiving ULTRACET and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when ULTRACET is used in conjunction with inhibitors of CYP2D6 [See Drug Interactions (7) in package insert].
  • Cytochrome P450 3A4 interaction:
    • The concomitant use of ULTRACET with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.
    • The concomitant use of ULTRACET with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.
    • Follow patients receiving ULTRACET and any CYP3A4 inhibitor or inducer for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when ULTRACET is used in conjunction with inhibitors and inducers of CYP3A4 [See Drug Interactions (7) in package insert].
• Hepatotoxicity:
  • ULTRACET contains tramadol hydrochloride and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.
  • The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
  • Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.
• Risks from concomitant use with benzodiazepines or other CNS depressants:
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTRACET with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [See Drug Interactions (7) in package insert].
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when ULTRACET is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [See Drug Interactions (7), Patient Counseling Information (17) in package insert].
• Serotonin syndrome risk:
  • Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, including ULTRACET, during concomitant use with serotonergic drugs.
  • Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [See Drug Interactions (7) in package insert]. This may occur within the recommended dosage range.
  • Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTRACET if serotonin syndrome is suspected.
• Increased risk of seizures:
  • Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range.
  • Concomitant use of tramadol increases the seizure risk in patients taking: [See Drug Interactions (7) in package insert].
    • Selective serotonin re-uptake inhibitors (SSRIs) and Serotonin-norepinephrine re-uptake inhibitors (SNRIs) antidepressants or anorectics,
    • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
    • Other opioids,
    • MAO inhibitors [See Warnings and Precautions (5.9), Drug Interactions (7) in package insert]
    • Neuroleptics, or
    • Other drugs that reduce the seizure threshold.
  • Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).
  • In tramadol overdose, naloxone administration may increase the risk of seizure.
• Suicide risk:
  • Do not prescribe ULTRACET for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed [See Drug Abuse and Dependence (9) in package insert].
  • Prescribe ULTRACET with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers, or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression [See Drug Interactions (7) in package insert].
  • Inform patients not to exceed the recommended dose and to limit their intake of alcohol [See Dosage and Administration (2), Warnings and Precautions (5.7, 5.8) in package insert].
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
• Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients:
  • The use of ULTRACET in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [See Contraindications (4) in package insert].
  • Patients with chronic pulmonary disease: ULTRACET-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ULTRACET [See Warnings and Precautions (5.3) in package insert].
  • Elderly, cachectic, or debilitated patients:
    • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, or altered clearance, compared to younger, healthier patients [See Warnings and Precautions (5.3) in package insert].
    • Monitor such patients closely, particularly when initiating and titrating ULTRACET and when ULTRACET is given concomitantly with other drugs that depress respiration [See Warnings and Precautions (5.8), Drug Interactions (7) in package insert]. Alternatively, consider the use of non-opioid analgesics in these patients.
• Severe hypotension: ULTRACET may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [See Drug Interactions (7) in package insert]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of ULTRACET. In patients with circulatory shock, ULTRACET may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ULTRACET in patients with circulatory shock.
• Risk of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness:
  • In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTRACET may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTRACET.
  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ULTRACET in patients with impaired consciousness or coma.
• Serious skin reactions: Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
• Risk of use in patients with gastrointestinal conditions:
  • ULTRACET is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [See Contraindications (4) in package insert].
  • The tramadol in ULTRACET may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
• Anaphylaxis and other hypersensitivity reactions:
  • Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens- Johnson syndrome. Patients with a history of anaphylactoid reactions to tramadol and other opioids may be at increased risk and therefore should not receive ULTRACET. If anaphylaxis or other hypersensitivity occurs, stop administration of ULTRACET immediately, discontinue ULTRACET permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [See Contraindications (4), Information for Patients (17) in package insert].
  • There have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue ULTRACET immediately and seek medical care if they experience these symptoms. Do not prescribe ULTRACET for patients with acetaminophen allergy.
• Increased risk of hepatotoxicity with concomitant use of other acetaminophen-containing products: Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, ULTRACET should not be used concomitantly with other acetaminophen containing products.
• Withdrawal:
  • Do not abruptly discontinue ULTRACET in a patient physically dependent on opioids. When discontinuing ULTRACET in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol and acetaminophen in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [See Dosage and Administration (2.4), Drug Abuse and Dependence (9.3)].
  • Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ULTRACET. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [See Drug Interactions (7) in package insert].
• Driving and operating machinery: ULTRACET may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ULTRACET and know how they will react to the medication [See Patient Counseling Information (17) in package insert].

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; HEPATOTOXICITY; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

ULTRACET exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing ULTRACET, and monitor all patients regularly for the development of these behaviors and conditions [See Warnings and Precautions (5.1) in package insert].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [See Warnings and Precautions (5.2) in package insert]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to

• complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
• consider other tools to improve patient, household, and community safety.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of ULTRACET. Monitor for respiratory depression, especially during initiation of ULTRACET or following a dose increase [See Warnings and Precautions (5.3) in package insert].

Accidental Ingestion
Accidental ingestion of even one dose of ULTRACET, especially by children, can result in a fatal overdose of tramadol [See Warnings and Precautions (5.3) in package insert].

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases occurred following tonsillectomy and/or adenoidectomy, and in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [See Warnings and Precautions (5.4) in package insert]. ULTRACET is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [See Contraindications (4) in package insert]. Avoid the use of ULTRACET in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol. [See Warnings and Precautions (5.4) in package insert].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ULTRACET during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [See Warnings and Precautions (5.5) in package insert].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRACET requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [See Warnings and Precautions (5.6), Drug Interactions (7) in package insert].

Hepatotoxicity

ULTRACET contains tramadol hydrochloride and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [See Warnings and Precautions (5.7) in package insert].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [See Warnings and Precautions (5.8) and Drug Interactions (7) in package insert].

• Reserve concomitant prescribing of ULTRACET and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Contraindicated for:

• All children younger than 12 years of age [See Warnings and Precautions (5.4) in package insert].
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [See Warnings and Precautions (5.4) in package insert].

ULTRAM^® is also contraindicated in patients with:

• Significant respiratory depression [See Warnings and Precautions (5.3) in package insert].
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [See Warnings and Precautions (5.12) in package insert].
• Known or suspected gastrointestinal obstruction, including paralytic ileus [See Warnings and Precautions (5.15) in package insert].
• Hypersensitivity to tramadol, any other component of this product or opioids [See Warnings and Precautions (5.16) in package insert].
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days [See Drug Interactions (7) in package insert].

• The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with ULTRAM^® exists:
  • Body as a whole: Malaise.
  • Cardiovascular: Vasodilation.
  • Central nervous system: Anxiety, confusion, coordination disturbance, euphoria, miosis, nervousness, sleep disorder.
  • Gastrointestinal: Abdominal pain, anorexia, flatulence.
  • Musculoskeletal: Hypertonia.
  • Skin: Rash.
  • Special senses: Visual disturbance.
  • Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.
• The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in postmarketing experience with tramadol-containing products:
  • Body as a whole: Accidental injury, allergic reaction, anaphylaxis, death, suicidal tendency, weight loss, serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).
  • Cardiovascular: Orthostatic hypotension, syncope, tachycardia.
  • Central nervous system: Abnormal gait, amnesia, cognitive dysfunction, depression, difficulty in concentration, hallucinations, paresthesia, seizure, tremor.
  • Respiratory: Dyspnea.
  • Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, urticaria, vesicles.
  • Sensory: Dysgeusia.
  • Urogenital: Dysuria, menstrual disorder.
• Other adverse experiences, causal relationship unknown: A variety of other adverse events were reported infrequently in patients taking ULTRAM during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.
  • Cardiovascular: Abnormal ECG, hypertension, hypotension, myocardial ischemia, palpitations, pulmonary edema, pulmonary embolism.
  • Central Nervous System: Migraine.
  • Gastrointestinal: Gastrointestinal bleeding, hepatitis, stomatitis, liver failure.
  • Laboratory Abnormalities: Creatinine increase, elevated liver enzymes, hemoglobin decrease, proteinuria.
  • Sensory: Cataracts, deafness, tinnitus.
• Consult package insert for additional information.

• Addiction, abuse and misuse:
  • ULTRAM contains tramadol, a Schedule IV controlled substance. As an opioid, ULTRAM exposes users to the risks of addiction, abuse, and misuse [See Drug Abuse and Dependence (9) in package insert].
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ULTRAM. Addiction can occur at recommended dosages and if the drug is misused or abused.
  • Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing ULTRAM, and monitor all patients receiving ULTRAM for the development of these behaviors and conditions.
  • Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as ULTRAM, but use in such patients necessitates intensive counseling about the risks and proper use of ULTRAM along with intensive monitoring for signs of addiction, abuse, and misuse.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing ULTRAM. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [See Patient Counselling Information (17) in package insert]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
• Opioid analgesic risk evaluation and mitigation strategy (REMS):
  • To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
    • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. 
    • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. 
    • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
    • Consider using other tools to improve patient, household, and community safety, such as patientprescriber agreements that reinforce patient-prescriber responsibilities.
  • To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
• Life-threatening respiratory depression:
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [See Overdosage (10) in package insert]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
  • While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ULTRAM, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy with and following dosage increases of ULTRAM.
  • To reduce the risk of respiratory depression, proper dosing and titration of ULTRAM are essential [See Dosage and Administration (2) in package insert]. Overestimating the ULTRAM dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
  • Accidental ingestion of even one dose of ULTRAM, especially by children, can result in respiratory depression and death due to an overdose of tramadol.
  • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [See Dosage and Administration (2.4) in package insert].
• Ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children:
  • Life-threatening respiratory depression and death have occurred in children who received tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to increased exposure to an active metabolite. Based upon post-marketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
    • ULTRAM is contraindicated for all children younger than 12 years of age [See Contraindications (4) in package insert].
    • ULTRAM is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [See Contraindications (4) in package insert].
    • Avoid the use of ULTRAM in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
    • As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose [See Use in Specific Populations (8.4), Overdosage (10) in package insert].
  • Nursing mothers: Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of CYP2D6 substrates being potentially exposed to life-threatening levels of the active metabolite Odesmethyltramadol (M1). At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby nursing from an ultra-rapid metabolizer mother taking ULTRAM could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression. For this reason, breastfeeding is not recommended during treatment with ULTRAM [See Use in Specific Populations (8.2) in package insert].
  • CYP2D6 genetic variability: ultra-rapid metabolizer: Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1×N or *1/*2×N). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who are ultra- rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [See Overdosage (10) in package insert]. Therefore, individuals who are ultra-rapid metabolizers should not use ULTRAM.
• Neonatal opioid withdrawal syndrome: Prolonged use of ULTRAM during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [See Use in Specific Populations (8.1) and Patient Counseling Information (17) in package insert].
• Risks of interactions with drugs affecting cytochrome P450 isoenzymes:
  • The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from ULTRAM are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRAM requires careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and μ-opioid agonist, and the active metabolite, M1, which is more potent than tramadol in μ-opioid receptor binding [See Drug Interactions (7) in package insert].
  • Risks of concomitant use or discontinuation of cytochrome P450 2D6 inhibitors:
    • The concomitant use of ULTRAM with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, M1. A decrease in M1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome.
    • Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression.
    • Follow patients receiving ULTRAM and any CYP2D6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when ULTRAM is used in conjunction with inhibitors of CYP2D6 [See Drug Interactions (7) in package insert].
  • Cytochrome P450 3A4 interaction:
    • The concomitant use of ULTRAM with cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.
    • The concomitant use of ULTRAM with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.
    • Follow patients receiving ULTRAM and any CYP3A4 inhibitor or inducer for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when ULTRAM is used in conjunction with inhibitors and inducers of CYP3A4 [See Drug Interactions (7) in package insert].
• Risks from concomitant use with benzodiazepines or other CNS depressants:
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTRAM with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [See Drug Interactions (7) in package insert].
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when ULTRAM is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [See Drug Interactions (7); and Patient Counseling Information (17) in package insert].
• Serotonin syndrome risk:
  • Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly during concomitant use with serotonergic drugs.
  • Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [See Drug Interactions (7) in package insert]. This may occur within the recommended dosage range.
  • Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTRAM if serotonin syndrome is suspected.
• Increased risk of seizure:
  • Seizures have been reported in patients receiving ULTRAM within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of ULTRAM above the recommended range.
  • Concomitant use of ULTRAM increases the seizure risk in patients taking [See Drug Interactions (7) in package insert]:
    • Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
    • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
    • Other opioids,
    • MAO inhibitors [See Warnings and Precautions (5.8); Drug Interactions (7) in package insert].
    • Neuroleptics, or
    • Other drugs that reduce the seizure threshold.
  • Risk of seizure may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In ULTRAM overdose, naloxone administration may increase the risk of seizure.
• Suicide risk:
  • Do not prescribe ULTRAM for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed [See Drug Abuse and Dependence (9) in package insert].
  • Prescribe ULTRAM with caution for patients with a history of misuse and/or are currently taking CNS-active drugs including tranquilizers or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression [See Drug Interactions (7) in package insert].
  • Inform patients not to exceed the recommended dose and to limit their intake of alcohol [See Dosage and Administration (2), Warnings and Precautions (5.7) in package insert].
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
• Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients:
  • The use of ULTRAM in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
  • Patients with chronic pulmonary disease: ULTRAM -treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ULTRAM [See Warnings and Precautions (5.3) in package insert].
  • Elderly, cachectic, or debilitated patients:
    • Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [See Warnings and Precautions (5.3) in package insert].
    • Monitor such patients closely, particularly when initiating and titrating ULTRAM and when ULTRAM is given concomitantly with other drugs that depress respiration [See Warnings and Precautions (5.7); Drug Interactions (7) in package insert]. Alternatively, consider the use of non-opioid analgesics in these patients.
• Severe hypotension: ULTRAM may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [See Drug Interactions (7) in package insert]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of ULTRAM. In patients with circulatory shock, ULTRAM may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ULTRAM in patients with circulatory shock.
• Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired cons ciousness:
  • In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTRAM may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTRAM.
  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of ULTRAM in patients with impaired consciousness or coma.
• Risks of use in patients with gastrointestinal conditions:
  • ULTRAM is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [See Contraindications (4) in package insert].
  • The tramadol in ULTRAM may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
• Anaphylaxis and other hypersensitivity reactions: Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with ULTRAM. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive ULTRAM [See Contraindications (4) in package insert]. If anaphylaxis or other hypersensitivity occurs, stop administration of ULTRAM immediately, discontinue ULTRAM permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. [See Contraindications (4); Patient Counselling Information (17) in package insert].
• Withdrawal:
  • Do not abruptly discontinue ULTRAM in a patient physically dependent on opioids. When discontinuing ULTRAM in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [See Dosage and Administration (2.4), Drug Abuse and Dependence (9.3) in package insert].
  • Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ULTRAM. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [See Drug Interactions (7) in package insert].
• Driving and operating machinery: ULTRAM may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ULTRAM and know how they will react to the medication [See Patient Counselling Information (17) in package insert].

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

ADDICTION, ABUSE AND MISUSE

ULTRAM exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing ULTRAM, and monitor all patients regularly for the development of these behaviors and conditions [See Warnings and Precautions (5.1) in package insert].

OPIOID ANALGESIC RISK EVALUATION AND MITIGATION STRATEGY (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [See Warnings and Precautions (5.2) in package insert]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to

• complete a REMS-compliant education program,
• counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
• emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
• consider other tools to improve patient, household, and community safety.

LIFE-THREATENING RESPIRATORY DEPRESSION

Serious , life-threatening, or fatal respiratory depression may occur with use of ULTRAM. Monitor for respiratory depression, especially during initiation of ULTRAM or following a dose increase [See Warnings and Precautions (5.3) in package insert].

ACCIDENTAL INGESTION

Accidental ingestion of ULTRAM, especially by children, can be fatal. [See Warnings and Precautions (5.3) in package insert].

ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [See Warnings and Precautions (5.4) in package insert]. ULTRAM is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [See Contraindications (4) in package insert]. Avoid the use of ULTRAM in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [See Warnings and Precautions (5.4) in package insert].

NEONATAL OPIOID WITHDRAWAL SYNDROME

Prolonged use of ULTRAM during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts . If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [See Warnings and Precautions (5.5) in package insert].

INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRAM requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [See Warnings and Precautions (5.6); Drug Interactions (7) in package insert].

RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [See Warnings and Precautions (5.7); Drug Interactions (7) in package insert].

• Reserve concomitant prescribing of ULTRAM and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit treatment to the minimum effective dosages and durations.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [See Adverse Reactions (6.3) in package insert].

• The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
  • Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [See Warnings and Precautions (5.1) in package insert].
  • Acute renal failure [See Warnings and Precautions (5.2) in package insert].
  • Central nervous system effects [See Warnings and Precautions (5.3) in package insert].
• The most common adverse reactions reported in at least 1 indication by > 10% of adult 182 patients treated with valacyclovir and observed more frequently with valacyclovir compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in > 10% 184 of pediatric patients < 18 years of age was headache.
• In 2 clinical trials for the treatment of herpes zoster, the adverse reactions reported by patients receiving valacyclovir 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities See Table 2 in package insert.
• Consult package insert for additional information.

• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS):  TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients  participating in clinical trials of valacyclovir at doses of 8 grams per day. Treatment with valacyclovir should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
• Acute renal failure:
  • Cases of acute renal failure have been reported in:  
    • Elderly patients with or without reduced renal function. Caution should be exercised when administering valacyclovir to geriatric patients, and dosage reduction is recommended for those with impaired renal function [See Dosage and Administration (2.4), Use in Specific Populations (8.5) in package insert]. 
    • Patients with underlying renal disease who received higher than recommended doses of valacyclovir for their level of renal function. Dosage reduction is recommended when administering valacyclovir to patients with renal impairment [See Dosage and Administration (2.4), Use in Specific Populations (8.6) in package insert]. 
    • Patients receiving other nephrotoxic drugs. Caution should be exercised when administering valacyclovir to patients receiving potentially nephrotoxic drugs. 
    • Patients without adequate hydration: Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients. 
  • In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [See Dosage and Administration (2.4), Adverse Reactions (6.3) in package insert].  
• Central nervous system effects: Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in elderly patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of valacyclovir for their level of renal function. Valacyclovir should be discontinued if central nervous system adverse reactions occur [See Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6) in package insert].

None listed in package insert.

Contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [See Adverse Reactions (6.1) in package insert].

• Pooled selected adverse events reported in > 5% of patients in two clinical studies included:
  • Gastrointestinal system: Diarrhea, nausea, vomiting, abdominal pain.
  • General disorders and administrative site conditions: Pyrexia.
  • Nervous system disorders: Headache, insomnia, peripheral neuropathy, parasthesia.
  • Eye disorders: Retinal detachment.
  • Hemic and lymphatic system: Neutropenia, anemia, thrombocytopenia, elevated serum creatinine.
• Consult package insert for additional information.

• Hematologic toxicity:
  • Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE or ganciclovir. VALCYTE should be avoided if the absolute neutrophil count is less than 500 cells/μL, the platelet count is less than 25,000/μL, or the hemoglobin is less than 8 g/dL. VALCYTE should also be used with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.
  • Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving VALCYTE [See Adverse Reactions (6.1) in package insert], complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment, and in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/μL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to VALCYTE because of increased plasma concentrations of ganciclovir after VALCYTE administration [See Clinical Pharmacology (12.3) in package insert].
• Acute renal failure: Acute renal failure may occur in:
  • Elderly patients with or without reduced renal function. Caution should be exercised when administering VALCYTE to geriatric patients, and dosage reduction is recommended for those with impaired renal function [See Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6) in package insert].
  • Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering VALCYTE to patients receiving potential nephrotoxic drugs.
  • Patients without adequate hydration. Adequate hydration should be maintained for all patients.
• Impairment of fertility: Based on animal data and limited human data, VALCYTE at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of VALCYTE [See Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1) in package insert].
• Fetal toxicity: Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2 times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, VALCYTE has the potential to cause birth defects. Pregnancy should be avoided in female patients taking VALCYTE and in females with male partners taking VALCYTE. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE because of the potential risk to the fetus. Similarly, males should be advised to use condoms during and for at least 90 days following treatment with VALCYTE [See Dosage and Administration (2.6), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1) in package insert].
• Mutagenesis and carcinogenesis: Animal data indicate that ganciclovir is mutagenic and carcinogenic. VALCYTE should therefore be considered a potential carcinogen in humans [See Dosage and Administration (2.6), Nonclinical Toxicology (13.1) in package insert].
• Information for patients:
  • Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
  • Serious adverse reactions: Inform patients that VALCYTE may cause granulocytopenia (neutropenia), anemia, thrombocytopenia and elevated creatinine levels and that dose modification or discontinuation of dosing may be required. Complete blood counts, platelet counts, and creatinine levels should be monitored frequently during treatment [See Warnings and Precautions (5.1) in package insert].
  • Pregnancy and contraception: Inform females of reproductive potential that VALCYTE causes birth defects in animals. Advise them to use effective contraception during and for at least 30 days following treatment with VALCYTE. Similarly, advise males to use condoms during and for at least 90 days following treatment with VALCYTE [See Use in Specific Populations (8.1, 8.3) in package insert].
  • Carcinogenicity: Advise patients that VALCYTE is considered a potential carcinogen [See Nonclinical Toxicity (13.1) in package insert].
  • Lactation: Advise mothers not to breast-feed if they are receiving VALCYTE because of the potential for hematologic toxicity and cancer in nursing infants, and because HIV can be passed to the baby in breast milk [See Use in Specific Populations (8.2) in package insert].
  • Infertility: Advise patients that VALCYTE may cause temporary or permanent female and male infertility [See Warnings and Precautions (5.3), Use in Specific Populations (8.3) in package insert].
  • Impairment of cognitive ability: Inform patients that tasks requiring alertness may be affected including the patient's ability to drive and operate machinery as seizures, dizziness, and/or confusion have been reported with the use of VALCYTE [See Adverse Reactions (6.1) in package insert].
  • Use in patients with CMV retinitis: Inform patients that VALCYTE is not a cure for CMV retinitis, and they may continue to experience progression of retinitis during or following treatment. Advise patients to have ophthalmologic follow- up examinations at a minimum of every 4 to 6 weeks while being treated with VALCYTE. Some patients will require more frequent follow-up.
  • Administration:
    • Inform adult patients that they should use VALCYTE tablets, not VALCYTE for oral solution [See Dosage and Administration (2.1) in package insert].
    • Inform patients to take VALCYTE with food to maximize bioavailability.
• Consult package insert for additional information.

WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

• Hematologic toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE [See Warnings and Precautions (5.1) in package insert].
• Impairment of fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [See Warnings and Precautions (5.3) in package insert].
• Fetal toxicity: Based on animal data, VALCYTE has the potential to cause birth defects in humans [See Warnings and Precautions (5.4) in package insert].
• Mutagenesis and carcinogenesis: Based on animal data, VALCYTE has the potential to cause cancers in humans [See Warnings and Precautions (5.5) in package insert].

Contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [See Adverse Reactions (6.3) in package insert].

• The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
  • Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [See Warnings and Precautions (5.1) in package insert].
  • Acute renal failure [See Warnings and Precautions (5.2) in package insert].
  • Central nervous system effects [See Warnings and Precautions (5.3) in package insert].
• The most common adverse reactions reported in at least 1 indication by > 10% of adult 182 patients treated with VALTREX and observed more frequently with VALTREX compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in > 10% 184 of pediatric patients < 18 years of age was headache.
• In 2 clinical trials for the treatment of herpes zoster, the adverse reactions reported by patients receiving VALTREX 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities See Table 2 in package insert.
• Consult package insert for additional information.

• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS):  TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients  participating in clinical trials of VALTREX at doses of 8 grams per day. Treatment with VALTREX should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur.
• Acute renal failure:
  • Cases of acute renal failure have been reported in:  
    • Elderly patients with or without reduced renal function. Caution should be exercised when administering VALTREX to geriatric patients, and dosage reduction is recommended for those with impaired renal function [See Dosage and Administration (2.4), Use in Specific Populations (8.5) in package insert]. 
    • Patients with underlying renal disease who received higher than recommended doses of VALTREX for their level of renal function. Dosage reduction is recommended when administering VALTREX to patients with renal impairment [See Dosage and Administration (2.4), Use in Specific Populations (8.6) in package insert]. 
    • Patients receiving other nephrotoxic drugs. Caution should be exercised when administering VALTREX to patients receiving potentially nephrotoxic drugs. 
    • Patients without adequate hydration: Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients. 
  • In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [See Dosage and Administration (2.4), Adverse Reactions (6.3) in package insert].  
• Central nervous system effects: Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in elderly patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of VALTREX for their level of renal function. VALTREX should be discontinued if central nervous system adverse reactions occur [See Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6) in package insert].

None listed in package insert.

Contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

• Due to oral doxycycline’s virtually complete absorption, side effects of the lower bowel, particularly diarrhea, have been infrequent.
• The following adverse reactions have been observed in patients receiving tetracyclines:
  • Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region.
  • Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines.
  • Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development. (See WARNINGS in package insert).
  • Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION in package insert)
  • Skin: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon.
  • Photosensitivity is discussed in WARNINGS in package insert.
  • Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS in package insert.)
  • Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus, and drug rash with eosinophilia and systemic symptoms (DRESS).
  • Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
  • Other: Bulging fontanels in infants and intracranial hypertension in adults. (See PRECAUTIONS – General in package insert.)
  • When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur.

• The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray- brown).This adverse reaction is more common during long-term use of the drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.
• Clostridioides difficile (formerly Clostridium difficile) associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Vibramycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
• C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following the use of antibacterial drugs. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
• If CDAD is suspected or confirmed, ongoing use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
• Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. (See ADVERSE REACTIONS in package insert.) If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.
• Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including Vibramycin. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and Vibramycin should be avoided because isotretinoin is also known to cause pseudotumor cerebri.
• Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.
• All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.
• Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.
• Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.
• Vibramycin Syrup contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
• General:
  • As with other antibacterial drugs, use of Vibramycin may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, Vibramycin should be discontinued and appropriate therapy instituted.
  • Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy, when indicated.
  • Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.
  • Doxycycline does not suppress P. falciparum’s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.
  • Prescribing Vibramycin in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
• Information for patients:
  • All patients taking doxycycline should be advised: 
    • To avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS in package insert.) 
    • To drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS in package insert.) 
    • That the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See DRUG INTERACTIONS in package insert.) 
    • That the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See DRUG INTERACTIONS in package insert.)
    • That the use of doxycycline might increase the incidence of vaginal candidiasis.
  • Patients should be counseled that antibacterial drugs, including Vibramycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Vibramycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Vibramycin or other antibacterial drugs in the future.
  • Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.
• Consult package insert for additional information.

None listed in package insert.

Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with:

• Significant respiratory depression [See WARNINGS in package insert].
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [See WARNINGS in package insert].
• Known or suspected gastrointestinal obstruction, including paralytic ileus [See WARNINGS in package insert].
• Hypersensitivity to hydrocodone or acetaminophen (e.g., anaphylaxis) [See WARNINGS, ADVERSE REACTIONS in package insert].

• The most frequently reported adverse reactions are light-headedness, dizziness, sedation, nausea and vomiting.
• Other adverse reactions include:
  • Central nervous system: Drowsiness, mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, psychological dependence, mood changes.
  • Gastrointestinal system: Constipation.
  • Genitourinary system: Ureteral spasm, spasm of vesical sphincters, and urinary retention.
  • Special senses: Cases of hearing impairment or permanent loss have been reported predominately in patients with chronic overdose.
  • Dermatological: Skin rash, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic reactions.
  • Hematological: Thrombocytopenia, agranulocytosis.
• Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
• Anaphylaxis: Anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and acetaminophen tablets.
• Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [See CLINICAL PHARMACOLOGY in package insert].

• Addiction, abuse, and misuse:
  • Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, a Schedule II controlled substance. As an opioid, hydrocodone bitartrate and acetaminophen tablets expose users to the risks of addiction, abuse, and misuse [See DRUG ABUSE AND DEPENDENCE in package insert].
  • Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydrocodone bitartrate and acetaminophen tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
  • Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydrocodone bitartrate and acetaminophen tablets, and monitor all patients receiving hydrocodone bitartrate and acetaminophen tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydrocodone bitartrate and acetaminophen tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydrocodone bitartrate and acetaminophen tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
  • Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [See PRECAUTIONS; Information for Patients/Caregivers in package insert]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
• Life-threatening respiratory depression:
  • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [See OVERDOSAGE in package insert]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
  • While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydrocodone bitartrate and acetaminophen tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 – 72 hours of initiating therapy with and following dosage increases of hydrocodone bitartrate and acetaminophen tablets.
  • To reduce the risk of respiratory depression, proper dosing and titration of hydrocodone bitartrate and acetaminophen tablets are essential [See DOSAGE AND ADMINISTRATION in package insert]. Overestimating the hydrocodone bitartrate and acetaminophen tablets dosage when converting patients from another opioid product can result in a fatal overdose.
  • Accidental ingestion of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone bitartrate and acetaminophen tablets.
• Neonatal opioid withdrawal syndrome: Prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [See PRECAUTIONS; Information for Patients/Caregivers, Pregnancy in package insert].
• Risks of concomitant use or discontinuation of Cytochrome P450 3A4 inhibitors and inducers:
  • Concomitant use of hydrocodone bitartrate and acetaminophen tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone bitartrate and acetaminophen tablets and prolong opioid adverse reactions, and which may cause potentially fatal respiratory depression [See WARNINGS in package insert], particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and acetaminophen tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in hydrocodone bitartrate and acetaminophen tablets-treated patients may increase hydrocodone plasma concentrations and prolong opoid adverse reactions. When adding CYP3A4 inhibitors or discontinuing CYP3A4 inducers in hydrocodone bitartrate and acetaminophen tablets-treated patients, follow patients at frequent intervals and consider dosage reduction of hydrocodone bitartrate and acetaminophen tablets until stable drug effects are achieved [See PRECAUTIONS; Drug Interactions in package insert].
  • Concomitant use of hydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. When using bydrocodone bitartrate and acetaminophen tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, follow patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [See PRECAUTIONS; Drug Interactions in package insert].
• Risks from concomitant use with benzodiazepines or other CNS depressants:
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydrocodone bitartrate and acetaminophen tablets with benzodiazepines or other CNS depressants (e.g., 2 non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
  • Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [See PRECAUTIONS; Drug Interactions in package insert].
  • If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
  • Advise both patients and caregivers about the risks of respiratory depression and sedation when hydrocodone bitartrate and acetaminophen tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [See PRECAUTIONS; Drug Interactions, Information for Patients/Caregivers in package insert].
• Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients:
  • The use of hydrocodone bitartrate and acetaminophen tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
  • Patients with chronic pulmonary disease: Hydrocodone bitartrate and acetaminophen tablet-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of hydrocodone bitartrate and acetaminophen tablets [See WARNINGS; Life-Threatening Respiratory Depression in package insert].
  • Elderly, cachectic, or debilitated patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [See WARNINGS; Life-Threatening Respiratory Depression in package insert].
  • Follow such patients closely, particularly when initiating and titrating hydrocodone bitartrate and acetaminophen tablets and when hydrocodone bitartrate and acetaminophen tablets are given concomitantly with other drugs that depress respiration [See WARNINGS; Life-Threatening Respiratory Depression in package insert]. Alternatively, consider the use of non-opioid analgesics in these patients.
• Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
• Severe hypotension: Hydrocodone bitartrate and acetaminophen tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [See PRECAUTIONS; Drug Interactions in package insert]. Follow these patients for signs of hypotension after initiating or titrating the dosage of hydrocodone bitartrate and acetaminophen tablets. In patients with circulatory shock hydrocodone bitartrate and acetaminophen tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. Avoid the use of hydrocodone bitartrate and acetaminophen tablets with circulatory shock.
• Hepatotoxicity:
  • Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.
  • The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
  • Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.
• Serious skin reactions: Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
• Hypersensitivity/Anaphylaxis: There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue hydrocodone bitartrate and acetaminophen tablets immediately and seek medical care if they experience these symptoms. Do not prescribe hydrocodone bitartrate and acetaminophen tablets for patients with acetaminophen allergy [See PRECAUTIONS; Information for Patients/Caregivers in package insert].
• Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness:
  • In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydrocodone bitartrate and acetaminophen tablets may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Follow such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydrocodone bitartrate and acetaminophen tablets.
  • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydrocodone bitartrate and acetaminophen tablets in patients with impaired consciousness or coma.
• Risks of use in patients with gastrointestinal conditions:
  • Hydrocodone bitartrate and acetaminophen tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.
  • The administration of hydrocodone bitartrate and acetaminophen tablets or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
  • Hydrocodone may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
• Increased risk of seizures in patients with seizure disorders: The hydrocodone in hydrocodone bitartrate and acetaminophen tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Follow patients with a history of seizure disorders for worsened seizure control during hydrocodone bitartrate and acetaminophen tablet therapy.
• Withdrawal:
  • Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including hydrocodone bitartrate and acetaminophen tablets. In these patients, mixed agonist/antagonist and partial analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
  • When discontinuing hydrocodone bitartrate and acetaminophen tablets, gradually taper the dosage [See DOSAGE AND ADMINISTRATION in package insert]. Do not abruptly discontinue hydrocodone bitartrate and acetaminophen tablets [See DRUG ABUSE AND DEPENDENCE in package insert] in patients who have been using hydrocodone bitartrate and acetaminophen tablets around the clock for more than 5 days.
• Risks of driving and operating machinery: Hydrocodone bitartrate and acetaminophen tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of hydrocodone bitartrate and acetaminophen tablets and know how they will react to the medication [See PRECAUTIONS;Information for Patients/Caregivers in package insert].
• Information for patients/caregivers: advise the patient to read the FDA-approved patient labeling (Medication Guide):
  • Addiction, abuse, and misuse: Inform patients that the use of hydrocodone bitartrate and acetaminophen tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [See WARNINGS in package insert]. Instruct patients not to share hydrocodone bitartrate and acetaminophen tablets with others and to take steps to protect hydrocodone bitartrate and acetaminophen tablets from theft or misuse.
  • Life-threatening respiratory depression: Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting hydrocodone bitartrate and acetaminophen tablets or when the dosage is increased, and that it can occur even at recommended dosages [See WARNINGS in package insert]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
  • Accidental Ingestion: Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [See WARNINGS in package insert]. Instruct patients to take steps to store hydrocodone bitartrate and acetaminophen tablets securely and to dispose of unused hydrocodone bitartrate and acetaminophen tablets by flushing down the toilet.
  • Interactions with benzodiazepines and other CNS depressants: Inform patients and caregivers that potentially fatal additive effects may occur if hydrocodone bitartrate and acetaminophen tablets are used with benzodiazepines and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [See WARNINGS, PRECAUTIONS; Drug Interactions in package insert].
  • Serotonin syndrome: Inform patients that hydrocodone bitartrate and acetaminophen tablets could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [See PRECAUTIONS; Drug Interactions in package insert].
  • Monoamine oxidase inhibitor (MAOI) interaction: Inform patients to avoid taking hydrocodone bitartrate and acetaminophen tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking hydrocodone bitartrate and acetaminophen tablets [See PRECAUTIONS; Drug Interactions in package insert].
  • Adrenal insufficiency: Inform patients that hydrocodone bitartrate and acetaminophen tablets could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [See WARNINGS in package insert].
  • Important administration instructions: Instruct patients how to properly take hydrocodone bitartrate and acetaminophen tablets [See DOSAGE AND ADMINISTRATION, WARNINGS in package insert].
  • Maximum daily dose of acetaminophen: Inform patients not to take more than 4000 milligrams of acetaminophen per day. Advise patients to call their prescriber if they take more than the recommended dose.
  • Hypotension: Inform patients that hydrocodone bitartrate and acetaminophen tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [See WARNINGS in package insert].
  • Anaphylaxis: Inform patients that anaphylaxis has been reported with ingredients contained in hydrocodone bitartrate and acetaminophen tablets. Advise patients how to recognize such a reaction and when to seek medical attention [See CONTRAINDICATIONS, ADVERSE REACTIONS in package insert].
  • Pregnancy:
    • Neonatal opioid withdrawal syndrome: Inform female patients of reproductive potential that prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [See WARNINGS, PRECAUTIONS; Pregnancy in package insert].
    • Embryo-fetal toxicity: Inform female patients of reproductive potential that hydrocodone bitartrate and acetaminophen tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [See PRECAUTIONS; Pregnancy in package insert].
  • Lactation: Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct nursing mothers to seek immediate medical care if they notice these signs [See PRECAUTIONS; Nursing Mothers in package insert].
  • Infertility: Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [See ADVERSE REACTIONS in package insert].
  • Driving or operating heavy machinery: Inform patients that hydrocodone bitartrate and acetaminophen tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [See WARNINGS in package insert].
  • Constipation: Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [See ADVERSE REACTIONS, CLINICAL PHARMACOLOGY in package insert].
  • Disposal of unused hydrocodone bitartrate and acetaminophen tablets: Advise patients to dispose of unused hydrocodone bitartrate and acetaminophen tablets by flushing unused tablets down the toilet.
• Consult package insert for additional information.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; HEPATOTOXICITY; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

• Addiction, Abuse, and Misuse:
• Hydrocodone bitartrate and acetaminophen tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing hydrocodone bitartrate and acetaminophen tablets, and monitor all patients regularly for the development of these behaviors and conditions [See WARNINGS in package insert].
• Life-Threatening Respiratory Depression
• Serious, life-threatening, or fatal respiratory depression may occur with use of hydrocodone bitartrate and acetaminophen tablets. Monitor for respiratory depression especially during initiation of hydrocodone bitartrate and acetaminophen tablets or following a dose increase [See WARNINGS in package insert].
• Accidental Ingestion
• Accidental ingestion of hydrocodone bitartrate and acetaminophen tablets, especially by children, can result in a fatal overdose of hydrocodone bitartrate and acetaminophen tablets [See WARNINGS in package insert].
• Neonatal Opioid Withdrawal Syndrome
• Prolonged use of hydrocodone bitartrate and acetaminophen tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [See WARNINGS in package insert].
• Cytochrome P450 3A4 Interaction
• The concomitant use of hydrocodone bitartrate and acetaminophen tablets with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentrations. Monitor patients receiving hydrocodone bitartrate and acetaminophen tablets and any cytochrome P450 3A4 inhibitor or inducer for signs of respiratory depression or sedation [See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS; Drug Interactions in package insert].
• Hepatotoxicity
• Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [See WARNINGS, OVERDOSAGE in package insert].
• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
• Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [See WARNINGS, PRECAUTIONS; Drug Interactions in package insert].
• Reserve concomitant prescribing of hydrocodone bitartrate and acetaminophen tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

Contraindicated in patients with a history of hypersensitivity to moxifloxacin, to other quinolones, or to any of the components in this medication.

• The most frequently reported ocular adverse events were conjunctivitis, decreased visual acuity, dry eye, keratitis, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, subconjunctival hemorrhage, and tearing. These events occurred in approximately 1% – 6% of patients.
• Non-ocular adverse events reported at a rate of 1% – 4% were fever, increased cough, infection, otitis media, pharyngitis, rash, and rhinitis.
• Consult package insert for additional information.

• Hypersensitivity reactions: In patients receiving systemically administered quinolones, including moxifloxacin, serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported, some following the first dose. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. If an allergic reaction to moxifloxacin occurs, discontinue use of the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.
• Growth of resistant organisms with prolonged use: As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining.
• Avoidance of contact lens wear: Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis.

None listed in package insert.

None listed in package insert.

None listed in package insert.

• Warnings for patients:
  • For external use only.
  • Do not use if you are sensitive to any ingredient in this product.
  • Ask a doctor before use if you have: 
    • Heart disease. 
    • High blood pressure. 
    • Narrow angle glaucoma. 
    • Trouble urinating.
  • When using this product:
    • Pupils may become enlarged temporarily causing light sensitivity.
    • Do not touch tip of container to any surface to avoid contamination.
    • Replace cap after each use.
    • Remove contact lenses before using.
    • Do not use if this solution changes color or becomes cloudy. 
    • Overuse may cause more eye redness. 
    • Some user may experience a brief tingling sensation.
  • Stop use and ask a doctor if: 
    • You feel eye pain. 
    • Changes in vision occur. 
    • Redness or irritation of the eye lasts. 
    • Condition worsens or lasts more than 72 hours.
  • Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Accidental swallowing by infants and children may lead to coma and marked reduction in body temperature.

None listed in package insert.

Contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation [See Adverse Reactions (6) in package insert].

• The following serious adverse reactions are described elsewhere in the labeling: 
  • Local adverse reactions – extravasation [See Warnings and Precautions (5.1) in package insert].
  • Exposure to sun or direct light [See Warnings and Precautions (5.2) in package insert].
  • Decreased vision after treatment [See Warnings and Precautions (5.3) in package insert].
  • Porphyria and hypersensitivity [See Contraindications (4) in package insert].
• Clinical trials experience:
  • Severe chest pain, vaso-vagal and hypersensitivity reactions have been reported. Vaso-vagal and hypersensitivity reactions on rare occasions can be severe. These reactions may include syncope, sweating, dizziness, rash, dyspnea, flushing and changes in blood pressure and heart rate. General symptoms can include headache, malaise, urticaria, and pruritus.
  • The most frequently reported adverse events to VISUDYNE (verteporfin for injection) are injection site reactions (including pain, edema, inflammation, extravasation, rashes, hemorrhage and discoloration) and visual disturbances (including blurred vision, flashes of light, decreased visual acuity and visual field defects, including scotoma). These events occurred in approximately 10% – 30% of patients.
  • The following events, listed by body system, were reported more frequently with Visudyne therapy than with placebo therapy and occurred in 1%­ – 10% of patients:
    • Ocular treatment site: Blepharitis, cataracts, conjunctivitis/conjunctival injection, dry eyes, ocular itching, severe vision decrease with or without subretinal/retinal or vitreous hemorrhage.
    • Body as a whole: Asthenia, fever, flu syndrome, infusion related pain primarily presenting as back pain, photosensitivity reactions.
    • Cardiovascular: Atrial fibrillation, hypertension, peripheral vascular disorder, varicose veins.
    • Dermatologic: Eczema.
    • Digestive: Constipation, gastrointestinal cancers, nausea.
    • Hemic and lymphatic: Anemia, white blood cell count decreased, white blood cell count increased.
    • Hepatic: Elevated liver function tests.
    • Metabolic/Nutritional: Albuminuria, creatinine increased.
    • Musculoskeletal: Arthralgia, arthrosis, myasthenia.
    • Nervous system: Hypesthesia, sleep disorder, vertigo.
    • Respiratory: Cough, pharyngitis, pneumonia.
    • Special senses: Cataracts, decreased hearing, diplopia, lacrimation disorder.
    • Urogenital: Prostatic disorder.
  • Severe vision decrease, equivalent of 4 lines or more, within 7 days after treatment has been reported in 1% – 5% of patients. Partial recovery of vision was observed in some patients. Photosensitivity reactions usually occurred in the form of skin sunburn following exposure to sunlight. The higher incidence of back pain in the VISUDYNE group occurred primarily during infusion.
  • The following adverse events have occurred either at low incidence (< 1%) during clinical trials or have been reported during the use of VISUDYNE in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to VISUDYNE, or a combination of these factors:
    • Ocular treatment site: Retinal detachment (nonrhegmatogenous), retinal or choroidal vessel nonperfusion, retinal pigment epithelial tear.
    • Non-ocular events: Chest pain and other musculoskeletal pain during infusion.

• Local adverse reactions – extravasation:
  • Standard precautions should be taken during infusion of VISUDYNE (verteporfin for injection) to avoid extravasation. Examples of standard precautions include, but are not limited to:
    • A free-flowing intravenous (IV) line should be established before starting VISUDYNE infusion and the line should be carefully monitored.
    • Due to the possible fragility of vein walls of some elderly patients, it is strongly recommended that the largest arm vein possible, preferably antecubital, be used for injection.
    • Small veins in the back of the hand should be avoided.
  • Extravasation of VISUDYNE, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling or discoloration at the injection site.
  • If extravasation does occur, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of local burn, which could be severe. Cold compresses should be applied to the injection site. Oral medications for pain relief may be administered.
• Exposure to sun or direct light: Following injection with VISUDYNE (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. In the event of extravasation during infusion, the extravasation area must be thoroughly protected from direct light until the swelling and discoloration have faded in order to prevent the occurrence of a local burn which could be severe. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light.
• Decreased vision after treatment: Patients who experience severe decrease of vision of 4 lines or more within 1 week after treatment should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician.
• Patient counseling information:
  • Advise patients who receive VISUDYNE that they will become temporarily photosensitive after the infusion. Patients should be advised to wear a wrist band to remind them to avoid direct sunlight for 5 days. During that period, patients should be advised to avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light. Sources of bright light include, but are not limited to, tanning salons, bright halogen lighting and high power lighting used in surgical operating rooms or dental offices. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 5 days following VISUDYNE administration.
  • If treated patients must go outdoors in daylight during the first 5 days after treatment, they should be advised to protect all parts of their skin and their eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light.
  • Patients should be advised to not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help inactivate the drug in the skin through a process called photobleaching.
  • Following VISUDYNE treatment, patients should be advised that they may develop visual disturbances such as abnormal vision, vision decrease, or visual field defects that may interfere with their ability to drive or use machines. Patients should be advised to not drive or use machines as long as these symptoms persist.
• Consult package insert for additional information.

None listed in package insert.

• Contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
• Coadministration of cisapride, pimozide or quinidine with voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of voriconazole with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg q24h or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of voriconazole with high-dose ritonavir (400 mg q12h) is contraindicated because ritonavir (400 mg q12h) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of voriconazole with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].
• Coadministration of voriconazole with St. John's Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration [See Drug Interactions (7) and Clinical Pharmacology (12.3) in package insert].

• The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%).
• The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.2, 5.3) and Adverse Reactions (6.2, 6.3) in package insert].
• Visual disturbances:
  • Voriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses.
  • There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema [See Warnings and Precautions (5.3) in package insert].
  • The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. The effects were noted early in administration of voriconazole and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal [See Warnings and Precautions (5.7) in package insert].
• Dermatological reactions:
  • Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown.
  • Serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.
  • In addition, voriconazole has been associated with photosensitivity skin reactions. Patients should avoid strong, direct sunlight during voriconazole therapy. In patients with photosensitivity skin reactions, squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, voriconazole should be discontinued [See Warnings and Precautions (5.13) in package insert].
• Less common adverse events: The following adverse events occurred in < 2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 2 [See in package insert] and does not include every event reported in the voriconazole clinical program.
  • Body as a whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [See Warnings and Precautions (5.6) in package insert], ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multiorgan failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.
  • Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) [See Warnings and Precautions (5.6) in package insert].
  • Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.
  • Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.
  • Hemic and lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.
  • Metabolic and nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia.
  • Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.
  • Nervous system: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.
  • Respiratory system: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.
  • Skin and appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma, sweating, toxic epidermal necrolysis, urticaria.
  • Special senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect. 
  • Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage.
• Consult package insert for additional information.

• Drug interactions: See Table 7 in package insert for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 8 in package insert for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [See Contraindications (4), and Drug Interactions (7) in package insert].
• Hepatic toxicity:
  • In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [See Adverse Reactions in package insert].
  • A higher frequency of liver enzyme elevations was observed in the pediatric population [See Adverse Reactions in package insert]. Hepatic function should be monitored in both adult and pediatric patients.
  • Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies continued use [See Dosage and Administration and Adverse Reactions in package insert].
• Patients with hepatic impairment (intravenous formulation):
  • It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving voriconazole [See Clinical Pharmacology (12.3) and Dosage and Administration (2.7) in package insert].
  • Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.
• Arrhythmias and QT prolongation:
  • Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.
  • Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:
    • Congenital or acquired QT prolongation.
    • Cardiomyopathy, in particular when heart failure is present.
    • Sinus bradycardia.
    • Existing symptomatic arrhythmias.
    • Concomitant medicinal product that is known to prolong QT interval [See Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3) in package insert].
  • Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [See Clinical Pharmacology (12.3) in package insert].
• Infusion related reactions: During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.
• Visual disturbances: The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [See Adverse Reactions in package insert].
• Serious exfoliative cutaneous reactions: Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.
• Photosensitivity:
  • Voriconazole has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued. In addition, voriconazole has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Patients should avoid strong, direct sunlight during voriconazole therapy.
  • The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.
• Renal toxicity:
  • Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function.
  • Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [See Clinical Pharmacology (12.3) and Dosage and Administration (2.5) in package insert].
  • In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy [See Clinical Pharmacology (12.3) and Dosage and Administration (2.8) in package insert].
• Embryo-fetal toxicity:
  • Voriconazole can cause fetal harm when administered to a pregnant woman.
  • In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality [See Use in Specific Populations (8.1) in package insert].
  • If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole [See Use in Specific Populations (8.3) in package insert].
• Laboratory tests:
  • Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.
  • Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
• Pancreatitis: Pancreatitis has been observed in patients undergoing treatment with voriconazole [See Adverse Reactions in package insert]. Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole treatment.
• Skeletal adverse reactions: Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [See Adverse Reactions (6.2) in package insert].
• Clinically significant drug interactions: See Table 10 in package insert for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 in package insert for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [See Contraindications (4) and Drug Interactions (7) in package insert].
• Galactose intolerance: Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

None listed in package insert.

None listed in package insert.

• The following adverse reactions are described elsewhere in the labeling:
  • Pigmentation [See Warnings and Precautions (5.1) in package insert].
  • Eyelash changes [See Warnings and Precautions (5.2) in package insert].
  • Intraocular inflammation [See Warnings and Precautions (5.3) in package insert].
  • Macular edema [See Warnings and Precautions (5.4) in package insert].
  • Bacterial keratitis [See Warnings and Precautions (5.5) in package insert].
  • Use with contact lens [See Warnings and Precautions (5.6) in package insert].
• Most common ocular adverse reactions with incidence ≥ 2% are conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%).
• Approximately 0.6% of patients discontinued therapy due to ocular adverse reactions including ocular hyperemia, conjunctival irritation, eye irritation, eye pain, conjunctival edema, vision blurred, punctate keratitis and foreign body sensation.
• Consult package insert for additional information.

• Pigmentation:
  • VYZULTA™ (latanoprostene bunod ophthalmic solution), 0.024% may cause changes to pigmented tissues. The most frequently reported changes with prostaglandin analogs have been increased pigmentation of the iris and periorbital tissue (eyelid).
  • Pigmentation is expected to increase as long as latanoprostene bunod ophthalmic solution is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of VYZULTA™, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes are likely to be reversible in most patients. Patients who receive prostaglandin analogs, including VYZULTA™, should be informed of the possibility of increased pigmentation, including permanent changes. The long-term effects of increased pigmentation are not known.
  • Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with VYZULTA™ (latanoprostene bunod ophthalmic solution), 0.024% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly [See Patient Counseling Information (17) in package insert].
• Eyelash changes: May gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and the number of lashes or hairs. Eyelash changes are usually reversible upon discontinuation of treatment.
• Intraocular inflammation: VYZULTA™ should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation as it may exacerbate this condition.
• Macular edema: Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin analogs. VYZULTA™ should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
• Bacterial keratitis: There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
• Use with contact lens: Contact lenses should be removed prior to the administration of VYZULTA™ because this product contains benzalkonium chloride. Lenses may be reinserted 15 minutes after administration.

None listed in package insert.

Contraindicated in patients with known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this product.

• The following adverse reactions were reported in post-marketing experience and are discussed in greater detail in other sections of the label:
  • Iris pigmentation changes [See Warnings and Precautions (5.1) in package insert].
  • Eyelid skin darkening [See Warnings and Precautions (5.1) in package insert].
  • Eyelash changes (increased length, thickness, pigmentation, and number of lashes) [See Warnings and Precautions (5.2) in package insert].
  • Intraocular inflammation (iritis/uveitis) [See Warnings and Precautions (5.3) in package insert].
  • Macular edema, including cystoid macular edema [See Warnings and Precautions (5.4) in package insert].
• Ocular adverse reactions and ocular signs/symptoms reported by 5% – 15% of patients receiving latanoprost: Foreign body sensation, punctate keratitis, stinging, conjunctival hyperemia, blurred vision, itching, burning, increased pigmentation of iris.
• Less than 1% of the patients treated with XALATAN required discontinuation of therapy because of intolerance to conjunctival hyperemia.
• Adverse reactions that were reported in 1% – 5% of patients receiving latanoprost:
  • Ocular events/Signs and symptoms: Excessive tearing, eyelid discomfort/pain, dry eye, eye pain, eyelid margin crusting, erythema of the eyelid, photophobia, eyelid edema.
  • Systemic events: Upper respiratory tract infection/nasopharyngitis/influenza, myalgia/back pain, rash, allergic skin reaction.
• The ocular event/signs and symptoms of blepharitis have been identified as “commonly observed” through analysis of clinical trial data.
• Consult package insert for additional information.

• Pigmentation: 
  • XALATAN has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes. Pigmentation is expected to increase as long as latanoprost is administered.
  • The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of latanoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. Beyond 5 years the effects of increased pigmentation are not known [See Clinical Studies (14.2) in package insert].
  • Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with XALATAN can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly [See Patient Counseling Information (17) in package insert].
• Eyelash changes: XALATAN may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment [See Patient Counseling Information (17) in package insert].
• Intraocular inflammation: XALATAN should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation because inflammation may be exacerbated.
• Macular edema: Macular edema, including cystoid macular edema, has been reported during treatment with XALATAN. XALATAN should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
• Herpetic keratitis: Reactivation of Herpes Simplex keratitis has been reported during treatment with XALATAN. XALATAN should be used with caution in patients with a history of herpetic keratitis. XALATAN should be avoided in cases of active herpes simplex keratitis because inflammation may be exacerbated.
• Bacterial keratitis: There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [See Patient Counseling Information (17) in package insert].
• Use with contact lenses: Contact lenses should be removed prior to the administration of XALATAN, and may be reinserted 15 minutes after administration.

None listed in package insert.

Contraindicated in patients with known hypersensitivity to latanoprost, or any other ingredients in this product.