Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration.

Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.

(5.8) Risk of Seizure : Present within recommended dosage range.

Risk is increased with higher than recommended doses and concomitant use of SSRIs, SNRIs, anorectics, tricyclic antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics, other drugs that reduce seizure threshold, in patients with epilepsy or at risk for seizures.

( 5.9 , 7 ) Risk of Suicide : Do not use tramadol hydrochloride extended-release tablets in suicidal or addiction-prone patients.

Use with caution in those taking tranquilizers, antidepressants or abuse alcohol.

( 5.10 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.

( 5.11 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.

( 5.12 ) Severe Hypotension: Monitor during dosage initiation and titration.

Avoid use of tramadol hydrochloride extended-release tablets in patients with circulatory shock.

( 5.1 3) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression.

Avoid use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma.

( 5.14 ) 5.1 Addiction, Abuse, and Misuse Tramadol hydrochloride extended-release tablet contains tramadol, a Schedule IV controlled substance.

As an opioid, tramadol hydrochloride extended-release tablet exposes users to the risks of addiction, abuse, and misuse.

Because extended-release products such as tramadol hydrochloride extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tramadol present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol hydrochloride extended-release 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 tramadol hydrochloride extended-release tablets, and monitor all patients receiving tramadol hydrochloride extended-release 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 tramadol hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Abuse or misuse of tramadol hydrochloride extended-release tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Consider these risks when prescribing or dispensing tramadol hydrochloride extended-release 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 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.

5.2 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 800-503-0784, or log on to www.opioidanalgesicrems.com .

The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint .

5.3 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)] .

Carbon dioxide (CO 2 ) 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 tramadol hydrochloride extended-release 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 tramadol hydrochloride extended-release tablets.

To reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential [see Dosage and Administration (2)] .

Overestimating the tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablet, especially by children, can result in respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

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 (2.5) ] .

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with tramadol hydrochloride extended-release tablet.

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose.

The presence of risk factors for overdose should not prevent the proper management of pain in any given patient.

Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone.

[see Warnings and Precautions (5.1, 5.7), Patient Counseling Information (17)].

5.4 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: Tramadol hydrochloride extended-release tablets are contraindicated for all children younger than 12 years of age [ see Contraindications (4) ].

Tramadol hydrochloride extended-release tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ].

Avoid the use of Tramadol hydrochloride extended-release 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 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) ].

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 Tramadol hydrochloride extended-release tablets 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 Tramadol hydrochloride extended-release tablets [ see Use in Specific Populations (8.2) ].

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/*1xN or *1/*2xN).

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)] .

Therefore, individuals who are ultra-rapid metabolizers should not use Tramadol hydrochloride extended-release tablets.

5.5 Neonatal Opioid Withdrawal Syndrome Prolonged use of tramadol hydrochloride extended-release 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 Use in Specific Populations (8.1), Patient Counseling Information (17)] .

5.6 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 tramadol hydrochloride extended-release tablets are complex.

Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol hydrochloride extended-release tablets 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)] .

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors of CYP2D6 [see Drug Interactions (7)] .

Cytochrome P450 3A4 Interaction The concomitant use of tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets 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 tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)] .

5.7 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol hydrochloride extended-release tablets 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)] .

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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when tramadol hydrochloride extended-release 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 Drug Interactions (7), Patient Counseling Information (17)] .

5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, including tramadol hydrochloride extended-release tablets, 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), 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)] .

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 tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.

5.9 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)] .

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 (5.8), Drug Interactions (7)] 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.

5.10 Suicide Risk Do not prescribe tramadol hydrochloride extended-release tablets 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 (9.2) ] Prescribe tramadol hydrochloride extended-release tablets 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) ].

Inform patients not to exceed the recommended dose and to limit their intake of alcohol [see Dosage and Administration (2.1), Warnings and Precautions (5.7, 5.8, 5.14)] .

5.11 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.

5.12 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of tramadol hydrochloride extended-release 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: Tramadol hydrochloride extended-release tablets-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 tramadol hydrochloride extended-release tablets [see Warnings and Precautions (5.3)].

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)].

Monitor such patients closely, particularly when initiating and titrating tramadol hydrochloride extended-release tablets and when tramadol hydrochloride extended-release tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.7)] .

Alternatively, consider the use of non-opioid analgesics in these patients.

5.13 Severe Hypotension Tramadol hydrochloride extended-release 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 Drug Interactions (7)].

Monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride extended-release tablets.

In patients with circulatory shock, tramadol hydrochloride extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure.

Avoid the use of tramadol hydrochloride extended-release tablets in patients with circulatory shock.

5.14 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol hydrochloride extended-release tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure.

Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol hydrochloride extended-release tablets.

Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma.

5.15 Risks of Use in Patients with Gastrointestinal Conditions Tramadol hydrochloride extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tramadol in tramadol hydrochloride extended-release 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.

5.16 Anaphylaxis and Other Hypersensitivity Reactions Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol.

When these events do occur it is often following the first dose.

Other reported hypersensitivity 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 tramadol hydrochloride extended-release tablets.

If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride extended-release tablets immediately, discontinue tramadol hydrochloride extended-release tablets 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 Patient Counseling Information (17)] .

5.17 Withdrawal Do not abruptly discontinue tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids.

When discontinuing tramadol hydrochloride extended-release tablets in a physically dependent patient, gradually taper the dosage.

Rapid tapering of tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9)].

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 tramadol hydrochloride extended-release tablets.

In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

5.18 Risks of Driving and Operating Machinery Tramadol hydrochloride extended-release 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 tramadol hydrochloride extended-release tablets and know how they will react to the medication [see Patient Counseling Information (17)].

5.19 Hyponatremia Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L).

Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy.

In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with tramadol hydrochloride extended-release tablets, especially during initiation of therapy.

If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue tramadol hydrochloride extended-release tablets [see Dosage and Administration: Safe Reduction or Discontinuation of Tramadol Hydrochloride Extended-Release Tablets (2.5)].

5.20 Hypoglycemia Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization.

In most cases, patients had predisposing risk factors (e.g.

diabetes).

If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration: Safe Reduction or Discontinuation of Tramadol Hydrochloride Extended-Release Tablets (2.5)].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including escitalopram, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort).

If such symptoms occur, discontinue escitalopram and initiate supportive treatment.

If concomitant use of escitalopram with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 4 , 5.2 ).

Discontinuation of Treatment with Escitalopram: A gradual reduction in dose rather than abrupt cessation is recommended whenever possible ( 5.3 ).

Seizures: Prescribe with care in patients with a history of seizure ( 5.4 ).

Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 5.5 ).

Hyponatremia: Can occur in association with SIADH ( 5.6 ) Abnormal Bleeding: Use caution in concomitant use with NSAIDs, aspirin, warfarin or other drugs that affect coagulation ( 5.7 ).

Interference with Cognitive and Motor Performance: Use caution when operating machinery ( 5.8 ).

Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.

( 5.9 ) Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses ( 5.10 ).

Sexual Dysfunction: Escitalopram may cause symptoms of sexual dysfunction ( 5.11 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table1.

Table 1: Risk Difference of the Numbers of Patients of Suicidal Thoughts and Behaviors in the Pooled-Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients TABLE 1 Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.

Consider changing the therapeutic regimen, including possibly discontinuing escitalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including escitalopram, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination) seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of escitalopram with MAOIs intended to treat psychiatric disorders is contraindicated.

Escitalopram should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking escitalopram.

Escitalopram should be discontinued before initiating treatment with the MAOI [ see Contraindications ( 4.1 ) and Dosage and Administration ( 2.5 and 2.6 ) ] .

If concomitant use of escitalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamine and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with escitalopram and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Discontinuation of Treatment with Escitalopram Tablets During marketing of escitalopram tablets and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with escitalopram.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration ( 2.4 )] .

5.4 Seizures Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram has not been systematically evaluated in patients with a seizure disorder.

These patients were excluded from clinical studies during the product’s premarketing testing.

In clinical trials of escitalopram, cases of convulsion have been reported in association with escitalopram treatment.

Like other drugs effective in the treatment of major depressive disorder, escitalopram tablets should be introduced with care in patients with a history of seizure disorder.

5.5 Activation of Mania/Hypomania In patients with bipolar disorder, treating a depressive episode with escitalopram or another antidepressant may precipate a mixed/manic episode.

In placebo-controlled trials of escitalopram in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treateds with escitalopram and in none of the 592 patients treated with placebo.

One additional case of hypomania has been reported in association with escitalopram treatment.

Activation of mania/hypomania has also been reported in small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder.

Prior to initiating treatment with escitalopram screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.3 )] .

5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including escitalopram.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram was discontinued.

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.

Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Geriatric Use ( 8.5 )] .

Discontinuation of escitalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.7 Abnormal Bleeding SSRIs and SNRIs, including escitalopram, may increase the risk of bleeding events.

Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of escitalopram and NSAIDs, aspirin, or other drugs that affect coagulation.

5.8 Interference with Cognitive and Motor Performance In a study in normal volunteers, escitalopram 10 mg/day did not produce impairment of intellectual function or psychomotor performance.

Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram tablets therapy does not affect their ability to engage in such activities.

5.9 Angle Closure Glaucoma Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including escitalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.10 Use in Patients with Concomitant Illness Clinical experience with escitalopram in patients with certain concomitant systemic illnesses is limited.

Caution is advisable in using escitalopram tablets in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

Escitalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.

In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased.

The recommended dose of escitalopram tablets in hepatically impaired patients is 10 mg/day [see Dosage and Administration ( 2.3 )] .

Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination.

Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with escitalopram tablets, however, it should be used with caution in such patients [see Dosage and Administration ( 2.3 )] .

5.11 Sexual Dysfunction Use of SSRIs, including escitalopram, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 ) ] .

In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.

In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of escitalopram and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.

When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.

Discuss potential management strategies to support patients in making informed decisions about treatment.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis: Risperidone tablets are not approved for use in patients with dementia-related psychosis ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of risperidone tablets and close monitoring.

( 5.3 ) Tardive dyskinesia: Consider discontinuing risperidone tablets if clinically indicated.

( 5.4 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular / cerebrovascular risk.

These metabolic changes include hyperglycemia, dyslipidemia, and weight gain.

( 5.5 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia and weakness.

Monitor glucose regularly in patients with diabetes or at risk for diabetes.

( 5.5 ) Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

( 5.5 ) Weight Gain : Significant weight gain has been reported.

Monitor weight gain.

( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration.

( 5.6 ) Orthostatic hypotension: For patients at risk, consider a lower starting dose and slower titration.

( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of clinically significant low white blood cell count (WBC).

Consider discontinuing risperidone tablets if a clinically significant decline in WBC occurs in the absence of other causative factors.

( 5.9 ) Potential for cognitive and motor impairment: Use caution when operating machinery.

( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.

( 5.11 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.

Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.

The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone tablets when compared to patients treated with risperidone tablets alone or with placebo plus furosemide.

No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.

Risperidone tablets are not approved for the treatment of dementia-related psychosis [see Boxed Warning ] .

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis.

In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo.

Risperidone tablets are not approved for the treatment of patients with dementia-related psychosis.

[see Boxed Warning and Warnings and Precautions (5.1) ] .

5.3 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected , immediately discontinue risperidone tablets and provide symptomatic treatment and monitoring.

5.4 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs.

Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome.

Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose.

The syndrome can develop after relatively brief treatment periods, even at low doses.

It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued.

Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process.

The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, risperidone tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.

Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.

In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response.

Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on risperidone tablets, drug discontinuation should be considered.

However, some patients may require treatment with risperidone tablets despite the presence of the syndrome.

5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk.

These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain.

While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone tablets.

Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.

Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood.

However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone tablets, should be monitored regularly for worsening of glucose control.

Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

Any patient treated with atypical antipsychotics, including risperidone tablets, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.

Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing.

In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone tablets, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone tablets.

Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

Table 2.

Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania Risperidone Tablets Placebo 1–8 mg/day >8–16 mg/day Mean change from baseline (mg/dL) Serum Glucose n=555 – 1.4 n=748 0.8 n=164 0.6 Proportion of patients with shifts Serum Glucose (<140 mg/dL to ≥200 mg/dL) 0.6% (3/525) 0.4% (3/702) 0% (0/158) In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).

Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table 3.

Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 years of age), Bipolar Mania (10–17 years of age), or Autistic Disorder (5 to 17 years of age) Risperidone Tablets Placebo 0.5-6 mg/day Mean change from baseline (mg/dL) Serum Glucose n=76 -1.3 n=135 2.6 Proportion of patients with shifts Serum Glucose (<100 mg/dL to ≥126 mg/dL) 0% (0/64) 0.8% (1/120) In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).

Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

Table 4.

Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible -Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania Risperidone Tablets Placebo 1–8 mg/day >8–16 mg/day Mean change from baseline (mg/dL) Cholesterol n=559 n=742 n=156 Change from baseline 0.6 6.9 1.8 Triglycerides n=183 n=307 n=123 Change from baseline -17.4 -4.9 -8.3 Proportion of patients with shifts Cholesterol (<200 mg/dL to ≥240 mg/dL) 2.7% (10/368) 4.3% (22/516) 6.3% (6/96) Triglycerides 1.1% 2.7% 2.5% (<500 mg/dL to ≥500 mg/dL) (2/180) (8/301) (3/121) In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).

Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5.

Table 5.

Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), or Autistic Disorder (5 to 17 Years of Age) Risperidone Tablets Placebo 0.5-6 mg/day Mean change from baseline (mg/dL) Cholesterol n=74 n=133 Change from baseline 0.3 -0.3 LDL n=22 n=22 Change from baseline 3.7 0.5 HDL n=22 n=22 Change from baseline 1.6 -1.9 Triglycerides n=77 n=138 Change from baseline -9.0 -2.6 Proportion of patients with shifts Cholesterol 2.4% 3.8% (<170 mg/dL to ≥200 mg/dL) (1/42) (3/80) LDL 0% 0% (<110 mg/dL to ≥130 mg/dL) (0/16) (0/16) HDL 0% 10% (≥40 mg/dL to <40 mg/dL) (0/19) (2/20) Triglycerides 1.5% 7.1% (<150 mg/dL to ≥200 mg/dL) (1/65) (8/113) In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).

Weight Gain Weight gain has been observed with atypical antipsychotic use.

Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

Table 6.

Mean Change in Body Weight (kg) and the Proportion of Subjects with =7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania Risperidone Tablets Placebo (n=597) 1–8 mg/day (n=769) >8–16 mg/day (n=158) Weight (kg) Change from baseline -0.3 0.7 2.2 Weight Gain ≥7% increase from baseline 2.9% 8.7% 20.9% In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).

Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7.

Table 7.

Mean Change in Body Weight (kg) and the Proportion of Subjects With =7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age) Placebo Risperidone Tablets 0.5–6 mg/day (n=375) (n=448) Weight (kg) Change from baseline 0.6 2.0 Weight Gain ≥7% increase from baseline 6.9% 32.6% In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).

In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients.

In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of risperidone tablets treatment.

The majority of that increase was observed within the first 6 months.

The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.

In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone tablets treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data).

The majority of that increase occurred within the first 6 months of exposure to risperidone tablets.

The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.

In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone tablets groups than the placebo group, but not dose related (1.90 kg in the risperidone tablets 0.5–2.5 mg group, 1.44 kg in the risperidone tablets 3–6 mg group, and 0.65 kg in the placebo group).

A similar trend was observed in the mean change from baseline in body mass index.

When treating pediatric patients with risperidone tablets for any indication, weight gain should be assessed against that expected with normal growth.

5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, risperidone tablets elevates prolactin levels and the elevation persists during chronic administration.

Risperidone tablets are associated with higher levels of prolactin elevation than other antipsychotic agents.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion.

This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer.

An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1) ] .

Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

5.7 Orthostatic Hypotension Risperidone tablets may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties.

Syncope was reported in 0.2% (6/2607) of risperidone tablets-treated patients in Phase 2 and 3 studies in adults with schizophrenia.

The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration ( 2.1 , 2.4 )] .

Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

A dose reduction should be considered if hypotension occurs.

Risperidone tablets should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and in the elderly and patients with renal or hepatic impairment.

Monitoring of orthostatic vital signs should be considered if hypotension occurs.

Clinically significant hypotension has been observed with concomitant use of risperidone tablets and antihypertensive medication.

5.8 Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone tablets, which may lead to falls and, consequently, fractures or other fall-related injuries.

For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect : In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone tablets.

Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia.

Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone tablets should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue risperidone tablets and have their WBC followed until recovery.

5.10 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reactions associated with risperidone tablets treatment, especially when ascertained by direct questioning of patients.

This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone tablets 16 mg/day) reported somnolence compared to 16% of placebo patients.

Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone tablets 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reation.

Since risperidone tablets have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone tablets therapy does not affect them adversely.

5.11 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone tablets-treated patients, two in association with hyponatremia.

Risperidone tablets should be used cautiously in patients with a history of seizures.

5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia.

Risperidone tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

[see Boxed Warning and Warnings and Precautions (5.1) ].

5.13 Priapism Priapism has been reported during postmarketing surveillance.

Severe priapism may require surgical intervention.

5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents.

Both hyperthermia and hypothermia have been reported in association with oral risperidone tablets use.

Caution is advised when prescribing for patients who will be exposed to temperature extremes.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy.

( 5.1 ) Omega-3-acid ethyl esters capsules may increase levels of low-density lipoprotein (LDL).

Monitor LDL levels periodically during therapy.

( 5.1 ) Use with caution in patients with known hypersensitivity to fish and/or shellfish.

( 5.2 ) There is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first months of initiating therapy.

( 5.3 ) 5.1 Monitoring: Laboratory Tests In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with omega-3-acid ethyl esters capsules.

In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.

In some patients, omega-3-acid ethyl esters capsule increases low-density lipoprotein cholesterol (LDL-C) levels.

LDL-C levels should be monitored periodically during therapy with omega-3-acid ethyl esters.

Laboratory studies should be performed periodically to measure the patient’s TG levels during therapy with omega-3-acid ethyl esters.

5.2 Fish Allergy Omega-3-acid ethyl esters capsules contain ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources.

It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to omega-3-acid ethyl esters capsules.

Omega-3-acid ethyl esters capsules should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

5.3 Recurrent Atrial Fibrillation (AF) or Flutter In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in subjects randomized to omega-3-acid ethyl esters who received 8 grams/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo.

Subjects in this trial had median baseline TG levels of 127 mg/dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline.

At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on omega-3-acid ethyl esters (primary endpoint, HR: 1.19; 95% CI: 0.93, 1.35).

In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on omega-3-acid ethyl esters (HR: 1.63; 95% CI: 0.91, 2.18).

For both strata combined, the HR was 1.25; 95% CI: 1.00, 1.40.

Although the clinical significance of these results is uncertain, there is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic AF or flutter in patients with paroxysmal or persistent AF, particularly within the first 2 to 3 months of initiating therapy.

Omega-3-acid ethyl esters capsules are not indicated for the treatment of AF or flutter.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Not Interchangeable with Extended Release Tacrolimus Products- Medication Errors: Instruct patients or caregivers to recognize the appearance of tacrolimus capsules ( 5.3 ) New Onset Diabetes After Transplant: Monitor blood glucose.

( 5.4 ) Nephrotoxicity: (acute and/or chronic); Reduce the dose; use caution with other nephrotoxic drugs.

( 5.5 ) Neurotoxicity: Including risk of Posterior Reversible Encephalopathy Syndrome (PRES); monitor for neurologic abnormalities; reduce or discontinue tacrolimus capsules and other immunosuppressants.

( 5.6 ) Hyperkalemia: Monitor serum potassium levels.

Consider carefully before using with other agents also associated with hyperkalemia.

( 5.7 ) Hypertension: May require antihypertensive therapy.

Monitor relevant drug-drug interactions.

( 5.8 ) Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis.

( 5.9 ) Not recommended for use with Sirolimus: Not recommended in liver and heart transplant due to increased risk of serious adverse reactions.

( 5.10 ) Myocardial Hypertrophy: Consider dose reduction/ discontinuation.

( 5.13 ) Immunizations: Avoid live vaccines.

( 5.14 ) Pure Red Cell Aplasia: Consider discontinuation of tacrolimus capsules.

( 5.15 ) 5.1 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including Tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin [ see Boxed Warning ].

The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, examine patients for skin changese; xposure to sunlight and UV light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients.

The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection.

The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.

Monitor EBV serology during treatment.

5.2 Serious Infections Patients receiving immunosuppressants, including tacrolimus are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections.

These infections may lead to serious, including fatal, outcomes.

Serious viral infections reported include: Polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection JC virus-associated progressive multifocal leukoencephalopathy (PML) Cytomegalovirus infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor disease are at higher risk of developing CMV viremia and CMV disease.

Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions ( 6.1 , 6.2 )].

5.3 Not Interchangeable With Extended-Release Tacrolimus Products – Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S.

This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under-or over-exposure to tacrolimus.

Tacrolimus is not interchangeable or substitutable with tacrolimus extended-release products.

Changes between tacrolimus immediate-release and extended-release dosage forms must occur under physician supervision.

Instruct patients and caregivers to recognize the appearance of tacrolimus capsules dosage forms [see Dosage Forms and Strengths ( 3 )] and to confirm with the healthcare provider if a different product is dispensed.

5.4 New Onset Diabetes After Transplant Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney, liver, and heart transplantation.

New onset diabetes after transplantation may be reversible in some patients.

African-American and Hispanic kidney transplant patients are at an increased risk.

Blood glucose concentrations should be monitored closely in patients using tacrolimus [see Adverse Reactions ( 6.1 )] .

5.5 Nephrotoxicity Tacrolimus like other calcineurin inhibitors, can cause acute or chronic nephrotoxicity.

Nephrotoxicity was reported in clinical trials [see Adverse Reactions ( 6.1 )].

Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range.

The risk for nephrotoxicity may increase when tacrolimus is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors) [see Drug Interactions ( 7.2 )] .

Monitor renal function and consider dosage reduction if nephrotoxicity occurs.

5.6 Neurotoxicity Tacrolimus may cause a spectrum of neurotoxicities.

The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions ( 6.1 , 6.2 )] .

As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of tacrolimus capsules if neurotoxicity occurs.

5.7 Hyperkalemia Hyperkalemia has been reported with tacrolimus use.

Serum potassium levels should be monitored.

Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy [see Adverse Reactions ( 6.1 )] .

Monitor serum potassium levels periodically during treatment 5.8 Hypertension Hypertension is a common adverse effect of tacrolimus therapy and may require antihypertensive therapy [see Adverse Reactions ( 6.1 )].

The control of blood pressure can be accomplished with any of the common antihypertensive agents, though careful consideration should be given prior to use of antihypertensive agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) [see Warnings and Precautions ( 5.7 )].

Calcium-channel blocking agents may increase tacrolimus blood concentrations and therefore require dosage reduction of tacrolimus [see Drug Interactions ( 7.2 )].

5.9 Anaphylactic Reactions with Tacrolimus Injection Anaphylactic reactions have occurred with injectables containing castor oil derivatives, including tacrolimus in a small percentage of patients (0.6%).

The exact cause of these reactions is not known.

Tacrolimus injection should be reserved for patients who are unable to take tacrolimus capsules orally.

Monitor patients for anaphylaxis when using the intravenous route of administration [ see Dosage and Administration ( 2.1 )].

5.10 Not Recommended for Use with Sirolimus Tacrolimus capsules are not recommended for use with sirolimus: The use of sirolimus with tacrolimus in studies of de novo liver transplant patients was associated with an excess mortality, graft loss, and hepatic artery thrombosis (HAT) and is not recommended.

The use of sirolimus (2 mg per day) with tacrolimus in heart transplant patients in a U.S.

trial was associated with increased risk of renal function impairment, wound healing complications, and insulin-dependent post-transplant diabetes mellitus, and is not recommended [see Clinical Studies ( 14.3 )].

5.11 Interactions with CYP3A4 Inhibitors and Inducers When co-administering tacrolimus with strong CYP3A4 inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) and strong inducers (e.g., rifampin, rifabutin), adjustments in the dosing regimen of tacrolimus and subsequent frequent monitoring of tacrolimus whole blood trough concentrations and tacrolimus-associated adverse reactions are recommended [see Drug Interactions ( 7 )].

5.12 QT Prolongation Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes.

Avoid tacrolimus in patients with congenital long QT syndrome.

In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

When co-administering tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval, a reduction in tacrolimus dose, frequent monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended.

Use of tacrolimus with amiodarone has been reported to result in increased tacrolimus whole blood concentrations with or without concurrent QT prolongation [see Drug Interactions ( 7 )].

5.13 Myocardial Hypertrophy Myocardial hypertrophy has been reported in infants, children, and adults, particularly those with high tacrolimus trough concentrations, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness.

This condition appears reversible in most cases following dose reduction or discontinuance of therapy.

In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered.

If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus capsules should be considered [see Adverse Reactions ( 6.2 )].

5.14 Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with Tacrolimus.

The use of live vaccines should be avoided during treatment with tacrolimus; examples include (not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with tacrolimus.

5.15 Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus.

A mechanism for tacrolimus-induced PRCA has not been elucidated.

All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA.

If PRCA is diagnosed, discontinuation of tacrolimus capsules should be considered [see Adverse Reactions ( 6.2 )].