TRAMADOL HCL ER

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 Tramadol hydrochloride extended-release tablet 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 tramadol hydrochloride extended-release tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)]. 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)]. 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 tramadol hydrochloride extended-release tablets. Monitor for respiratory depression, especially during initiation of tramadol hydrochloride extended-release tablets or following a dose increase. Instruct patients to swallow tramadol hydrochloride extended-release tablets intact, and not to cut, break, chew, crush, or dissolve the tablets to avoid exposure to a potentially fatal dose of tramadol [see Warnings and Precautions (5.3)]. Accidental Ingestion Accidental ingestion of even one dose of tramadol hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of tramadol [see Warnings and Precautions (5.3)]. 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)]. Tramadol hydrochloride extended-release tablets are 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)]. 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. [see Warnings and Precautions (5.4)] Neonatal Opioid Withdrawal Syndrome Prolonged use of tramadol hydrochloride extended-release 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 and Precautions (5.5)]. 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 tramadol hydrochloride extended-release tablet 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)]. 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)]. Reserve concomitant prescribing of tramadol hydrochloride extended-release Injection 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.

WARNINGS SECTION Seizure Risk Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous postmarketing 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: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or Other opioids. Administration of tramadol may enhance the seizure risk in patients taking: MAO inhibitors (see also WARNINGS - Use with MAO Inhibitors ), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of convulsions 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 tramadol hydrochloride extended-release tablets for patients who are suicidal or addiction-prone. Prescribe tramadol hydrochloride extended-release tablets with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess. Tell your patients not to exceed the recommended dose and to limit their intake of alcohol. Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including tramadol hydrochloride extended-release tablets, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose. (See CLINICAL PHARMACOLOGY - Pharmacokinetics ). Serotonin syndrome 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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations. Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Anaphylactoid Reactions Serious and rarely fatal anaphylactoid 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 codeine and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets (see CONTRAINDICATIONS ). Respiratory Depression Administer tramadol hydrochloride extended-release tablets cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS Seizure Risk and OVERDOSAGE ). Interaction With Central Nervous System (CNS) Depressants Tramadol hydrochloride extended-release tablets should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol hydrochloride extended-release tablets increase the risk of CNS and respiratory depression in these patients. Increased Intracranial Pressure or Head Trauma Tramadol hydrochloride extended-release tablets should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride extended-release tablets. (see WARNINGS - Respiratory Depression ). Use in Ambulatory Patients Tramadol hydrochloride extended-release 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. The patient using this drug should be cautioned accordingly. Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors Use tramadol hydrochloride extended-release tablets with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol hydrochloride extended-release tablets with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. Withdrawal Withdrawal symptoms may occur if tramadol hydrochloride extended-release tablet is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering tramadol hydrochloride extended-release tablets. Misuse, Abuse and Diversion of Opioids Tramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing tramadol hydrochloride extended-release tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Tramadol hydrochloride extended-release tablets could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION ). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Interactions with Alcohol and Drugs of Abuse Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

ADVERSE REACTIONS SECTION The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS (5.1)] Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS (5.3)] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see WARNINGS AND PRECAUTIONS (5.4)] Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS (5.5)] Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS AND PRECAUTIONS (5.7)] Serotonin Syndrome [see WARNINGS AND PRECAUTIONS (5.8)] Seizures [see WARNINGS AND PRECAUTIONS (5.9)] Suicide [see WARNINGS AND PRECAUTIONS (5.10)] Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS (5.11)] Severe Hypotension [see WARNINGS AND PRECAUTIONS (5.13)] Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS (5.15)] Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.16)] Withdrawal [see WARNINGS AND PRECAUTIONS (5.17)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tramadol hydrochloride was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain. Of these patients, 375 were 65 years old or older. Table 1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to tramadol hydrochloride administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride and the active control groups, TYLENOL with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride groups. Table 1: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride in Chronic Trials of Nonmalignant Pain (N=427) Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% “CNS Stimulation”1 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10% 1 “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations Incidence 1% to Less than 5% Possibly Causally Related 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 tramadol hydrochloride 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. Incidence Less than 1%, Possibly Causally Related The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol 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. Special Senses: Dysgeusia. Urogenital: Dysuria, Menstrual disorder. Other Adverse Experiences, Causal Relationship Unknown A variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride during clinical trials and/or reported in postmarketing experience. A causal relationship between tramadol hydrochloride 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. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of tramadol hydrochloride. Because these reactions are 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. 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. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY (12.2)]. QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting. Eye disorders – mydriasis Metabolism and nutrition disorders – Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see WARNINGS AND PRECAUTIONS (5.19)]. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see WARNINGS AND PRECAUTIONS (5.20)]. Nervous system disorders – movement disorder, speech disorder Psychiatric disorders – delirium