Tramadol Hydrochloride and Acetaminophen 37.5 mg; 325 mg Tablet, 60-count — NDC 63187-084-60 (Billing 63187-0084-60)

WARNINGS Hepatotoxicity Tramadol hydrochloride and acetaminophen tablets contain tramadol hydrochloride and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product.

The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products (see Boxed Warning). The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen.

Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. 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 reuptake 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 and Serotonin Re-uptake 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, or CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure. Suicide Risk • Do not prescribe tramadol hydrochloride and acetaminophen tablets for patients who are suicidal or addiction-prone. • Prescribe tramadol hydrochloride and acetaminophen tablets with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess and who suffer from emotional disturbance or depression.

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. 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 (see WARNINGS, Risk of Overdosage ).

Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including tramadol hydrochloride and acetaminophen 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). Hypersensitivity/ anaphylaxis Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these events do… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Table 2 reports the incidence rate of treatment-emergent adverse events over five days of tramadol hydrochloride and acetaminophen tablets use in clinical trials (subjects took an average of at least 6 tablets per day). Table 2: Incidence of Treatment-Emergent Adverse Events (≥2%) Body System Preferred Term Tramadol Hydrochloride and Acetaminophen Tablets (N=142) % Gastrointestinal System Disorders Constipation 6 Nausea 3 Diarrhea 3 Dry Mouth 2 Psychiatric Disorders Somnolence 6 Anorexia 3 Insomnia 2 Central & Peripheral Nervous System Dizziness 3 Skin and Appendages Sweating Increased 4 Pruritus 2 Reproductive Disorders, Male * Prostatic Disorder 2 * Number of males = 62 Incidence at least 1%, causal relationship at least possible or greater: the following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of tramadol hydrochloride and acetaminophen tablets.

Body as a Whole – Asthenia, fatigue, hot flushes Central and Peripheral Nervous System – Dizziness, headache, tremor Gastrointestinal System – Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting Psychiatric Disorders – Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence Skin and Appendages – Pruritus, rash, increased sweating. Selected Adverse events occurring at less than 1% : the following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in tramadol hydrochloride and acetaminophen tablets clinical trials.

Body as a Whole – Chest pain, rigors, syncope, withdrawal syndrome Cardiovascular Disorders – Hypertension, aggravated hypertension, hypotension Central and Peripheral Nervous System – Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo Gastrointestinal System – Dysphagia, melena, tongue edema Hearing and Vestibular Disorders – Tinnitus Heart Rate and Rhythm Disorders – Arrhythmia, palpitation, tachycardia Liver and Biliary System – Hepatic function abnormal Metabolic and Nutritional Disorders – Weight decrease Psychiatric Disorders – Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking Red Blood Cell Disorders – Anemia Respiratory System – Dyspnea Urinary System – Albuminuria, micturition disorder, oliguria, urinary retention Vision Disorders – Abnormal vision Other clinically significant adverse experiences previously reported with tramadol hydrochloride: Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure and gastrointestinal bleeding.

Reported laboratory abnormalities included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Other clinically significant adverse experiences previously reported with acetaminophen: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

PRECAUTIONS General The recommended dose of tramadol hydrochloride and acetaminophen tablets should not be exceeded. Do not coadminister tramadol hydrochloride and acetaminophen tablets with other tramadol or acetaminophen-containing products (see WARNINGS, Use With Other Acetaminophen-containing Products and Risk of Overdosage ). Pediatric Use The safety and effectiveness of tramadol hydrochloride and acetaminophen tabletshas not been studied in the pediatric population.

Geriatric Use In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease and multiple drug therapy. Acute Abdominal Conditions The administration of tramadol hydrochloride and acetaminophen tablets may complicate the clinical assessment of patients with acute abdominal conditions . Use in Renal Disease Tramadol hydrochloride and acetaminophen tablets have not been studied in patients with impaired renal function.

Experience with tramadol suggests that impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of tramadol hydrochloride and acetaminophen tablets be increased not to exceed 2 tablets every 12 hours. Use in Hepatic Disease Tramadol hydrochloride and acetaminophen tablets have not been studied in patients with impaired hepatic function.

The use of tramadol hydrochloride and acetaminophen tablets in patients with hepatic impairment is not recommended (see WARNINGS, Use With Alcohol ). Information for Patients • Do not take tramadol hydrochloride and acetaminophen tablets if you are allergic to any of its ingredients. • If you develop signs of allergy such as a rash or difficulty breathing, stop taking tramadol hydrochloride and acetaminophen tablets and contact your healthcare provider immediately. • Do not take more than 4,000 milligrams of acetaminophen per day.

Call your doctor if you took more than the recommended dose. • Do not take tramadol hydrochloride and acetaminophen tablets in combination with other tramadol or acetaminophen-containing products, including over-the-counter preparations. • Tramadol hydrochloride and acetaminophen tabletsmay cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. • Tramadol hydrochloride and acetaminophen tablets may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. • Tramadol hydrochloride and acetaminophen tablets should not be taken concomitantly with alcohol-containing beverages during the course of treatment with tramadol hydrochloride and acetaminophen tablets. • Tramadol hydrochloride and acetaminophen tablets should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate-containing analgesics. • Inform the physician if you are pregnant, think you might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery ). • Understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures, hepatic toxicity and death.

Drug Interactions CYP2D6 and CYP3A4 Inhibitors Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics ), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome. Serotonergic Drugs There have been postmarketing reports of serotonin syndrome with use of tramadol a… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Abuse Tramadol has mu-opioid agonist activity. Tramadol hydrochloride and acetaminophen tablets, a tramadol-containing product, can be abused and may be subject to criminal diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations.

Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of tramadol hydrochloride and acetaminophen tablets can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.

Concerns about abuse and addiction should not prevent the proper management of pain. However all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Proper assessment of the patient and periodic reevaluation of therapy are appropriate measures that help to limit the potential abuse of this product.

Tramadol hydrochloride and acetaminophen tablets are intended for oral use only. Dependence Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see also WARNINGS, Withdrawal ).

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with tramadol hydrochloride and acetaminophen tablets.