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 acetaminophencontaining products. (See WARNINGS, Use With Other Acetaminophen-containing Products and Risk of Overdosage). Pediatric Use The safety and effectiveness of tramadol hydrochloride and acetaminophen tablets has 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 has not been studied in patients with impaired renal function. Experience with tramadol suggest 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 has 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 it 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 tablets may 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 and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when tramadol hydrochloride and acetaminophen tablets is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John’s Wort. If concomitant treatment of tramadol hydrochloride and acetaminophen tablets with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Triptans Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when tramadol hydrochloride and acetaminophen tablets are coadministered with a triptan. If concomitant treatment of tramadol hydrochloride and acetaminophen tablets with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). Use With Carbamazepine Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen tablets and carbamazepine is not recommended. Use With Quinidine Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Potential for Other Drugs to Affect Tramadol In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort, with tramadol hydrochloride and acetaminophen tablets may affect the metabolism of tramadol leading to altered tramadol exposure. Potential for Tramadol to Affect Other Drugs In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals. Use With Cimetidine Concomitant administration of tramadol hydrochloride and acetaminophen tablets and cimetidinehas not been studied. Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol hydrochloride and acetaminophen tablets dosage regimen is recommended. Use With Digoxin Postmarketing surveillance of tramadol has revealed rare reports of digoxin toxicity. Use With Warfarin-Like Compounds Postmarketing surveillance of both tramadol and acetaminophen individual products have revealed rare alterations of warfarin effect, including elevation of prothrombin times. While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when tramadol hydrochloride and acetaminophen tablets and warfarin-like compounds are administered concurrently. Carcinogenesis, Mutagenesis, Impairment of Fertility There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to evaluate carcinogenesis, mutagenesis, or impairment of fertility. A slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.5 times the maximum daily human tramadol dosage of 185 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or 1 time the maximum daily human tramadol dosage). Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans. No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (350 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tramadol dosage of 185 mg/m2. Pregnancy Teratogenic Effects: Pregnancy Category C No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and acetaminophen. The tramadol/acetaminophen combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg tramadol/acetaminophen (300/2604 mg/m2 or 1.6 times the maximum daily human tramadol/acetaminophen dosage of 185/1591 mg/m2), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Non-teratogenic Effects: Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.6 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human tramadol dosage). There are no adequate and well-controlled studies in pregnant women. Tramadol hydrochloride and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during postmarketing. Labor and Delivery Tramadol hydrochloride and acetaminophen tablets should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE).Tramadol has been shown to cross the placenta.The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor. The effect of tramadol hydrochloride and acetaminophen tablets, if any, on the later growth, development, and functional maturation of the child is unknown. Nursing Mothers Tramadol hydrochloride and acetaminophen tablets are not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mcg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.