Tramadol Hydrochloride (Page 4 of 8)

7.4 Triptans

Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when Tramadol Hydrochloride Extended-Release is co-administered with a triptan. If concomitant treatment of Tramadol Hydrochloride Extended-Release with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS ( 5.3)].

7.5 Interaction With Central Nervous System (CNS) Depressants

Tramadol Hydrochloride Extended-Release should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol Hydrochloride Extended-Release increases the risk of CNS and respiratory depression in these patients [see WARNINGS AND PRECAUTIONS ( 5.6)].

7.6 Quinidine

Quinidine is a strong inhibitor of CYP2D6. Coadministration of quinidine with an extended-release tramadol product resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure. The clinical consequences of these findings are unknown. [ See CLINICAL PHARMACOLOGY ( 12.3)]. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

7.7 Digoxin and Warfarins

Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

7.8 CYP3A4 Inducers

Administration of CYP3A4 inducers, such as carbamazepine, rifampin and St. John’s Wort, with Tramadol Hydrochloride Extended-Release may affect the metabolism of tramadol leading to reduced tramadol exposure [see CLINICAL PHARMACOLOGY ( 12.3)].

Patients taking carbamazepine, a CYP3A4 inducer, 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 Extended-Release and carbamazepine is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Use Tramadol Hydrochloride Extended-Release during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products. Tramadol Hydrochloride Extended-Release should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (1.6-fold the maximum daily human dose (MDHD)) in rats and 100 mg/kg (approximately 6.5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2.3-fold MDHD), 80 mg/kg in rats (2.6-fold MDHD) or 300 mg/kg in rabbits (Approximately 19-fold MDHD).

Non-teratogenic Effects

Tramadol caused a reduction in neonatal body weight at a dose of 50 mg/kg (1.6-fold the MDHD) and reduced pup survival at an oral dose of 80 mg/kg (approximately 2.6-fold MDHD) when rats were treated during late gestation throughout lactation period.

8.2 Labor and Delivery

Tramadol Hydrochloride Extended-Release 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 post-partum withdrawal symptoms in the newborn [see DRUG ABUSE AND DEPENDENCE ( 9.3)]. 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 Extended-Release, if any, on the later growth, development, and functional maturation of the child is unknown.

8.3 Nursing Mothers

Tramadol Hydrochloride Extended-Release is 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 mg 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 µg of M1. It is not known whether this drug is excreted in human milk following an oral dose.

8.4 Pediatric Use

The safety and efficacy of Tramadol Hydrochloride Extended-Release in patients under 18 years of age have not been established. The use of Tramadol Hydrochloride Extended-Release in the pediatric population is not recommended.

8.5 Geriatric Use

In general, caution should be used when selecting the dose for an elderly patent. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to Tramadol Hydrochloride Extended-Release in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia. For this reason, Tramadol Hydrochloride Extended-Release should be used with great caution in patients older than 75 years of age [see DOSAGE AND ADMINISTRATION ( 2.4)].

8.6 Patients with Renal Impairment

Tramadol Hydrochloride Extended-Release has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Hydrochloride Extended-Release should not be used in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION ( 2.5) and CLINICAL PHARMACOLOGY ( 12.3)].

8.7 Patients with Hepatic Impairment

Tramadol Hydrochloride Extended-Release has not been studied in patients with hepatic impairment. The limited availability of dose strengths of Tramadol Hydrochloride Extended-Release does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Hydrochloride Extended-Release should not be used in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION ( 2.6) and CLINICAL PHARMACOLOGY ( 12.3)].

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