Based on pooled multiple-dose pharmacokinetics studies for ULTRAM ER in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.

Drug Interactions

The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown.

Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol exposure (see PRECAUTIONS - DRUG INTERACTIONS).

Quinidine

Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of ULTRAM ER 100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and the exposure of M1 decreased 50-60% (see PRECAUTIONS - DRUG INTERACTIONS). In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Carbamazepine

Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended (see PRECAUTIONS - DRUG INTERACTIONS).

Cimetidine

Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the ULTRAM ER dosage regimen with cimetidine is recommended.

Clinical Studies

ULTRAM ER was studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12-week, randomized, double-blind, placebo-controlled trials. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥ 40 mm, off previous medications, on a 0 – 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies:

In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment was initiated at 100 mg QD for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in the ULTRAM ER treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the ULTRAM ER 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with ULTRAM ER 100 mg and 20% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 3).

Figure 3

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