OPANA ER (Page 3 of 11)

Renal Impairment

Data from a pharmacokinetic study involving 24 patients with renal dysfunction show an increase of 26%, 57%, and 65% in oxymorphone bioavailability in mild (creatinine clearance 51-80 mL/min; n=8), moderate (creatinine clearance 30-50 mL/min; n=8), and severe (creatinine clearance <30 mL/min; n=8) patients, respectively, compared to healthy controls.

Drug-Drug Interactions

In vitro studies revealed little to no biotransformation of oxymorphone to 6-OH-oxymorphone by any of the major cytochrome P450 (CYP P450) isoforms at therapeutically relevant oxymorphone plasma concentrations.

No inhibition of any of the major CYP P450 isoforms was observed when oxymorphone was incubated with human liver microsomes at concentrations of ≤ 50 μM. An inhibition of CYP3A4 activity occurred at oxymorphone concentrations ≥150 µM. Therefore, it is not expected that oxymorphone, or its metabolites will act as inhibitors of any of the major CYP P450 enzymes in vivo.

Increases in the activity of the CYP 2C9 and CYP 3A4 isoforms occurred when oxymorphone was incubated with human hepatocytes. However, clinical drug interaction studies with OPANA ER showed no induction of CYP450 3A4 or 2C9 enzyme activity, indicating that no dose adjustment for CYP 3A4- or 2C9-mediated drug-drug interactions is required.

CLINICAL TRIALS

The efficacy and safety of OPANA ER have been evaluated in double-blind, controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate to severe pain including low back pain.

12-Week Study in Opioid-Naïve Patients with Low Back Pain

Patients with chronic low back pain who were suboptimally responsive to their current non-opioid therapy entered a 4-week, open-label dose titration phase. Patients initiated therapy with two days of treatment with OPANA ER 5 mg, every 12 hours. Thereafter, patients were titrated to a stabilized dose, at increments of 5-10 mg every 12 hours every 3-7 days. Of the patients who were able to stabilize within the Open-Label Titration Period, the mean±SD VAS score at Screening was 69.4±11.8 mm and at Baseline (beginning of Double-Blind Period) were 18.5±11.2 mm and 19.3±11.3 mm for the oxymorphone ER and placebo groups, respectively. Sixty three percent of the patients enrolled were able to titrate to a tolerable dose and were randomized into a 12-week double-blind treatment phase with placebo or their stabilized dose of OPANA ER. The mean±SD stabilized doses were 39.2±26.4 mg and 40.9±25.3 mg for the OPANA ER and placebo groups, respectively; total daily doses ranged from 10-140 mg. During the first 4 days of double-blind treatment patients were allowed an unlimited number of OPANA, an immediate-release (IR) formulation of oxymorphone, 5 mg tablets, every 4-6 hours as supplemental analgesia; thereafter the number of OPANA was limited to two tablets per day. This served as a tapering method to minimize opioid withdrawal symptoms in placebo patients. Sixty-eight percent of patients treated with OPANA ER completed the 12-week treatment compared to forty seven percent of patients treated with placebo. OPANA ER provided superior analgesia compared to placebo. The analgesic effect of OPANA ER was maintained throughout the double-blind treatment period in 89% of patients who completed the study. These patients reported a decrease, no change, or a ≤10 mm increase in VAS score from Day 7 until the end of the study.

A significantly higher proportion of OPANA ER patients (81.4%) had at least a 30% reduction in pain score from screening to study endpoint compared to placebo patients (51.7%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 1.

Figure 1: Percent Reduction in Average Pain Intensity from Screening to Final Visit

Figure 1
(click image for full-size original)

12-Week Study in Opioid-Experienced Patients with Low Back Pain

Patients currently on chronic opioid therapy entered a 4-week, open-label titration phase with OPANA ER dosed every 12 hours at an approximated equianalgesic dose of their pre-study opioid medication. Of the patients who were able to stabilize within the Open‑Label Titration Period, the mean±SD VAS score at Screening was 69.5±17.0 mm and at Baseline (beginning of Double-Blind Period) were 23.9±12.1 mm and 22.2±10.8 mm for the oxymorphone ER and placebo groups, respectively. Stabilized patients entered a 12‑week double-blind treatment phase with placebo or their stabilized dose of OPANA ER. The mean±SD stabilized doses were 80.9±59.3 mg and 93.3±61.3 mg for the OPANA ER and placebo groups, respectively; total daily doses ranged from 20-260 mg. During the first 4 days of double-blind treatment, patients were allowed an unlimited number of OPANA 5 mg tablets, every 4-6 hours as supplemental analgesia; thereafter the number of OPANA was limited to two tablets per day. This served as a tapering method to minimize opioid withdrawal symptoms in placebo patients. Fifty seven percent of patients were titrated to a stabilized dose within approximately 4 weeks of OPANA ER dose titration. Seventy percent of patients treated with OPANA ER and 26% of patients treated with placebo completed the 12-week treatment. OPANA ER provided superior analgesia compared to placebo . The analgesic effect of OPANA ER was maintained throughout the double-blind treatment period in 80 % of patients who completed the study. These patients reported a decrease, no change, or a ≤10 mm increase in VAS score from Day 7 until the end of the study.

A significantly higher proportion of OPANA ER patients (79.7%) had at least a 30% reduction in pain score from screening to study endpoint compared to placebo patients (34.8%). Proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2.

Figure 2: Percent Reduction in Average Pain Intensity from Screening to Final Visit

Figure 2
(click image for full-size original)

INDICATIONS AND USAGE

OPANA ER is indicated for the relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time.

OPANA ER is not intended for use as a prn analgesic.

OPANA ER is not indicated for pain in the immediate post-operative period (12-24 hours following surgery) for patients not previously taking opioids because of the risk of oversedation and respiratory depression requiring reversal with opioid antagonists.

OPANA ER is not indicated for pain in the post-operative period if the pain is mild or not expected to persist for an extended period of time.

CONTRAINDICATIONS

OPANA ER is contraindicated in patients with a known hypersensitivity to oxymorphone hydrochloride or to any of the other ingredients in OPANA ER, or with known hypersensitivity to morphine analogs such as codeine.

OPANA ER is not indicated for pain in the immediate post-operative period (the first 12-24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. OPANA ER is only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the post-operative pain is expected to be moderate or severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines).

OPANA ER is contraindicated in any situation where opioids are contraindicated such as: patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute or severe bronchial asthma or hypercarbia.

OPANA ER, like all opioids, is contraindicated in any patient who has or is suspected of having paralytic ileus.

OPANA ER is contraindicated in patients with moderate and severe hepatic impairment (see CLINICAL PHARMACOLOGY, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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