Pharmacology Update

Hydromorphone HCl Extended-Release Tablets (Exalgo™) CII

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A once-daily controlled-release formulation of hydromorphone has been approved by the FDA. The product uses an osmotically controlled oral delivery system developed by Alza Corporation. It is marketed by Neuromed Pharmaceuticals as Exalgo™.

Indications

Controlled-release hydromorphone is indicated for the management of moderate-to-severe pain in opioid-tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time.1 Opioid tolerance is defined as those patients taking daily doses of at least 60 mg of morphine, 30 mg of oxycodone, 8 mg of hydromorphone, 25 mg of oral oxymorphone, or 25 µg of transdermal fentanyl per hour.1

Dosage

The dose ranges from 8 mg to 64 mg once daily. The dose should be reduced in patients with moderate- to-severe hepatic dysfunction or moderate renal dysfunction. It may be taken without regards to meals. The tablet should not be broken, crushed, chewed, or its content dissolved. This could lead to the absorption of a potentially fatal dose. If a decision should be made to discontinue the drug, the dose should be reduced by 25%-30% every 2-3 days down to a dose of 8 mg before discontinuation.1

The drug is available as 8 mg, 12 mg, and 16 mg tablets.

Potential Advantages

The controlled-release formulation reduces the fluctuation between peak and trough concentrations associated with the immediate-release tablet and allows it to be dosed once-daily.1 The bioavailability of once-daily dosing of the controlled-release formulation is comparable to the immediate-release formulation taken 4 times daily.1 The extended-release formulation may have a lower abuse potential than an immediate-release formulation.2

Potential Disadvantages

It takes 3-4 days for steady-state plasma concentrations to be reached.1 The extended-release formulation should be avoided in patients with narrowing or obstruction of the gastrointestinal tract or motility abnormality. The formulation also contains sodium metabisulfite that may cause an allergic-type reaction in susceptible individuals. Results from in vivo data suggest that alcohol increases the peak concentration of hydromorphone (mean, 10%-31%), but not the extent of absorption. The use of alcohol should be avoided with hydromorphone.

Comments

Hydromorphone is a mu-opioid agonist that is formulated as a controlled-release formulation to provide a convenient once-daily dosing. In a double-blind, placebo-controlled, randomized withdrawal study in opioid-tolerant patients with moderate-to-severe low back pain, controlled-release hydromorphone was superior to placebo in providing analgesia.1 In a randomized, open-label, non- inferiority analysis (n = 138) once-daily hydromorphone and twice-daily oxycodone extended-release provided comparable relief of pain in patients with chronic, moderate-to-severe osteoarthritis pain.3 The mean daily dose (SD) of hydromorphone at 6 weeks was 15.8 mg (10.5 mg) vs 24.0 mg (11.7 mg) for oxycodone. There was no statistical difference in adverse events; however, somnolence was numerically higher with hydromorphone (25.4% vs 17.9%) and dizziness higher with oxycodone (22.4% vs 14.1%). The altered rate of absorption may lower the abuse potential by delaying the penetration of hydromorphone into the central nervous system.2

Clinical Implications

Hydromorphone has been used as an analgesic since 1994. A controlled-release formulation provides continuous delivery of drug over 24 hours. Many patients may prefer long-acting compared to short-acting opioids.4 A previously approved extended-release capsule (Palladone™) was voluntarily withdrawn from the market after an FDA advisory warned of overdose potential when taken with alcohol. Hydromorphone HCl extended-release tablets offers a new extended-release opioid analgesic for chronic pain patients.

References

1. Exalgo Prescribing Information. Cambridge, MA: Neuromed Pharmaceuticals Inc.; March 2010.

2. Shram MJ, et al. Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone. J Clin Psychopharmacol 2010;30:25-33.

3. Hale M, et al. Efficacy and tolerability of once-daily OROS hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: Results of a 6-week, randomized, open-label, noninferiority analysis. Clin Ther 2007;29:874-888.

4. Rauck RL. What is the case for prescribing long- acting opioids over short-acting opioids for patients with chronic pain? A critical review. Pain Pract 2009;9:468-479.