Drug Updates

Drug Safety

The Food and Drug Administration (FDA) performed a review of bisphosphonates, prompted by growing evidence over how long patients should continue using these agents.¹ Concerns include osteonecrosis of the jaw, atypical femur fractures, and esophageal cancer in women that used this class of agents for three or more years. Three long-term trials were evaluated, looking at the meaningful endpoint of vertebral fracture rate, rather than any other endpoint previously identified as being important. When fracture data was pooled across trials in patients treated continuously for at least six years, fracture rates ranged from 9.3% to 10.6% for bisphosphonate therapy, whereas the fracture rate for patients switched to placebo was 8% to 8.8%. This raises the question of whether continuing bisphosphonates provides any additional fracture prevention benefit. In addition, more data are needed to determine whether markers of bone mineral density or bone turnover reliably help decisions related to continuing or interrupting bisphosphonate treatment. No studies have yet determined how long bisphosphonate benefits last. Although some patients may safely continue to take the drug, some may benefit from discontinuation. New treatment algorithms are needed, in light of available safety information.

Drug Approvals

After a long wait, clopidogrel (generic Plavix) has been FDA approved as a generic.² Two dosage forms were approved—75 mg and 300 mg. Clopidogrel is approved for secondary stroke and myocardial infarction prophylaxis and for patients with peripheral artery disease. It became available from at least eight manufacturers in mid-May.

Hydromorphone 8 mg tablets (generic Dilaudid) are now available for treatment of pain.³

The first generic morphine sulfate oral solution available in 100 milligrams per 5 mL (20 milligrams per 1 mL) was recently FDA approved for relieving moderate to severe acute and chronic pain in opioid-tolerant patients.⁴ This form had been available but had not been FDA approved. It is now approved and meets U.S. safety requirements for approved drugs.

Phentermine HCl orally disintegrating tablets (Suprenza) have been FDA approved as a short-term adjunct in the management of exogenous obesity.⁵ Phentermine, a sympathomimetic amine anorectic, is FDA approved for treating obesity in patients with an initial body mass index of ≥30kg/m2 or ≥27kg/m2 in the presence of other risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia).

A supplemental New Drug Application (sNDA) has been submitted to the FDA seeking approval for the use of oral rivaroxaban (Xarelto) to treat deep vein thrombosis (DVT) or pulmonary embolism and prevent recurrent venous thromboembolism.⁶ Rivaroxaban is an oral anticoagulant, a factor Xa inhibitor, currently approved for the prophylaxis of DVT in people undergoing knee- or hip-replacement surgery and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. On May 23, an FDA advisory committee recommended against approving rivaroxaban for treating acute coronary syndromes, citing missing safety and outcomes data.⁷ At press time, the FDA was expected to render a decision by the end of June.

Pipeline

CB-5945 is an oral mu opioid receptor and delta opioid receptor antagonist, currently in phase II clinical trials to treat opioid-induced constipation in patients with abdominal symptoms on chronic opioid therapy for persistent noncancer-related pain.⁸ In two phase II clinical trials, the drug was dosed once and twice daily over four weeks, with opioid consumption, pain scores, and adverse events monitored. The most commonly reported adverse events were abdominal pain and upper respiratory tract infection. Gastrointestinal-related adverse events were mostly mild with a low incidence. Phase III trials are planned.

Epratuzumab, an intravenous (IV), anti-CD22 monoclonal antibody, is being studied for the treatment of moderate-to-severe systemic lupus erythematosus (SLE).⁹ In a recent study, white women with a mean age of 40 (n=227), positive antinuclear antibodies, and scores of six or higher on the SLE Disease Activity Index were enrolled. Initially, 45% were on immunosuppressive agents, including azathioprine, methotrexate (MTX), or mycophenolate mofetil, and 47% were also receiving antimalarials. The mean baseline corticosteroid dose was 14 mg. The British Isles Lupus Assessment Group index-based Combined Lupus Assessment was used to measure disease activity. Twice as many epratuzumab-treated patients who received a cumulative dose of 1,200 mg over 12 weeks had a response rate compared with placebo-treated patients (43% versus 21%, P=0.02). At least one adverse event was exhibited by 75% of patients, which was most often a headache or a minor infection. Fewer than 10% of patients experienced a serious adverse event. Like rituximab, epratuzumab depletes B cells, causing a partial depletion of approximately 30%. A phase III clinical trial is now evaluating four doses of 600 mg (total 2,400 mg) given weekly every three months for up to a year.

An sNDA has been submitted for hydrocodone bitartrate extended-release capsules, an investigational treatment for chronic pain.¹⁰ This product is a potentially novel, oral, single-entity extended-release formulation of hydrocodone (without acetaminophen) for managing moderate to severe chronic pain in patients requiring around-the-clock opioid therapy. If approved, this agent could be the first nonacetaminophen-containing single-entity hydrocodone therapy.

In early May, an FDA advisory panel voted 18 to 4 in favor of approving lorcaserin, a potentially new treatment for obesity.¹¹ Modest weight loss was identified in overweight and obese individuals in the clinical studies, but not to the degree that was expected. Additionally, the incidence of valvulopathy was low in the studies and was not long term. The advisory panel members made some suggestions for lorcaserin if approved. They asked that the manufacturers conduct follow-up studies to assess cardiovascular effects or recommend receiving an echocardiogram prior to drug prescribing. At press time, the FDA was expected to make a final decision by the end of June.

Secukinumab, an IV interleukin-17 targeting monoclonal antibody, recently appeared promising in the treatment of ankylosing spondylitis in a phase II clinical study presented at the British Society of Rheumatology meeting.¹² Twenty-three patients received two infusions, and by Week 6, 61% (n=14) exhibited at least a 20% improvement. Patients received two IV 10-mg/kg doses on Days 1 and 22. These patients could have used up to three disease-modifying antirheumatic drugs (DMARDs) in the past. Of these patients, half had previously received treatment with an anti–tumor necrosis factor–alpha (TNF-α) agent. Ninety-two percent of treated patients completed the study, with 35% showing at least a 40% improvement in the assessment of SpondyloArthritis International Society response criteria including pain, spinal mobility, and function. Patients that received prior anti-TNF therapy had a lower 20% response rate (30% versus 85% of those that had previously not received anti-TNF agents). Adverse effects were mostly mild infections.

Tofacitinib, an oral janus kinsase inhibitor for the treatment of rheumatoid arthritis (RA), has received an approval recommendation from the FDA Arthritis Advisory Committee.¹³ The committee voted eight to two in favor of approving tofacitinib for adults with moderate-to-severe active RA in those who have not had an adequate response to one or more DMARDs. The agent had overwhelmingly positive efficacy information according to the committee, which was demonstrated in five phase III clinical trials with statistically significant increases seen on ACR 20, 50, and 70 responses. Radiographic outcomes were less clear. Safety discussions were raised related to the incidence of serious infections, which included pneumonia and skin and soft tissue infections.

Twelve cases of tuberculosis and 19 cases of herpes zoster were also reported. Additionally, malignancy was reported in 66 patients treated with tofacitinib, while the cancer rates increased over the study duration. From baseline to Month 6, cancer rates were 0.79 per 100 patient-years, and at Month 24, they were 1.43 per 100 patient-years. Seven tofacitinib-treated patients developed lymphoma; none of the placebo-treated patients did. Infections and malignancies seemed to be dose related (at 10 mg); a 5 mg dose was also studied.

Drug News

In another study presented at the British Society of Rheumatology meeting, tocilizumab monotherapy or combined with MTX in patients with at least moderate disease activity led to significant and very early suppression of RA disease activity and damage in a large cohort of patients (n=556).¹⁴ The relative risk of achieving remission at Month 6 was 40% among those patients that received tocilizumab plus MTX, compared with 35% for patients that received tocilizumab monotherapy (P=0.19). In a substudy following three months of treatment, preerosive changes detectable on MRI were reversed from baseline, with significant changes in synovitis scores. As early as two weeks following treatment, inflammatory changes were already seen on MRI. Most study participants were women, with a mean age of 53 years and mean RA duration of eight years. This study suggests that tocilizumab could be used as monotherapy in patients unwilling or unable to take MTX.

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis—Where do we go from here? N Engl J Med. 2012. DOI 10.1056/NEJMP1202619.
2. Gever J. Plavix generic competitors get green light. Published May 17, 2012. Available at www.medpagetoday.com/Cardiology/Prevention/32758. Accessed May 25, 2012.
3. Will D. Elite Pharmaceuticals announces first shipment of generic hydromorphone product. Published March 13, 2012. Available at www.elitepharma.com/investor_relations.asp?goto=342. Accessed May 25, 2012.
4. Phillips P. Covidien’s Mallinckrodt business launches morphine sulfate oral solution in U.S. Published March 22, 2012. Available at http://investor.covidien.com/phoenix.zhtml?c=207592&p=irol-newsArticle&ID=1675292&highlight=. Accessed May 25, 2012.
5. Akrimax to launch Suprenza ODT. Published April 10, 2012. Available at www.empr.com/akrimax-to-launch-suprenza-odt/article/235824/?DCMP=EMC-MPR_WeeklyNewsbrief. Accessed May 25, 2012.
6. sNDAs submitted for Xarelto for treatment and prevention of recurrent venous thromboembolism. Published May 2, 2012. Available at www.empr.com/sndas-submitted-for-xarelto-for-treatment-and-prevention-of-recurrent-venous-thromboembolism/article/239285/. Accessed May 7, 2012.
7. Walker EP. FDA panel narrowly rejects Xarelto for ACS. Published May 23, 2012. Available at www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/32888. Accessed May 25, 2012.
8. Han DH. Peripheral opioid receptor antagonist CB-5945 improves bowel motility. Published May 19, 2012. Available at www.empr.com/peripheral-opioid-receptor-antagonist-cb-5945-improves-bowel-motility/article/241906/. Accessed May 21, 2012.
9. Walsh N. Novel biologic targets lupus. Published May 2, 2012. Available at www.medpagetoday.com/MeetingCoverage/BSR/32462?utm_source=WC&utm_medium=email&utm_campaign=Meeting_Roundup_BSR. Accessed May 11, 2012.
10. NDA submitted for Zohydro for treatment of chronic pain. Published May 2, 2012. Available at www.empr.com/nda-submitted-for-zohydro-for-treatment-of-chronic-pain/article/239283/. Accessed May 7, 2012.
11. Dane L. FDA panel backs Arena, Eisai’s Lorqess. Published May 10, 2012. Available at www.firstwordpharma.com/node/982229. Accessed May 25, 2012.
12. Walsh N. IL-17 blocker promising for spondylitis. Published May 1, 2012. Available at www.medpagetoday.com/Rheumatology/BSR/32449. Accessed May 7, 2012.
13. Walsh N, Agus ZS. Pfizer’s arthritis pill gets nod from FDA panel. Published May 9, 2012. Available at www.medpagetoday.com/Rheumatology/Arthritis/32594. Accessed May 10, 2012.
14. Walsh N. Biologic works as monotherapy in early RA. Published May 3, 2012. Available at www.medpagetoday.com/MeetingCoverage/BSR/32500?utm_source=WC&utm_medium=email&utm_campaign=Meeting_Roundup_BSR. Accessed May 11, 2012.