Drug Updates

According to a meta-analysis published in JAMA, the anti–interleukin (IL)-12/23 agents ustekinumab and briakinumab and the anti–tumor necrosis-alpha (TNF-α) agents adalimumab, etanercept, and infliximab do not increase the rate of major adverse cardiovascular events (MACE).¹ Randomized, placebo-controlled, double-blind, monotherapy studies in patients with chronic plaque psoriasis were evaluated. More than 10,000 patients met the inclusion criteria in 22 randomized controlled trials. The primary outcome was a major adverse cardiovascular event, a composite endpoint of myocardial infarction (MI), cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of the study in patients that received at least one dose of placebo or the study drug. All studies had at least a 12-week placebo-controlled phase, except for the infliximab studies, which had a 10-week placebo-controlled phase. The event rates were as follows: five of the 1,471 patients that received ustekinumab and five of the 1,428 patients that received briakinumab had an MI or stroke or died of heart-related causes, compared with none of the 1,474 patients given placebo. The investigators noted that the difference did not reach statistical significance. One of the 1,032 adalimumab-treated patients had an event, which was concluded to be “no difference” compared with placebo-treated patients. No patients that received etanercept (n=1,679) or infliximab (n=1,147) had a MACE. The briakinumab event rate was further scrutinized by the investigators, and the investigational studies were discontinued to further evaluate the potential mechanisms related to the MACE rates in these patients. Additionally, the manufacturer amended the open-label continuation trials to withdraw any patients with two or more predefined cardiovascular risk factors who had not experienced failure of prior anti–TNF-α therapies. The authors note that until further data are available, clinicians should use extra vigilance of cardiovascular risk factors when beginning anti–IL-12/23 therapies in patients with psoriasis.

Bisphosphonates (e.g., alendronate, etidronate, ibandronate, risedronate, risedronate delayed release, tiludronate), were evaluated on September 9, 2011 at a Food and Drug Administration (FDA) Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory meeting.^2,3 Bisphosphonate studies have shown that these agents have proven beneficial within the first three years of treatment in preventing osteoporosis fractures. However, when treatment is continued beyond five years, there does not appear to be a use benefit compared with using “no drug.” Additionally, women who have stopped taking bisphosphonates after five years of treatment seem to have a similar risk of fracture reduction and amount of increased bone density compared with women who continue to receive bisphosphonates. In regard to side effects such as unusual femur breaks, osteonecrosis of the jaw, or esophageal cancer, there is no conclusive evidence that bisphosphonates cause these effects. However, these serious but rare effects are difficult to study and cannot be ruled out as being caused by bisphosphonates. The long-term safety of bisphosphonates is still unclear due to conflicting study results. (See the October 2011 issue of Drug Safety Quarterly, available at www.rheumatology.org in the “Publications” menu, for more information.)

As also noted in the October 2011 Drug Safety Quarterly, Citalopram has recently been identified as causing dose-dependent QT interval prolongation.^4,5 Electrocardiogram changes can lead to the fatal arrhythmia called Torsade de Pointes. It is therefore recommended that this antidepressant no longer be prescribed at doses greater than 40 mg per day. Additionally, citalopram should not be used in patients with congenital long QT syndrome. Patients with congestive heart failure, bradyarrhythmias, or who are predisposed to hypokalemia or hypomagnesemia due to concomitant illness or drugs are at a higher risk of developing Torsade de Pointes. The citalopram drug label, including both brand and generic formulations, have been updated to include this warning. It is not clear whether these effects are seen with the S-enantiomer escitalopram.

Leflunomide tablets have undergone a label change related to the addition of peripheral neuropathy as a warning.⁶ There have been cases of peripheral neuropathy reported in patients receiving leflunomide, and most have recovered following discontinuation of the agent. Some patients, however, have had persistent symptoms. Patients that are older than age 60 years, are diabetic, and/or are receiving concomitant neurotoxic medications, may be at an increased the risk for developing peripheral neuropathy. If a patient taking leflunomide develops peripheral neuropathy, the therapy should be discontinued. Utilization of the leflunomide drug elimination procedure may be necessary.⁷

A recent study in Gastroenterology found that proton pump inhibitors (PPIs), which are often prescribed along with nonsteroidal antiinflammatory drugs (NSAIDs), may exacerbate NSAID-induced injury within the small intestine.⁸ This study evaluated the effects of omeprazole or lansoprazole for nine days on celecoxib- and naproxen-induced intestinal bleeding and ulceration in a rat model. The hematocrit was also measured. Both PPIs aggravated NSAID-induced intestinal ulceration and bleeding. Enteric microbial shifts occurred, which may provide a partial mechanism for this drug-induced effect.

Labeling of tacrolimus capsules have been updated to reflect the occurrence of cases of pure red cell aplasia (PRCA).⁹ Individuals at increased risk include those with parvovirus B19 infection, underlying disease, or use of concomitant drugs also associated with the development of PRCA. Consider drug discontinuation if PRCA occurs.

The labels for TNF-α inhibitors were updated in September to include a new warning related to the risk of developing serious and sometimes fatal infections from Legionella or Listeria.¹⁰ In a similar manner in 2008, the product labels were updated to reflect the risk of developing histoplasmosis and other invasive fungal infections. According to the FDA (from Adverse Events Reporting System data, 1999–2010), there were 80 reports of patients who developed Legionella pneumonia following the use of TNF-α inhibitors. Fourteen of these patients died. (See the October 2011 issue of Drug Safety Quarterly, available at www.rheumatology.org in the “Publications” menu, for more information.)

TNF-α inhibitors may be associated with a slight increase in the development of nonmelanoma skin cancers.¹¹ This is according to Mariette et al following their meta-analysis in a recent issue of Annals of Rheumatic Diseases.¹² There were 21 full-text articles and 8 abstracts that met their inclusion criteria. Certolizumab pegol and golimumab were not included in this analysis. In addition, Amari et al. found similar results in an observational study in 20,648 RA patients.¹³ They identified an incidence of nonmalignant skin cancer as 18.9/100 patient-years in those that received TNF-α inhibitors compared to 12.7/100 patient-years in those that received nonbiologic disease-modifying antirheumatic drugs. These authors note that this should prompt rheumatologists and other clinicians to carefully and systemically screen all patients that receive TNF-α inhibitors for precancerous lesions and skin cancer.

According to the FDA, zoledronic acid is now contraindicated for use in patients with significant renal impairment.¹⁴ This comes after they received 20 reports of acute renal failure leading to death, or requiring dialysis in patients with a creatinine clearance (CrCl) of less than 35 mLs/min or in patients that had evidence of acute renal failure. Clinicians need to screen patients for renal dysfunction before commencing zoledronic acid. Other risk factors that should be taken into consideration before prescribing this agent include advanced age, concomitant therapy with other potential nephrotoxins, dehydration secondary to fever, sepsis, or gastrointestinal losses, or diuretic therapy. In 2009, the zoledronic acid label was changed to recommend serum creatinine measurement prior to each dose, noting that renal failure was a risk with use of this agent. The patient’s actual body weight and the Cockcroft-Gault equation should be used to calculate the CrCl.

New Drug Approvals

Tapentadol extended-release tablets (Nucynta ER) have been approved by the FDA as a twice-daily continuous, around-the-clock opioid analgesic to treat moderate to severe chronic pain in adults when analgesia is needed for an extended period of time.¹⁵ A Risk Evaluation and Mitigation Strategy (REMS) is available for this medication. This REMS educates prescribers about the potential for abuse, misuse, overdose, and addiction from exposure to tapentadol extended release. Similar to the immediate-release tapentadol product, this product is classified as a Schedule II. It is available in 50-mg, 100-mg, 150-mg, 200-mg, and 250-mg strengths.

Tocilizumab (RoActemra) has been approved in the European Union (EU) to treat active systemic juvenile idiopathic arthritis (SJIA) in patients two years of age and older who have inadequately responded to previous therapy with NSAIDs and systemic corticosteroids.¹⁶ The agent can be used as monotherapy or as combination therapy along with methotrexate. The agent was already approved in the EU for adults with rheumatoid arthritis. In the United States, it was already approved for use in patients with SJIA age two years and older.

Pipeline

Canakinumab, an investigational IL-1-beta protein targeted monoclonal antibody, has met primary and secondary endpoints in a study of patients with SJIA.¹⁷ Eighty-four patients 2 to 19 years old with active SJIA were treated in a phase III trial and received either a single subcutaneous dose of canakinumab (ACZ885) or placebo. At Day 15, 84% of patients in the treatment arm achieved at least a 30% improvement in SJIA compared with 10% of placebo-treated patients. The studies are continuing in this patient population.

Michele Kaufman is a freelance medical writer based in New York City and a clinical pharmacist at New York Downtown Hospital.

References

1. Ryan C, Leonardi CL, Kreuger JG, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: A meta-analysis of randomised controlled trials. JAMA. 2011;306:864-871.
2. U.S. Food and Drug Administration. The Food and Drug Administration (FDA) Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM270958.pdf. Published September 9, 2011. Accessed October 10, 2011.
3. Wilson D. F.D.A. Staff: 5 years may be enough for bone drugs. http://prescriptions.blogs.nytimes.com/2011/09/07/f-d-a-staff-5-years-may-be-enough-for-bone-drugs/?emc=eta1. Published September 7, 2011. Accessed September 21, 2011.
4. Gever J. FDA warns against high-dose citalopram. www.medpagetoday.com/Psychiatry/Depression/28180. Published August 24, 2011. Accessed September 21, 2011.
5. U.S. Food and Drug Administration. Celexa (citalopram hydrobromide): Drug Safety Communication – Abnormal heart rhythms associated with high doses. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm269481.htm. Published August 24, 2011. Accessed September 21, 2011.
6. U.S. Food and Drug Administration. Arava (leflunomide) tablets. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm230245.htm. Published July 2011. Accessed September 21, 2011.
7. Arava prescribing information. www.accessdata.fda.gov/drugsatfda_docs/label/2011/020905s022lbl.pdf. Published July 8, 2011. Accessed September 21, 2011.
8. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 2011;141:1314-1322.
9. Prograf label. www.accessdata.fda.gov/drugsatfda_docs/label/2011/050708s036s037,050709s028s030lbl.pdf. Published July 14, 2011. Accessed September 21, 2011
10. Lowes R. TNF blockers get boxed warning on 2 bacterial infections. www.medscape.com/viewarticle/749273?sssdmh=dm1.716535&src=nl_newsalert. Published September 7, 2011. Accessed September 21, 2011.
11. DeNoon DJ. Rheumatoid arthritis drugs may have small skin cancer risk – Study shows TNF inhibitors have no increased risk of other cancers. www.webmd.com/rheumatoid-arthritis/news/20110907/rheumatoid-arthritis-drugs-may-have-small-skin-cancer-risk?src=RSS_PUBLIC. Published September 7, 2011. Accessed September 21, 2011.
12. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: A systematic review and meta-analysis. Ann Rheum Dis. 2011;70:1895-1904.
13. Amari W, Zeringue L, McDonal JR, Caplan L, Eisen SA, Ranganathan P. Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis. Rheumatology. 2011;50:1431-1439.
14. Gever J. Reclast gets FDA kidney failure warning. www.medpagetoday.com/ProductAlert/Prescriptions/28320?utm_source=breaking-news&utm_medium=email&utm_campaign=breaking-news#.Tl_iQUUbywI.email. Published September 1, 2011. Accessed September 21, 2011.
15. NUCYNTA® ER (Tapentadol Extended-Release Tablets) receives FDA approval for the management of moderate to severe chronic pain. www.marketwatch.com/story/nucynta-er-tapentadol-extended-release-tablets-receives-fda-approval-for-the-management-of-moderate-to-severe-chronic-pain-2011-08-26. Published August 26, 2011. Accessed September 21, 2011.
16. Dane L. EU regulators approve Roche’s RoActemra for juvenile arthritis. www.firstwordpharma.com/node/895069. Published August 3, 2011. Accessed September 21, 2011.
17. Novartis present positive data from trial of Ilaris in SJIA. www.firstwordpharma.com/node/907942. Published September 19, 2011. Accessed September 21, 2011.