Pharmacy & Therapeutics - March 2009 - (Page 139) DRUG FORECAST Table 1 Cryopyrin-Associated Periodic Syndromes Syndrome Familial cold auto-inflammatory syndrome Muckle–Wells syndrome Severity Mild Disease Onset First six months of life Childhood Neonatum period or early in infancy Attack Duration < 24 hours Clinical Manifestations Cold temperature–induced fever, urticaria, rash, headache, nausea, sweating, drowsiness, extreme thirst, conjunctivitis, blurred vision, ocular pain, polyarthralgia Urticaria, fever, arthralgia, conjunctivitis, abdominal pain, progressive hearing loss, nephropathy, renal amyloidosis Nonpruritic urticaria-like rash, central nervous system involvement (headache, macrocephaly, cerebral atrophy, chronic aseptic meningitis, high-frequency hearing loss, ocular changes, developmental delay), lymphadenopathy, hepatosplenomegaly Moderate 24–48 hours Continuous, with episodes of worsening Neonatal-onset Severe multisystemic inflammatory disease Adapted from references 1 and 3–5. scores from baseline to the end of treatment. Patients receiving rilonacept improved within several days of initiating therapy. The mean change in symptom scores from the baseline evaluation to the endpoint in the first study was –0.5 in placebo patients and –2.4 in rilonacept patients, with a 95% confidence interval (CI) for a between-group difference of –2.4 to –1.3. The study demonstrated that patients receiving treatment experienced a larger reduction in mean symptom scores. In the second study, mean symptom scores of patients who switched to placebo increased (0.9), compared with patients who continued with rilonacept (0.1), for a 95% CI for a between-group difference of –1.3 to –0.4.8 These figures (0.9 and 0.1) represent the least-square mean change from baseline to endpoint (for the mean symptom score). The first study also evaluated serum amyloid A levels (normal range, 0.7–6.4 mg/L) and CRP levels (normal range, 0 to–8.4 mg/L). Both serum amyloid A and CRP are usually elevated during active disease. At the end of six weeks of rilonacept therapy, both mean serum amyloid A levels (pre-treatment baseline value = 60 mg/L, week six = 4 mg/L) and CRP levels (pre-treatment baseline value = 22 mg/L, week six = 2 mg/L) were reduced when compared with the baseline level. Conversely, the placebo patients showed relatively no change in mean serum amyloid A levels (pre-treatment baseline value = 110 mg/L, week six = 110 mg/L) or CRP levels (pre-treatment baseline value = 30 mg/L, week six = 28 mg/L) compared with the baseline value.8 The most common adverse effects associated with rilonacept in these trials, from most to least frequent, were injection-site reactions, upper respirator y tract infections, sinusitis, cough, hypoesthesia, nausea, diarrhea, stomach discomfort, and urinary tract infections.12 The product information for rilonacept mentions six serious adverse effects during the trials, which were reported by four patients, as follows: Mycobacterium intracellular infection, gastrointestinal bleeding, colitis, sinusitis, bronchitis, and Streptococcus pneumoniae meningitis.8 PRECAUTIONS AND WARNINGS Rilonacept may inter fere with the body’s immune response to infection; therefore, treatment should not be instituted in patients with active or chronic infections. Therapy should be discontinued if a serious infection develops. Although the impact of the drug on the development of malignancies has not been studied, treatment with rilonacept may increase this risk. No data are available on the concomitant administration of live or inactivated vaccines and rilonacept. Live vaccines should not be given to patients who are being treated with rilonacept; it is recommended that patients receive all necessary vaccinations before starting treatment, including pneumococcal and inactivated influenza vaccines. If a hypersensitivity reaction occurs when rilonacept is given, therapy should be discontinued.8 DRUG INTERACTIONS To date, drug-interaction studies have not been performed for rilonacept; however, an increased incidence of serious infections has been associated with the use of IL-1 blockers in combination with tumor necrosis factor (TNF) inhibitors. Concomitant administration of rilonacept with TNF inhibitors is therefore not recommended. In addition, based on the potential pharmacological interaction of rilonacept with drugs that block IL-1 or its receptors, the concomitant administration of these agents is not recommended. Cytochrome P450 enzyme formation is suppressed by increased levels of IL-1 during chronic inflammation. Because rilonacept binds to IL-1, it has the potential of normalizing low CYP 450 enzyme levels. Therefore, therapeutic drug monitoring should be initiated when rilonacept is given with CYP 450 substrates that have narrow therapeutic indexes, such as warfarin (Coumadin, BristolMyers Squibb); doses of those medications may need to be adjusted.8 MONITORING REQUIREMENTS Patients with chronic inflammation, as in the case of CAPS, may have reduced cholesterol and lipid levels. Rilonacept decreases the inflammatory response; as a result, patients may have increases in total cholesterol, high-density lipoprotein-cholesterol, low-density lipoproteincholesterol, and triglyceride levels. 8 Physicians should monitor patients’ lipid profiles two to three months after therapy has been started. Lipid-lowering agents should be considered, as needed, according to patients’ cardiovascular risk factors and current guidelines.8 Vol. 34 No. 3 • March 2009 • P&T® 139
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