Real-world analysis of the Celgene Global Drug Safety database: early discontinuation of lenalidomide in patients with myelodysplastic syndromes due to non-serious rash.

BACKGROUND: Lenalidomide is approved for treating transfusion-dependent anemia due to lower-risk del(5q) myelodysplastic syndromes (MDS). In clinical trials, rash was common, although severe rash was infrequent. To examine rash in patients with MDS treated with lenalidomide in the real world, the Celgene Global Drug Safety database was analyzed and compared with clinical trials. MATERIALS AND METHODS: Adverse event reports in the post-marketing setting and in the MDS-003/004 clinical trials were analyzed by action taken with lenalidomide, seriousness/grade, time to onset, and treatment duration. RESULTS: Globally, 16,942 reports representing 36,793 adverse events from the post-marketing setting were submitted to the Global Drug Safety database between December 27, 2005 and June 13, 2013. Most rash adverse events were non-serious (Global Drug Safety database, 91%) or grade 1/2 (MDS-003/004 trials, 87%-93%). Unexpectedly, rash, occurring at a median of 9 days after treatment initiation, was the leading cause of permanent discontinuation of lenalidomide. Seventy-two percent of non-serious rash adverse events led to early permanent discontinuation within two cycles, while in the MDS-003/004 pivotal clinical trials, only 2%-3% of rash adverse events led to permanent discontinuation. CONCLUSION: Non-serious rash was the most common reason for permanent discontinuation of lenalidomide in real-world settings. Managing lenalidomide-related rash using published recommendations might improve treatment duration and optimize patient outcomes.

Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior.

BACKGROUND: Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome. METHOD: In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001. RESULTS: Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings. CONCLUSION: The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.

No clinically significant drug interactions between lenalidomide and P­glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers.

PURPOSE: Lenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated. METHODS: Two phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300-600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs. RESULTS: There were no significant changes in the maximum concentration (C max) and area under the plasma concentration-time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed. CONCLUSIONS: There are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.

The clinical safety of lenalidomide in multiple myeloma and myelodysplastic syndromes.

INTRODUCTION: Lenalidomide is an IMiDs® oral immunomodulatory compound developed for the treatment of patients with multiple myeloma (MM) and myelodysplastic syndromes (MDS). Long-term continuous treatment with lenalidomide beyond first response may be important to optimize responses and delay relapse. AREAS COVERED: This review summarizes the lenalidomide mechanism of action, pharmacodynamics, key clinical studies with a focus on safety and post-marketing surveillance data. The necessity for early adverse-event management, including dose modifications for neutropenia and thrombocytopenia, and venous thromboembolism prophylaxis, where applicable, in order to maintain patients on treatment and achieve optimal efficacy, is discussed. Secondary primary malignancies in MM and progression to acute myeloid leukemia in MDS patients in the context of lenalidomide treatment are also discussed. Finally, as lenalidomide is renally excreted, the requirement for dose adjustment according to creatinine clearance is discussed. EXPERT OPINION: Lenalidomide is highly effective and generally well tolerated. Most adverse events occur early during the course of treatment and are manageable. Lenalidomide is not associated with peripheral neuropathy and has a lack of cumulative toxicity, making it an effective treatment option for long-term use in the management of MM and low/intermediate-1-risk MDS, specifically with chromosome 5q deletion with or without other cytogenetic abnormalities.