US Pharm. 2011;36(11)(Oncology suppl):16-20.
ABSTRACT: Nearly 200 drugs currently on the market for the treatment of various disease states have demonstrated significant risk to consumers, to the extent that the FDA requires drug-specific risk evaluation mitigation strategies (REMS) to ensure that the benefits of the drug outweigh the risks. A surprisingly small number of the vast array of drugs requiring REMS are used to treat malignancies. Isotretinoin and thalidomide, in particular, have been around for decades and are known for their teratogenic potential. Regardless, these two agents have entered the cancer arena through the back door by providing significant antineoplastic efficacy. Newer anticancer drugs are designed to target specific signaling pathways and are linked to unique toxicities. Some of the toxicities of these agents warrant REMS by FDA standards, and REMS are employed to mitigate the adverse risks while preserving the benefits of therapy.
The FDA has been involved in the management of drug safety for many years. The Food and Drug Administration Amendments Act (FDAAA), a landmark legislation that created a new standard for drug safety and pharmacovigilance, was passed in 2007.1 The FDAAA granted the FDA greater authority to manage and assess known or potential serious risks associated with drugs or biological products by means of risk evaluation mitigation strategies (REMS). REMS is a program that is intended to ensure that the benefits of a particular drug outweigh the risks during any part of the drug’s lifecycle. The FDA determines whether risk-mitigation actions are necessary for the approval of a drug. A REMS may be a formal part of a New Drug Application (NDA) at the time of submission, or it may be required at a later date based on new safety information received during postapproval. The FDAAA gives the FDA the authority to inspect and enforce the sponsor’s (manufacturer’s) compliance with the approved REMS. The FDA can order the performance of postapproval studies to evaluate a drug’s safety, require that new safety information be added to product labeling, deem a drug or biological agent misbranded, or impose civil monetary penalties for noncompliance with the approved REMS.
A REMS submitted for FDA approval by a drug’s sponsor typically outlines the goals of the program and includes specific elements necessary for evaluating the effectiveness of the interventions and ensuring the drug’s safe and appropriate use.1 Nearly 200 drugs for various disease states have demonstrated enough risk to consumers to warrant REMS. Most REMS require the distribution of a patient medication guide highlighting important safety information about the drug. Other common components, if deemed necessary by the FDA, include a communication plan, Elements to Assure Safe Use, and an implementation plan. The FDA requires an assessment of REMS performance at 1.5, 3, and 7 years postapproval, at a minimum.
Surprisingly, only a small percentage of all oncologic drugs require REMS.2 Older drugs, such as thalidomide and isotretinoin, have demonstrated significant antitumor activity in certain malignancies in addition to their approved indications, but are highly teratogenic. Advances in technology and a better understanding of the biology of diseases have generated substantial interest among researchers to develop novel agents that target signaling pathways linked to cancer survival. Novel agents such as monoclonal antibodies and tyrosine kinase inhibitors (TKIs) constitute a growing number of new anticancer agents entering the market. Although these agents are designed to target molecular pathways, off-target effects can manifest as life-threatening organ toxicity severe enough to warrant REMS. This review will summarize the various REMS for pharmaceutical agents used to treat cancer. TABLE 1 outlines the oncologic agents to date that require REMS, and TABLE 2 identifies oncologic agents recently removed from REMS.
Older Oncologic Agents
Isotretinoin (Accutane, Amnesteem, Claravis, Sotret): Isotretinoin, a derivative of retinoic acid, revolutionized the treatment of acne by providing a potentially curative option for patients with severe recalcitrant nodulocystic acne that is unresponsive to conventional therapies.3 Although approved only for severe acne, isotretinoin also has been used to treat malignancies such as neuroblastomas, basal and squamous cell skin cancers, and cutaneous T-cell lymphomas such as mycosis fungoides and Sézary syndrome.
The best-known adverse effect of isotretinoin is its severe teratogenic potential.4 An early attempt by the FDA and the sponsor of Accutane to reduce fetal exposure to isotretinoin involved the implementation of a risk-management program called S.M.A.R.T. (System to Manage Accutane Related Teratogenicity). Launched in 2002, S.M.A.R.T. featured office-based patient education including medication guides, standardized informed consent, yellow prescription qualification stickers, and dispensing restrictions. When S.M.A.R.T. failed to demonstrate a clear impact on the overall fetal isotretinoin exposure rate, the FDA required the manufacturers of isotretinoin to develop a more comprehensive risk-management system. In March 2006, a restricted-distribution program called iPLEDGE was implemented. iPLEDGE, a shared registry system, tracks isotretinoin users throughout their therapeutic course. The program strategy includes mandatory registration of prescribers, pharmacies, and wholesalers. To receive isotretinoin, a patient must be registered with iPLEDGE and meet all requirements. The program captures real-time results of pregnancy tests for verification prior to dispensing each month. Shortly after the FDAAA was passed, isotretinoin was added to the list of drugs requiring REMS, and in October 2010 the FDA approved iPLEDGE as a REMS element. The program covers all brand and generic isotretinoin products, and assessments of iPLEDGE performance are submitted annually to the FDA. Other required elements of the REMS appear in TABLE 1.
Thalidomide (Thalomid): First marketed in Europe as an OTC sedative, thalidomide was widely used by pregnant women for the treatment of nausea and vomiting. In 1961, following the recognition of numerous devastating cases of birth defects caused by the drug, thalidomide was withdrawn from the worldwide market.5 Today, thalidomide is used as an immunomodulating agent; it is FDA approved for the treatment of multiple myeloma in conjunction with dexamethasone, as well as for the treatment of skin manifestations secondary to erythema nodosum leprosum (ENL) and for postremission maintenance therapy to prevent ENL recurrence.6
Because of the potential for severe teratogenic effects, thalidomide is contraindicated in pregnant women and in women of childbearing potential unless the patient is using two forms of reliable contraception and provides proof of compliance with serial pregnancy testing while receiving therapy. The drug is contraindicated in sexually active men not using a latex condom.6 Thalidomide is available only through a restricted-distribution program called S.T.E.P.S. (System for Thalidomide Education and Prescribing Safety), a risk-mitigation strategy designed to prevent fetal toxicities associated with this medication. S.T.E.P.S. was implemented in 1998 as part of the approval process for ENL and subsequently was one of the first programs adopted for REMS. The S.T.E.P.S. program requires that all patients, pharmacists, and physicians be registered with the sponsor and that patients be tested for pregnancy prior to, during, and after treatment. S.T.E.P.S. update reports are submitted to the FDA every 3 years. Other elements of the REMS are summarized in TABLE 1.
Newer Oncologic Agents
Lenalidomide (Revlimid): Lenalidomide is an oral analogue of thalidomide that is approved for use in a subgroup of patients with transfusion-dependent myelodysplastic syndrome (MDS) harboring a deletion 5q chromosomal abnormality; it also is approved in combination with dexamethasone for use in patients with multiple myeloma who have received prior therapy.7 As with thalidomide, lenalidomide is contraindicated during pregnancy owing to its severe teratogenic potential.7 Since its approval for MDS in 2005, lenalidomide has been available only through a special restricted-distribution program, called RevAssist, that serves as a risk-mitigation program similar to S.T.E.P.S. Shortly after the passage of the FDAAA, RevAssist was adopted for REMS. Other elements of the REMS include a medication guide and an implementation system. The goals of the program are to prevent fetal exposure to lenalidomide and to educate patients and health care providers about the risks of therapy. The sponsor was required to submit REMS assessments at 6 months following the launch date and then annually. Unlike thalidomide, lenalidomide is available only through specialty pharmacies.
Nilotinib (Tasigna): Nilotinib is one of three TKIs approved to treat Philadelphia chromosome–positive chronic myelogenous leukemia (CML); the others are imatinib (Gleevec) and dasatinib (Sprycel). Specifically, nilotinib is a second-generation TKI approved for front-line treatment of chronic-phase (CP) CML and CP and accelerated-phase CML that is resistant or intolerant to imatinib.8 Nilotinib and dasatinib, a more potent generation of TKIs, produce deeper and faster responses than imatinib in the front-line setting.9,10 Despite similar mechanisms of action, the TKIs exhibit different adverse effects. Because of the risk of QT prolongation and reported episodes of sudden cardiac death with nilotinib, the FDA required a REMS for this TKI only. The REMS goal is to minimize the occurrence of QT prolongation and cardiac complications by educating prescribers and patients about the cardiac risks associated with nilotinib, the importance of minimizing potential drug–drug and drug–disease interactions, and the necessity of reducing medication errors involving drug–food interactions and incorrect dosing intervals.2 The REMS elements necessary for achieving these goals are a medication guide and a communication plan. Before initiating therapy, the patient should have a corrected QT assessment including a baseline cardiac history, ECG, serum electrolytes (potassium, calcium, and magnesium), and a review of concomitant medications. Electrolyte correction should be done before nilotinib is started and should be closely monitored throughout therapy. ECG should be repeated 7 days after nilotinib is initiated, and periodically thereafter as clinically indicated. Medications that are known to be strong CYP3A4 inhibitors and/or prolong the QT interval should be avoided.
Vandetanib (Caprelsa): Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection TK.11,12 Inhibition of these TKs interferes with multiple intracellular signaling pathways involved in tumor growth, progression, and angiogenesis.13,14 Vandetanib recently was approved for the treatment of medullary thyroid cancer based on the results of the ZETA trial, a phase III, multicenter, double-blind study that randomized 331 patients (2:1) with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg or placebo.15 In this pivotal study, vandetanib patients demonstrated a significant (P <.0001) improvement in progression-free survival compared with placebo. Vandetanib was the first drug approved by the FDA for the treatment of metastatic medullary thyroid cancer in adults who are ineligible for surgery.
QT prolongation and reports of torsades de pointes and sudden death are addressed in a boxed warning. In order to prescribe and dispense the drug, health care providers and pharmacies must be certified through the CAPRELSA REMS Program.16 Elements of the program are listed in TABLE 1. Program certification requires completion of prescriber education, training, and enrollment. Vandetanib is dispensed exclusively through a specialty pharmacy that partners with AstraZeneca. Patients should also receive an FDA-approved medication guide discussing the potential risks of QT prolongation associated with vandetanib.
Before therapy is initiated, a QT assessment should be made, including a baseline cardiac history, ECG, analysis of serum electrolytes (potassium, calcium, and magnesium) and thyroid-stimulating hormone, and a review of concomitant medications.16 Electrolytes should be corrected and all medications known to prolong QT should be avoided, if possible. ECG should be repeated at 2 to 4 weeks and 8 to 12 weeks after treatment with vandetanib is initiated, then every 3 months thereafter. Additionally, electrolytes should be closely monitored.
Ipilimumab (Yervoy): Ipilimumab is a fully humanized monoclonal antibody that targets the cytotoxic T-lymphocyte antigen (CTLA-4), a molecule on cytotoxic T-lymphocytes that is involved in the downregulation of T-cell response.17 Thus, inhibition of CTLA-4 activity potentiates an antitumor T-cell response. A phase III, randomized trial compared ipilimumab, ipilimumab plus glycoprotein 100 peptide vaccine (gp100), and gp100 alone in 676 patients with previously treated unresectable stage III or IV melanoma. Significantly, survival was prolonged by 3.6 months (10.0 vs. 6.4 months) in patients receiving ipilimumab with or without gp100, compared with those taking gp100 alone.18 Based on the improved survival data, the FDA approved ipilimumab for the treatment of adults with unresectable or metastatic melanoma.
Most adverse events reported for ipilimumab were immune-related and occurred in approximately 60% of ipilimumab patients, compared with 32% in those taking gp100 alone.18 The skin and the gastrointestinal tract were most often affected, and the most common immune-related event was diarrhea. Twelve of 14 deaths in the phase III study were related to ipilimumab.
Prompt medical attention and early initiation of corticosteroids are essential for managing serious immune-related adverse events.19 For this reason, the FDA mandated a REMS for ipilimumab to inform health care providers, cancer-treatment infusion centers, and cancer-related organizations about these potentially fatal immune-mediated toxicities (i.e., enterocolitis, hepatitis, skin toxicity, nervous-system toxicity, endocrinopathy).20 The REMS meets the minimum timetable for assessments, and approved elements include an extensive communication plan consisting of several components: a “dear healthcare provider” letter; a booklet designed to educate health care providers about the signs, symptoms, and medical management of treatment-mediated adverse reactions; and a nurse-directed checklist designed to foster recognition of early signs and symptoms of immune-mediated complications.21 Patients receive a medication guide and a wallet card listing their prescriber contact information and the symptoms associated with treatment.21
Conclusion
REMS serve as a tool to ultimately ensure patient safety while preserving the benefit of drug therapy. REMS continue to evolve and seemingly increase in number. Although targeted therapies are changing the way cancer is treated, they also may be associated with new toxicities. In many cases, these toxicities may not emerge until after the drug is approved. Several oncologic agents have recently been removed from REMS. Even after a drug is removed from REMS, the FDA-approved medication guide remains part of the approved labeling and provides important patient and provider education. It is important for pharmacists to stay abreast of not only the new oncologic agents and their associated toxicities, but also the drug-specific REMS requirements.
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