Interchangeability, Safety and Efficacy of Modified-Release Drug Formulations in the USA: The Case of Opioid and Other Nervous System Drugs

• Published in: Clinical drug investigation 2016-04, Vol.36 (4), p.281-292
• Main Authors: Seoane-Vazquez, Enrique, Rodriguez-Monguio, Rosa, Hansen, Richard
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - administration & dosage; Analgesics, Opioid - adverse effects; Analgesics, Opioid - therapeutic use; Antidepressive Agents, Second-Generation - administration & dosage; Antidepressive Agents, Second-Generation - adverse effects; Antidepressive Agents, Second-Generation - therapeutic use; Bupropion - administration & dosage; Bupropion - adverse effects; Bupropion - therapeutic use; Centers for Medicare and Medicaid Services (U.S.); Central Nervous System Agents - administration & dosage; Central Nervous System Agents - adverse effects; Central Nervous System Agents - therapeutic use; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - therapeutic use; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Overdose - epidemiology; Drugs, Generic; Humans; Internal Medicine; Medicine; Medicine & Public Health; Methylphenidate - administration & dosage; Methylphenidate - adverse effects; Methylphenidate - therapeutic use; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Product Surveillance, Postmarketing; Psychotropic Drugs - administration & dosage; Psychotropic Drugs - adverse effects; Psychotropic Drugs - therapeutic use; Risk Assessment; Therapeutic Equivalency; United States; United States Food and Drug Administration
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-015-0374-7

Background and Objectives Modified-release drugs may provide clinical advantages compared to immediate-release forms and improve convenience to the patient and health outcomes. Concerns have been raised regarding interchangeability, efficacy, and safety of modified-release formulations. This study analyses all US Food and Drug Administration (FDA)-approved modified-release formulations and market trends, and illustrates how bioequivalence and safety of generic modified-release products compare to their respective brand name drugs and other generic drugs with different formulation design characteristics. This study also examines major concerns related to modified-release formulations: safety of opioids and bioequivalence of generic bupropion and methylphenidate. Methods Study data were derived from the FDA electronic versions of the FDA’s Orange Book (OB) and the FDA safety communications web page. Medicare Part D utilization and expenditures data were extracted from the Centers for Medicare and Medicaid. Results In May 2015, 276 (11.9 %) of the 2325 active ingredients and fixed-dose combinations listed in the FDA’s Orange Book had at least one modified-release form approved by the FDA. The number of approvals increased over time; 52.5 % of modified releases were approved in the period 2000–May 2015. The FDA required a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of extended-release opioids outweighed its risks of overdose and abuse. The REMS involved 16 new drug applications and 25 abbreviated new drug applications. Conclusions The FDA addressed interchangeability problems with generic modified-release alternatives of bupropion and methylphenidate including lack of bioequivalence, reduced efficacy, and increased incidence of adverse events. Systematic post-marketing surveillance studies are needed to assess differences in safety, interchangeability, and efficacy of drugs with modified- and immediate-release formulations.