Felodipine is a second generation calcium channel blocker and commonly used antihypertensive agent. Felodipine therapy has been associated with a low rate of serum enzyme elevations, but has not been convincingly linked to instances of clinically apparent, acute liver injury.
Felodipine (fe loe' di peen) belongs to the dihydropyridine group of calcium channel blockers (with amlodipine, isradipine and nifedipine) and is used primarily in the therapy of hypertension. Like other calcium channel blockers, felodipine acts by blocking the influx of calcium ions into vascular smooth muscle and cardiac muscle cells during depolarization, which results in arterial vasodilation and decrease in cardiac work and oxygen consumption. Felodipine was approved in the United States in 1991 and currently more than 3 million prescriptions are filled yearly. The current sole indication is treatment of hypertension, either alone or with other antihypertensive agents. Felodipine is available in multiple generic forms and under the commercial name Plendil in 2.5, 5 and 10 mg extended release tablets. The recommended dose in adults is 2.5 to 10 mg once daily, generally starting at the lowest dose and adjusting upward. Like other calcium channel blockers, felodipine is generally well tolerated, but side effects can include dizziness, flushing, headache, fatigue, nausea, diarrhea, peripheral edema, palpitations and rash.
Hepatotoxicity, Outcome and Management
Felodipine therapy has been associated with low rates of serum enzyme elevations (<1% to 5%) which in many studies were no higher than occurred with placebo. ALT elevations were usually mild, asymptomatic and transient and often resolved even with continuation of therapy. Despite 20 years of clinical use, cases of clinically apparent liver injury due to felodipine have not been published. Thus, acute liver injury due to felodipine must be rare, if it occurs at all.
Likelihood score: E (Unlikely cause of clinically apparent liver injury).
Felodipine, however, can have significant drug-drug interactions. Felodipine is metabolized by the cytochrome P450 enzyme, CYP3A4, which is found in intestine and liver. Grapefruit juice can increases felodipine levels by inhibiting expression of intestinal CYP3A4 which ordinarily metabolizes it. Similarly, systemic drugs that inhibit CYP 3A4 (such as itraconazole or cimetidine) can increase and drugs that stimulate CYP 3A4 (such as phenytoin or phenobarbital) can lower felodipine levels significantly. Because felodipine can interact with other agents that are metabolized by the hepatic microsomal enzyme system, it may affect the risk of hepatotoxicity with other agents.
REPRESENTATIVE TRADE NAMES
Felodipine – Generic, Plendil®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 11 January 2017
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Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. FEVER Study Group. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005; 23: 2157-72. PubMed Citation (A trial in 9800 patients treated with diuretics with or without felodipine for an average of 3 years reported no liver related adverse events).
Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. PubMed Citation (Summary of 25 years of adverse drug reaction reporting in Sweden identified 103 cases of drug induced acute liver failure; felodipine was possibly linked one case, but another hepatotoxic agent was being used [details not provided]).
Frishman WH, Hainer JW, Sugg J; M-FACT Study Group. A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT). Am J Hypertens 2006; 19: 388-95. PubMed Citation (In a controlled trial of multiple combinations of metoprolol and felodipine or placebo in 1092 patients with hypertension, no liver related side effects were reported).
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of literature of drug induced liver injury in Latin American countries published
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due to calcium channel blockers [amlodipine in 1 and verapamil in 3
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