Amlodipine and Autoimmune Disease: Clinical Considerations

What amlodipine is labeled for

Amlodipine besylate (Norvasc) is a dihydropyridine calcium channel blocker sold as 2.5, 5 and 10 mg tablets; the brand was first approved in 1992 and generic tablets are widely available [1][2]. The labeled indications are hypertension, chronic stable angina, vasospastic (Prinzmetal) angina, and, in patients with recently documented coronary artery disease who do not have heart failure or an ejection fraction below 40%, reduction of angina hospitalizations and coronary revascularization procedures [1]. Autoimmune disease is not among them [1].

The drug inhibits calcium influx across cell membranes, with a greater effect on vascular smooth muscle than on cardiac muscle, and acts as a peripheral arterial vasodilator that lowers peripheral vascular resistance and blood pressure [1]. Onset is gradual and serum calcium is not affected [1]. Adult hypertension dosing starts at 5 mg once daily with a 10 mg maximum; the label allows 2.5 mg as a starting dose for small, fragile or elderly patients, for hepatic insufficiency, or when amlodipine is added to other antihypertensives, with 7 to 14 days between titration steps [1]. Known sensitivity to amlodipine is the only contraindication in the label, and there is no boxed warning [1].

Does amlodipine cause drug-induced lupus?

Drug-induced lupus is not named in the Norvasc label's clinical trial or postmarketing adverse reaction lists [1]. The label's under-1% list does include arthralgia, rash, angioedema, vasculitis and allergic reaction among events where a causal relationship is uncertain [1]. Postmarketing reports name gynecomastia, jaundice and hepatic enzyme elevations, and a possible association with extrapyramidal disorder [1].

A 2011 review in Drug Safety notes that early reports ranked procainamide and hydralazine as the drugs with the highest risk of drug-induced lupus and quinidine as moderate, with all other drugs considered low or very low risk [3]. That ranking is not specific to amlodipine. The same review notes that standardized diagnostic criteria for drug-induced lupus have not been established, that the diagnosis requires a link in timing between drug exposure and symptoms, and that symptoms generally resolve once the drug is stopped [3].

Adverse event reports cannot settle how often this happens: the FDA states that such reports cannot be used to estimate incidence and that a report does not establish that the drug caused the event [4].

Cyclosporine and tacrolimus: the autoimmune-relevant interactions

The label says amlodipine may increase the systemic exposure of cyclosporine or tacrolimus, recommends frequent monitoring of trough blood levels of both, and says to adjust the dose when appropriate [1].

For cyclosporine, trough levels rose by an average of 40% in a prospective study of 11 renal transplant patients given amlodipine [1]. For tacrolimus, exposure rose 2.5- to 4-fold in nine healthy Chinese volunteers who express CYP3A5, did not rise in six non-expressers, and rose 3-fold in one non-expresser renal transplant patient after amlodipine was started for post-transplant hypertension [1].

When a CYP3A inhibitor is added

The label says moderate and strong CYP3A inhibitors raise amlodipine exposure and may require a dose reduction, with monitoring for hypotension and edema [1]. Diltiazem 180 mg daily given with amlodipine 5 mg in elderly hypertensive patients raised amlodipine exposure by 60%; erythromycin did not significantly change exposure, but strong inhibitors such as itraconazole and clarithromycin may raise concentrations further [1].

In an Ontario retrospective cohort of older adults (mean age 76) taking a calcium channel blocker, more than half of them amlodipine, those newly given clarithromycin (n=96,226) had more outcomes within 30 days than those given azithromycin (n=94,083): hospitalization with acute kidney injury 0.44% vs 0.22% (odds ratio 1.98, 95% CI 1.68-2.34), hospitalization with hypotension 0.12% vs 0.07% (odds ratio 1.60), and death from any cause 1.02% vs 0.59% (odds ratio 1.74) [5].

Common effects and warnings in the label

Edema is the most common adverse reaction and is dose related: 1.8% at 2.5 mg, 3.0% at 5 mg and 10.8% at 10 mg, versus 0.6% on placebo [1]. It was more frequent in women (14.6% vs 5.1% on placebo) than in men (5.6% vs 1.4% on placebo) [1]. About 1.5% of patients stopped amlodipine for adverse reactions versus about 1% on placebo [1].

The label warns that symptomatic hypotension is possible, particularly in severe aortic stenosis, though acute hypotension is unlikely given the gradual onset [1]. Worsening angina and acute myocardial infarction can develop after starting or increasing the dose, particularly in severe obstructive coronary artery disease [1]. It advises slow titration in severe hepatic impairment, where the plasma half-life is 56 hours [1].

Pregnancy and breastfeeding

The label states that limited postmarketing data are not sufficient to inform a drug-associated risk of major birth defects or miscarriage [1]. In rats at about 10 times the maximum recommended human dose, litter size fell by about 50%, intrauterine deaths rose about 5-fold, and gestation and labor were prolonged [1]. Amlodipine is present in human milk at an estimated median relative infant dose of 4.2%, with no adverse effects observed in breastfed infants [1].