Is Rosuvastatin a Calcium Channel Blocker? No, It's a Statin

What class of drug is rosuvastatin?

Rosuvastatin is a statin. It inhibits HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a cholesterol precursor [1]. Amlodipine belongs to a different class: it is a dihydropyridine calcium channel blocker that inhibits calcium ion 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 [2].

Crestor is labeled to reduce the risk of major adverse cardiovascular events in adults at increased risk. As an adjunct to diet and exercise it is labeled to lower LDL-C in adults with primary hypercholesterolemia, in children aged 8 and older with heterozygous familial hypercholesterolemia, and in children aged 7 and older with the homozygous form. As an adjunct to diet it is also labeled for adults with primary dysbetalipoproteinemia or hypertriglyceridemia [1]. Norvasc is labeled for hypertension, chronic stable angina, vasospastic angina, and, in patients with angiographically documented coronary artery disease who do not have heart failure or an ejection fraction below 40%, to reduce hospitalization for angina and coronary revascularization procedures [2].

Rosuvastatin carries no blood pressure indication and amlodipine carries no lipid indication [1][2].

What evidence supports each drug on its own?

JUPITER randomized 17,802 apparently healthy men aged 50 and older and women aged 60 and older with LDL-C under 130 mg/dL and hsCRP of 2.0 mg/L or higher to rosuvastatin 20 mg daily or placebo. It stopped early at a median of 1.9 years: LDL-C fell 50% and hsCRP 37%, and the primary endpoint of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina or cardiovascular death occurred at 0.77 vs 1.36 per 100 person-years (HR 0.56, 95% CI 0.46 to 0.69) [4].

CAMELOT randomized 1991 patients with angiographically documented coronary artery disease and diastolic blood pressure under 100 mm Hg (baseline 129/78) to amlodipine 10 mg, enalapril 20 mg or placebo for 24 months. Cardiovascular events occurred in 110 patients (16.6%) on amlodipine and 151 (23.1%) on placebo (HR 0.69, 95% CI 0.54 to 0.88, P=0.003), while blood pressure fell 4.8/2.5 mm Hg on amlodipine and 4.9/2.4 on enalapril [5].

ASCOT-BPLA randomized 19,257 hypertensive patients aged 40 to 79 with at least three other cardiovascular risk factors to an amlodipine-based regimen (adding perindopril as needed) or an atenolol-based regimen, and stopped after a median of 5.5 years. The primary endpoint of nonfatal myocardial infarction and fatal coronary heart disease was not significantly different (429 vs 474 events; HR 0.90, 95% CI 0.79 to 1.02), but total cardiovascular events and procedures were fewer (1362 vs 1602; HR 0.84), as were strokes (327 vs 422; HR 0.77) and all-cause deaths (738 vs 820; HR 0.89) [6].

Can you take rosuvastatin and amlodipine together?

The two labels describe the relevant interactions for each drug separately. Amlodipine is a weak CYP3A inhibitor, and its documented statin interaction is with simvastatin: amlodipine 10 mg raised simvastatin exposure 77%, and the Norvasc label limits simvastatin to 20 mg daily in patients taking amlodipine [2]. Rosuvastatin's clearance does not depend on CYP3A4 to a clinically significant extent; itraconazole, a strong CYP3A4 inhibitor, raised rosuvastatin AUC only about 1.4-fold [1]. The Norvasc label also states that co-administered amlodipine does not affect exposure to atorvastatin [3], and a fixed-dose tablet combining amlodipine with atorvastatin (Caduet, approved in 2004) exists [3].

If a switch happens, what changes?

A switch is not a dose-for-dose swap. The dose numbers are not comparable: rosuvastatin is labeled at 5 to 40 mg once daily and amlodipine at 5 to 10 mg once daily [1][2]. Each drug has a different job: rosuvastatin is labeled for lipid lowering and cardiovascular risk reduction, and amlodipine for blood pressure and angina [1][2].

Dosing rules from each label

The Crestor label says it can be taken at any time of day, with or without food, and that the AUC does not differ between evening and morning dosing; LDL-C is assessed as early as 4 weeks after starting [1]. Aluminum or magnesium hydroxide antacid taken at the same time cut rosuvastatin AUC by about 50%, and the label says to take Crestor at least 2 hours before the antacid [1]. For Asian patients the label recommends a starting dose of 5 mg once daily and reports approximately 2-fold higher median exposure than in White controls [1][7]. In severe renal impairment (creatinine clearance under 30 mL/min/1.73 m2, not on hemodialysis), the label says start at 5 mg and do not exceed 10 mg daily [1].

The Norvasc label gives a usual starting dose of 5 mg once daily with a maximum of 10 mg. It says patients who are small, fragile or elderly, patients with hepatic insufficiency, and patients adding amlodipine to other antihypertensives may start at 2.5 mg, and that 7 to 14 days should pass between titration steps [2]. The terminal half-life is about 30 to 50 hours and the labeled regimen is once daily [2]. Renal impairment does not significantly change amlodipine pharmacokinetics, while elderly patients and those with hepatic insufficiency have roughly 40% to 60% higher AUC [2].

What side effects does each carry?

Amlodipine's dose-related effects in the label's placebo-controlled trials: edema in 1.8% at 2.5 mg, 3.0% at 5 mg and 10.8% at 10 mg vs 0.6% on placebo; dizziness 1.1%, 3.4% and 3.4% vs 1.5%; flushing 0.7%, 1.4% and 2.6% vs 0.0%; palpitation 0.7%, 1.4% and 4.5% vs 0.6% [2]. Edema was more frequent in women (14.6% vs 5.1% on placebo), and discontinuation for adverse reactions was about 1.5% vs about 1% [2]. Gingival hyperplasia and angioedema are listed among events seen in under 1% of patients, where a causal relationship is uncertain [2]. The label also warns that worsening angina and acute myocardial infarction can develop after starting or increasing the dose, particularly in severe obstructive coronary artery disease, and that symptomatic hypotension is possible, particularly in severe aortic stenosis [2].

Rosuvastatin: in 12-week placebo-controlled trials, myalgia 2.8% vs 1.3%, headache 5.5% vs 5.0% and nausea 3.4% vs 3.1% [1]. In JUPITER, myalgia 7.6% vs 6.6%, arthralgia 3.8% vs 3.2%, and diabetes mellitus reported in 2.8% vs 2.3%, with mean HbA1c 0.1% higher on rosuvastatin [1]. Transaminases above 3 times the upper limit of normal occurred in 1.1% on Crestor vs 0.5% on placebo in pooled trials [1]. The label carries a myopathy and rhabdomyolysis warning and says patients should be told to promptly report unexplained muscle pain, tenderness or weakness, particularly with malaise or fever; risk factors include age 65 or older, uncontrolled hypothyroidism, renal impairment, certain other drugs and higher doses, and Asian patients may be at higher risk [1].

What else interacts with each drug?

For amlodipine, diltiazem 180 mg daily with amlodipine 5 mg raised amlodipine exposure 60%, and the label says to monitor for hypotension and edema [2]. In an Ontario cohort of adults with a mean age of 76, adding clarithromycin rather than azithromycin to a calcium channel blocker (amlodipine in more than half) was associated with 30-day hospitalization for acute kidney injury in 0.44% vs 0.22% (OR 1.98, 95% CI 1.68 to 2.34) [8]. Amlodipine may raise cyclosporine trough levels by about 40% and tacrolimus exposure 2.5- to 4-fold in CYP3A5 expressers [2].

For rosuvastatin, the label caps the dose at 5 mg daily with cyclosporine, says to avoid gemfibrozil (or if unavoidable start at 5 mg and do not exceed 10 mg), and sets dose limits with several HIV and hepatitis C antivirals [1]. It also notes that rosuvastatin significantly increased the INR in patients on warfarin and says to check INR before starting and often enough after starting, titration or stopping [1].