Are there prescription medicines I should avoid if I am taking amlodipine?

Online databases of drug-drug interactions are available that list medications to be avoided or used with caution when taking amlodipine.¹ The majority of these drugs are metabolized by or interfere with the function of the enzyme CYP3A4. In addition, other medicines that lower blood pressure taken together with amlodipine can increase the anti-hypertensive effect and should be used with caution, and blood pressure effects monitored closely.²

CYP3A4 is a liver enzyme used to clear amlodipine and other drugs from the body. Drugs called CYP3A4 inhibitors interact with amlodipine (a CYP3A4 substrate) and can increase amlodipine levels in the body. These include some, but not all, antibiotics and protease inhibitors used to treat viruses like HIV and hepatitis C.^3–6 Other CYP3A4 substrates, like simvastatin, may be elevated in the blood stream when taken at the same time as amlodipine.^7–9 In these instances, amlodipine is acting as a CYP3A4 inhibitor.

Some CYP3A4 drugs have been tested in patients taking amlodipine. Results of these studies suggest that amlodipine and other drugs that enhance or inhibit availability of CYP3A4 should be used together cautiously, or not at all, and the patient should be monitored for drug effects or toxicity when these drugs are co-administered.^7,10–16 Some of these studies are summarized below.

Statins

Wang et al measured clinical outcomes in patients taking both a calcium channel blocker (CCB) that inhibits CYP3A4, including amlodipine, and a statin in a population-based cohort study between 1997 and 2011.⁷ Patients who received CYP3A4-metabolized statins along with the CCB, had significantly higher risk of acute kidney injury (adjusted odds ration [OR] =2.12; 95% confidence interval [CI]=1.35–3.35), hyperkalemia (adjusted OR=2.94; CI=1.36–6.35), acute myocardial infarction (adjusted OR=1.55; CI=1.16–2.07), and acute ischemic stroke (adjusted OR=1.35; CI=1.08–1.68) than those who received non-CYP3A4-metabolized statins. The authors recommend caution when co-prescribing CYP3A-metabolized statins, such as simvastatin, with CCBs that inhibit CYP3A4, like amlodipine.

Zhou et al conducted a systematic literature review searching for reports of drug-drug interactions between dihydropyridine calcium channel-blockers (DHP-CCBs) and statins from 1987 to 2013.⁹ Three articles were identified that specifically reported the effects of the co-administration of amlodipine and simvastatin.^10,11,17 In all three, the concurrent dosing of amlodipine and simvastatin resulted in increased levels of simvastatin. One article developed a model to estimate the optimal simvastatin levels when the drug is co-administered with amlodipine.¹⁷ The authors determined that patients needed to take 60% of the usual simvastatin dose to achieve therapeutic levels when it is co-administered with amlodipine.

Clopidogrel

Lexicomp drug interaction database considers the combination of clopidogrel and amlodipine a risk category C: monitor therapy. Gremmel  et al used a prospective observational analysis to study the interaction of the anti-platelet agent, clopidogrel, with CCBs in 162 patients who were followed after stent placement.¹² All patients were taking the anti-platelet therapy clopidogrel, 53 of whom were also taking a CCB, of which, 44 were taking amlodipine. The patients taking any CCB therapy had significantly higher platelet reactivity than those who were not (p < 0.001). A multivariate regression analysis confirmed that CCB therapy was an independent predictor of reduced effectiveness of the platelet inhibitor.

A systematic literature search of PubMed, MEDLINE, Web of Science, and the Cochrane Library analyzed drug-drug interactions between clopidogrel and other medications, including CCBs.¹³  The authors concluded that clopidogrel efficacy is expected to be reduced when taken with CCBs. Drug therapy with clopidogrel may need to be tailored in patients who continue with CCB therapy while on antiplatelet therapy.

Clarithromycin

Lexicomp drug interaction database considers the combination of clarithromycin and amlodipine a risk category D: consider therapy modification. Gandhi et al conducted a population-based retrospective cohort study from 2003 to 2012 that studied patients who had taken a CCB, the majority of which had taken amlodipine, and one of two macrolide antibiotics, either clarithromycin (n= 96,226) or azithromycin (n=94,083).¹⁴ Clarithromycin is a CYP3A4 inhibitor while azithromycin is not. Patients taking any CCB with clarithromycin had a significantly higher risk of hospitalization with acute kidney injury (420 patients of 96,226 taking clarithromycin [0.44%] vs 208 patients of 94,083 taking azithromycin [0.22%]; odds ratio [OR], 1.98 [CI, 1.68-2.34]). Coadministration of a calcium channel blocker and clarithromycin also resulted in a higher risk of hospitalization for hypotension (111 patients taking clarithromycin [0.12%] versus 68 of patients taking azithromycin [0.07%]; (OR =1.6, CI = 1.18-2.16) and all-cause mortality. 984 (1.02%) of patients taking clarithromycin versus 555 (0.59%) of patients taking azithromycin died during the period of study (OR, 1.74 [CI 1.57-1.93]).

Indinavir and Ritonavir

In a randomized open-label drug interaction study, Glesby et al measured the plasma drug concentration over time (referred to as the area under the curve, or AUC) of amlodipine among 18 healthy HIV-seronegative volunteers before and after taking indinavir and ritonavir.¹⁸ Mean AUC of amlodipine over 24 hours increased from 122 ng · h/mL before taking the protease inhibitors to 230 ng · h/mL after taking the protease inhibitor (p < 0.0001), while the AUC of these protease inhibitors was unchanged over the same time. The authors concluded that if amlodipine and these protease inhibitors must be given together, the dosage of amlodipine should start low and be titrated upwards carefully.

Cyclosporine

Cai, Huang, and Yang et al followed 150 kidney transplant patients with hypertension who were taking cyclosporine to reduce the risk of organ rejection.¹⁵ The patients were randomly assigned treatment with amlodipine 5 mg or valsartan 80 mg for their hypertension. Blood pressure and plasma levels of cyclosporine were measured over the 24-week trial.  Although both antihypertensives produced a satisfactory reduction of blood pressure, patients in the amlodipine group had a significantly greater reduction of diastolic blood pressure than those in the valsartan group.  However, the administration of amlodipine significantly increased the plasma concentration of cyclosporine, compared to the patients taking valsartan. The authors conclude that plasma concentrations of cyclosporine should be monitored closely in transplant patients who are taking amlodipine.

Antiviral Agents for Hepatitis C Virus

Menon et al studied the drug-drug interactions of anti-viral drugs used to treat hepatitis C with amlodipine and other drugs.¹⁶ Coadministration of amlodipine with the combination regimen of ombitasvir (OBV), paritaprevir with ritonavir (PTV/r), and dasabuvir (DSV) increased amlodipine AUC by 157%, and decreased PTV AUC by 22%. Ritonavir, OBV, and DSV exposures were unaffected. The authors concluded that no dosage changes were needed in the antiviral regimen. The need for changes in the amlodipine regimen was not discussed.

Lee et al conducted an open-label non-randomized study of 21 healthy volunteers taking combination amlodipine-atorvastatin intermittently during their treatment with the protease inhibitor telaprevir.¹⁹ Plasma levels of each drug were measured several times during the 28-day study. The authors found that simultaneous use of telaprevir and amlodipine resulted in overexposure to amlodipine.

Sildenafil

Webb et al studied the effects of sildenafil combined with blood-pressure lowering drugs, including amlodipine, in a double-blind placebo-controlled crossover study.²⁰ Sixteen hypertensive men who were taking 5 mg or 10 mg of amlodipine received a single dose of sildenafil 100 mg or placebo two hours after their usual dose of amlodipine. Blood pressure levels were taken before and after dosing with sildenafil or placebo and plasma levels of amlodipine were obtained before the sildenafil dosing and for regular intervals up to eight hours after dosing.The bioavailability of amlodipine was not altered significantly by the dosing with sildenafil. A single 100 mg dose of sildenafil taken two hours after a dose of amlodipine (5 or 10 mg) was associated with significant decreases in mean maximum supine and standing systolic and diastolic blood pressures compared with placebo plus amlodipine. Supine systolic pressure dropped 8 mm Hg more and diastolic pressure dropped 7 mmHg more after sildenafil than after placebo (p < 0.002).

^References

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