AMLODIPINE Drug Interactions: What You Need to Know

INTERACTIONS Data from a drug-drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine are not altered when the drugs are co-administered. The effect of amlodipine on the pharmacokinetics of atorvastatin showed no effect on the C max : 91% (90% confidence interval: 80 to 103%), but the AUC of atorvastatin increased by 18% (90% confidence interval: 109 to 127%) in the presence of amlodipine, which is not clinically meaningful. No drug interaction studies have been conducted with amlodipine besylate and atorvastatin calcium and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: Amlodipine Increased Risk of Myopathy and Rhabdomyolysis ( 2 , 5.1 , 7.3 , 12.3 ) Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir,letermovir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Consider the risk/benefit of concomitant use with atorvastatin Other Lipid-Lowering Medications: Increased risk of myopathy (7) . Rifampin should be simultaneously co-administered with atorvastatin ( 7.4 ).

Oral

Contraceptives: Norethindrone and ethinyl estradiol may be increased ( 7.5 ). Digoxin: Patients should be monitored appropriately ( 7.5 ).

7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span>. CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Sildenafil

Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology ( 12.2 ) ].

7.2 Impact of Amlodipine on Other Drugs Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 ) ]</span>.

Atorvastatin

The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology ( 12.3 ) ].

7.3 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters.

Table

3 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Table

3: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [ see Clinical Pharmacology ( 12.3) ]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin. Intervention : Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [ see Clinical Pharmacology (12.3 )]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention : Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir,fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg. In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration ( 2 )].Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.

Select Azole

Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [ see Clinical Pharmacology ( 12.3 )]. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [ see Dosage and Administration ( 2 )]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

Niacin Clinical

Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (>1 gram/day niacin) with atorvastatin. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil)

Clinical

Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Colchicine Clinical

Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention : Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Grapefruit Juice Clinical

Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin.

7.4 Drug Interactions that may Decrease Exposure to Atorvastatin Table 4 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them.

Table

4: Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention : Administer atorvastatin and rifampin simultaneously.

7.5 Atorvastatin Effects on Other Drugs Table 5 presents atorvastatin effect on other drugs and instructions for preventing or managing them.

Table

5: Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [ see Clinical Pharmacology ( 12.3 )]. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin.

Digoxin Clinical

Impact : When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [ see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor patients taking digoxin appropriately.

4 CONTRAINDICATIONS

• Do not coadminister aliskiren with angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, including amlodipine and benazepril hydrochloride capsules in patients with diabetes.
• Amlodipine and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, to amlodipine, or to any of the excipients of amlodipine and benazepril hydrochloride capsules.
• Amlodipine and benazepril hydrochloride capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride capsules within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan [see Warnings and Precautions (5.1) ].
• Do not coadminister aliskiren with ACE inhibitors, including amlodipine and benazepril hydrochloride capsules, in patients with diabetes. (4)
• Amlodipine and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema or patients who are hypersensitive to benazepril or to amlodipine. (4)
• Amlodipine and benazepril hydrochloride capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride capsules within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan. ( 4 )

AND PRECAUTIONS Anticipate hypotension in volume-or salt-depleted patients with treatment initiation. Start treatment under close supervision ( 5.2 ). Increased angina or myocardial infarction may occur upon dosage initiation or increase ( 5.3 ). Impaired renal function: changes in renal function may occur ( 5.4 ). Sprue-like enteropathy has been reported. Consider discontinuation of amlodipine and olmesartan medoxomil tablets in cases where no other etiology is found ( 5.6 ).

5.1 Fetal Toxicity Amlodipine and olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets as soon as possible [ see Use in Specific Populations ( 8.1 )].

5.2 Hypotension in Volume- or Salt-Depleted Patients Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with amlodipine and olmesartan medoxomil tablets under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.3 Increased Angina or Myocardial Infarction Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

5.4 Impaired Renal Function Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with amlodipine and olmesartan medoxomil tablets because of the olmesartan medoxomil component <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]</span> . In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and amlodipine and olmesartan medoxomil tablets.

5.5 Patients with Hepatic Impairment Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of amlodipine and olmesartan medoxomil tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in hepatically impaired patients <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> . Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½ ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Sprue-like Enteropathy Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of amlodipine and olmesartan medoxomil tablets in cases where no other etiology is identified.

5.7 Electrolyte Imbalances Amlodipine and olmesartan medoxomil tablets contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

5.1 Fetal Toxicity Amlodipine and olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets as soon as possible [ see Use in Specific Populations ( 8.1 )].

5.2 Hypotension in Volume- or Salt-Depleted Patients Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with amlodipine and olmesartan medoxomil tablets under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.3 Increased Angina or Myocardial Infarction Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

5.4 Impaired Renal Function Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with amlodipine and olmesartan medoxomil tablets because of the olmesartan medoxomil component <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]</span> . In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and amlodipine and olmesartan medoxomil tablets.

5.5 Patients with Hepatic Impairment Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of amlodipine and olmesartan medoxomil tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in hepatically impaired patients <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> . Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½ ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Sprue-like Enteropathy Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of amlodipine and olmesartan medoxomil tablets in cases where no other etiology is identified.

5.7 Electrolyte Imbalances Amlodipine and olmesartan medoxomil tablets contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.