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CADUET®Drug Interactions (amlodipine besilate, atorvastatin calcium)

7 DRUG 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 Cmax: 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 CADUET and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below:

Amlodipine

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Atorvastatin

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 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:
  1. Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended.
  2. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.
  3. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir do not exceed atorvastatin 20 mg.
  4. In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration (2)].
  5. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin
  6. 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's 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.
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