Norvasc Protect 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 C_max: 91% (90% confidence interval [CI]: 80%-103%), but the AUC of atorvastatin increased by 18% (90% CI: 109%-127%) in the presence of amlodipine.
No drug interaction studies have been conducted with Amlodipine besilate/Atorvastatin calcium (Norvasc Protect) and other drugs, although studies have been conducted using the individual amlodipine and atorvastatin components, as described as follows: Amlodipine Interactions: Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg of amlodipine in elderly hypertensive patients (69-87 years of age) resulted in a 57% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers (18-43 years of age) did not significantly change amlodipine systemic exposure (22% increase in AUC). Although the clinical relevance of these findings is uncertain, the pharmacokinetic variations may be more pronounced in the elderly.
Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors.
Clarithromycin: Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.
CYP3A4 Inducers: There are no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. The study did not allow examination of the effect of genetic polymorphism in CYP3A4, the primary enzyme responsible for metabolism of amlodipine; therefore, administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased BP-lowering effects.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin, or indomethacin).
In the following studies, there were no significant changes in the pharmacokinetics of either amlodipine or another drug within the study, when co-administered.
Special Studies: Effect of Other Agents on Amlodipine: Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Aluminum/Magnesium (Antacid): Co-administration of an aluminum/magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own BP-lowering effect.
Special Studies: Effect of Amlodipine on Other Agents: Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients. Various studies in renal transplant patients report that amlodipine co-administration with cyclosporine affect trough concentrations of cyclosporine from no change up to an average increase of 40%. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
Drug/Laboratory Test Interactions: None known.
Atorvastatin Interactions: The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying doses of niacin or cytochrome P450 3A4/transporter inhibitors (e.g., erythromycin and azole antifungals) (see as follows and also Use in Combination with Other Medicinal Compounds under Dosage & Administration and Skeletal Muscle Effects under Precautions).
Inhibitors of Cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on cytochrome P450 3A4.
Erythromycin/Clarithromycin: Co-administration of atorvastatin and erythromycin (500 mg four times daily) or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Skeletal Muscle Effects under Precautions and Pharmacology: Pharmacokinetics under Actions).
Protease Inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Diltiazem Hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin (see Pharmacology: Pharmacokinetics under Actions).
Cimetidine: An atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen (see Pharmacology: Pharmacokinetics under Actions).
Itraconazole: Concomitant administration of atorvastatin (20-40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC (see Pharmacology: Pharmacokinetics under Actions).
Grapefruit Juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L/day) (see Pharmacology: Pharmacokinetics under Actions).
Transporter Inhibitors: Atorvastatin is a substrate of the hepatic transporters (see Pharmacology: Pharmacokinetics under Actions).
Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (ratio of AUC: 8.7; see Pharmacology: Pharmacokinetics under Actions). Cyclosporine is an inhibitor of organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, multi-drug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP) as well as CYP3A4, thus it increases exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Do not exceed 10 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29; see Pharmacology: Pharmacokinetics under Actions). Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin daily (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
The magnitude of CYP3A- and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine.
Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Use with caution and lowest dose necessary (see Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations (see Pharmacology: Pharmacokinetics under Actions).
Antacids: Co-administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides decreased atorvastatin plasma concentrations (ratio of AUC: 0.66); however, LDL-C reduction was not altered.
Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.
Colestipol: Plasma concentrations of atorvastatin were lower (ratio of concentration: 0.74) when colestipol was administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg of atorvastatin were co-administered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased (ratio of AUC: 1.15) following administration of digoxin with 80 mg of atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Azithromycin: Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.
Oral Contraceptives: Co-administration of atorvastatin with an oral contraceptive containing norethindrone and ethinyl estradiol increased the area under the concentration versus time curve (AUC) values for norethindrone (ratio of AUC: 1.28) and ethinyl estradiol (ratio of AUC: 1.19), respectively. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: An atorvastatin interaction study with warfarin was conducted, and no clinically significant interactions were observed.
Fusidic Acid: Although interaction studies with atorvastatin and fusidic acid have not been conducted, there is an increased risk of rhabdomyolysis in patients receiving a combination of statins, including atorvastatin, and fusidic acid. The mechanism of this interaction is not known. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should only be considered on a case by case basis and under close medical supervision. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Colchicine: Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Other Concomitant Therapy: In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.