Interactions : אינטראקציות

8 DRUG INTERACTIONS

8.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with LIPITOR 
LIPITOR is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). LIPITOR 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 Lipitor 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 LIPITOR 
Cyclosporine or Gemfibrozil
Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Clinical Impact: 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 LIPITOR.
Intervention: Concomitant use of cyclosporine or gemfibrozil with LIPITOR is not recommended.
Anti-Viral Medications
Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of LIPITOR 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 LIPITOR.
Intervention: • Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with LIPITOR 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 LIPITOR 20 mg.
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• In patients taking nelfinavir, do not exceed LIPITOR 40 mg [see Dosage and Administration (3)].
• Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with LIPITOR.
• 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
Atorvastatin plasma levels were significantly increased with concomitant administration of Clinical Impact: LIPITOR with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3)].
In patients taking clarithromycin or itraconazole, do not exceed LIPITOR 20 mg [see Dosage and Administration (3)]. Consider the risk/benefit of concomitant use of other azole antifungals or Intervention: macrolide antibiotics with LIPITOR. 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
Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid Clinical Impact: modifying dosages of niacin (>1 gram/day niacin) with LIPITOR.
Consider if the benefit of using lipid modifying dosages of niacin concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, Intervention: 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)
Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is Clinical Impact: increased with concomitant use of fibrates with LIPITOR.
Consider if the benefit of using fibrates concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and Intervention: symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine Clinical Impact: with LIPITOR.
Consider the risk/benefit of concomitant use of colchicine with LIPITOR. If concomitant use is Intervention: decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can Clinical Impact: raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking Intervention:
LIPITOR.

8.2 Drug Interactions that may Decrease Exposure to LIPITOR

Table 4 presents drug interactions that may decrease exposure to LIPITOR and instructions for preventing or managing them.

Table 4: Drug Interactions that may Decrease Exposure to LIPITOR

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


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8.3 LIPITOR Effects on Other Drugs

Table 5 presents LIPITOR’s effect on other drugs and instructions for preventing or managing them.
Table 5: LIPITOR Effects on Other Drugs

Oral Contraceptives
Co-administration of LIPITOR and an oral contraceptive increased plasma concentrations of Clinical Impact: norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)].
Intervention:   Consider this when selecting an oral contraceptive for patients taking LIPITOR.
Digoxin
When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin Clinical Impact: concentrations increased [see Clinical Pharmacology (12.3)].
Intervention:   Monitor patients taking digoxin appropriately.