Lipitor (Page 4 of 10)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of LIPITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with LIPITOR therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)] .

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

7 DRUG INTERACTIONS

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 CYP 3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .

7.1 Strong Inhibitors of CYP 3A4

LIPITOR is metabolized by cytochrome P450 3A4. Concomitant administration of LIPITOR with strong inhibitors of CYP 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 CYP 3A4.

Clarithromycin

Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 80 mg with clarithromycin (500 mg twice daily) compared to that of LIPITOR alone [see Clinical Pharmacology (12.3)] . Therefore, in patients taking clarithromycin, caution should be used when the LIPITOR dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .

Combination of Protease Inhibitors

Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR with several combinations of protease inhibitors [see Clinical Pharmacology (12.3)] . In patients taking tipranavir plus ritonavir or glecaprevir plus pibrentasvir, concomitant use of LIPITOR should be avoided. In patients taking lopinavir plus ritonavir, or simeprevir, use the lowest necessary LIPITOR dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of LIPITOR should not exceed 20 mg. In patients taking nelfinavir the dose of LIPITOR should not exceed 40 mg and close clinical monitoring is recommended [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .

Itraconazole

Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)] . Therefore, in patients taking itraconazole, caution should be used when the LIPITOR dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)] .

7.2 Grapefruit Juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).

7.3 Cyclosporine

Atorvastatin is a substrate of the hepatic transporters. Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 10 mg and cyclosporine 5.2 mg/kg/day compared to that of LIPITOR alone [see Clinical Pharmacology (12.3)] .

The co-administration of LIPITOR with cyclosporine should be avoided [see Warnings and Precautions (5.1)] .

7.4 Glecaprevir and Pibrentasvir; Elbasvir and Grazoprevir

Concomitant administration of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.

Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministration of LIPITOR in patients receiving concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.

Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of LIPITOR should not exceed 20 mg daily in patients receiving concomitant medications with products containing elbasvir and grazoprevir [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] .

7.5 Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of LIPITOR with gemfibrozil should be avoided [see Warnings and Precautions (5.1)] .

7.6 Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, LIPITOR should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1)] .

7.7 Niacin

The risk of skeletal muscle effects may be enhanced when LIPITOR is used in combination with niacin; a reduction in LIPITOR dosage should be considered in this setting [see Warnings and Precautions (5.1)] .

7.8 Rifampin or other Inducers of Cytochrome P450 3A4

Concomitant administration of LIPITOR 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, simultaneous co-administration of LIPITOR with rifampin is recommended, as delayed administration of LIPITOR after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

7.9 Digoxin

When multiple doses of LIPITOR and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)]. Patients taking digoxin should be monitored appropriately.

7.10 Oral Contraceptives

Co-administration of LIPITOR and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)] . These increases should be considered when selecting an oral contraceptive for a woman taking LIPITOR.

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