Lipitor (Page 4 of 11)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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, fatigue, tendon rupture, hepatic failure, dizziness, memory impairment, depression, and peripheral neuropathy.

6.3 Pediatric Patients (ages 10–17 years)

In a 26-week controlled study in boys and postmenarchal girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of LIPITOR 10 to 20 mg daily was generally similar to that of placebo [see Clinical Studies (14.6) and Use in Special Populations, Pediatric Use (8.4)].

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 protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (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 Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 40 mg with ritonavir plus saquinavir (400 mg twice daily) or LIPITOR 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) compared to that of LIPITOR alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking HIV protease inhibitors, caution should be used when the LIPITOR dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].
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 Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)].

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 and 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)]. In cases where co-administration of LIPITOR with cyclosporine is necessary, the dose of LIPITOR should not exceed 10 mg [see Warnings and Precautions, Skeletal Muscle (5.1)].

7.4 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.

7.5 Digoxin

When multiple doses of LIPITOR and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.

7.6 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.

7.7 Warfarin

LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

LIPITOR is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.

There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2) [see Contraindications, Pregnancy (4.3)].

In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day.

Statins may cause fetal harm when administered to a pregnant woman. LIPITOR should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking LIPITOR, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.

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