ATORVASTATIN CALCIUM (atorvastatin calcium propylene glycol solvate 20 mg) Dailymed

Women who are pregnant or may become pregnant. Atorvastatin may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of atorvastatin use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. ATORVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see ].  

Women who are pregnant or may become pregnant. Atorvastatin may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of atorvastatin use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. ATORVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ].  

It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require atorvastatin treatment should not breastfeed their infants [see ].

Pregnancy Category X 

Pregnancy Category X  Atorvastatin calcium 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. Atorvastatin calcium 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  atorvastatin calcium, 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.

It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin treatment should be advised not to nurse their infants [see ].

Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6) ; Adverse Reactions, Pediatric Patients (ages 10 to 17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ]. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia (14.5) ].

Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2) ]. Distribution: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3) ].  Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.  Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Specific Populations Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5) ].  Pediatric: Pharmacokinetic data in the pediatric population are not available.  Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.  Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5) , Warnings and Precautions, Skeletal Muscle (5.1) ].  Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.  Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1) ].  TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin Dose (mg) Change in AUC Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). Change in Cmax See Sections 5.1 and 7 for clinical significance.Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold Telaprevir 750 mg q8h, 10 days 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold , The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20% Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold Grapefruit Juice, 240 mL QDGreater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). 40 mg, SD ↑ 37% ↑ 16% Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38% Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 % Cimetidine 300 mg QD, 4 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11% Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26%Single sample taken 8 to 16 h post dose. Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34% Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1% Rifampin 600 mg QD, 7 days (co-administered)Due to the dual interaction mechanism of rifampin, 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. 40 mg SD ↑ 30% ↑ 2.7 fold Rifampin 600 mg QD, 5 days (doses separated) 40 mg SD ↓ 80% ↓ 40% Gemfibrozil 600mg BID, 7 days 40mg SD ↑ 35% ↓ Less than 1% Fenofibrate 160mg QD, 7 days 40mg SD ↑ 3% ↑ 2% TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Change in AUC Change in Cmax 80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11% 80 mg QD for 14 days See Section 7 for clinical significance.Digoxin 0.25 mg QD, 20 days ↑ 15% ↑ 20 % 40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1mg - ethinyl estradiol 35µg ↑ 28% ↑ 19% ↑ 23%↑ 30% 10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change 10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% ↓ 18% 10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin calcium tablets. Discuss future pregnancy plans with your patients, and discuss when to stop atorvastatin calcium tablets if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking atorvastatin calcium tablets and call their healthcare professional.

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin calcium tablets. Discuss future pregnancy plans with your patients, and discuss when to stop atorvastatin calcium tablets if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking atorvastatin calcium tablets and call their healthcare professional.