Atorvastatin Calcium Drug Information

Important Dosage Information

Take atorvastatin calcium tablets orally once daily at any time of the day, with or without food. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust the dosage if necessary.

Recommended Dosage in Adult Patients

The recommended starting dosage of atorvastatin calcium tablets are 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily.

Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended starting dosage of atorvastatin calcium tablets are 10 mg once daily.

Dosage Modifications Due to Drug Interactions

Concomitant use of atorvastatin calcium tablets with the following drugs requires dosage modification of atorvastatin calcium tablets. Anti-Viral Medications In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium tablets 20 mg once daily. In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg once daily.

Select Azole Antifungals or Macrolide Antibiotics In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium tablets 20 mg once daily. For additional recommendations regarding concomitant use of atorvastatin calcium tablets with other anti-viral medications, azole antifungals or macrolide antibiotics, see Drug Interactions.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin Calcium- Treated with any Dose and Greater than Placebo Other adverse reactions reported in placebo-controlled trials include: Body as a whole: malaise, pyrexia Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous system: nightmare Respiratory system: epistaxis Skin and appendages: urticaria Special senses: vision blurred, tinnitus Urogenital system: white blood cells urine positive Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin calcium in clinical trials.

The incidence of these abnormalities was mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms.

Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin calcium. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin group (0.3%) compared to the low-dose atorvastatin group (0.1%).

Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium vs. 18 placebo).

The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin calcium vs. 4% placebo). Adverse Reactions from Clinical Studies of Atorvastatin Calcium in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of atorvastatin calcium. 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. Gastrointestinal disorders: pancreatitis General disorders: fatigue Hepatobiliary Disorders: fatal and non-fatal hepatic failure Immune system disorders: anaphylaxis Injury: tendon rupture Musculoskeletal and connective tissue disorders: rhabdomyolysis, myositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Nervous system disorders: dizziness, peripheral neuropathy. There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins.

Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric disorders: depression Respiratory disorders: interstitial lung disease Skin and subcutaneous tissue disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them.

Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2).

Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking nelfinavir, do not exceed atorvastatin 40 mg. 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 Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.

Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Table 3 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them. Table 3: Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Intervention: Administer atorvastatin and rifampin simultaneously.

Atorvastatin Calcium Effects on Other Drugs Table 4 presents

Atorvastatin’s effect on other drugs and instructions for preventing or managing them. Table 4: Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin.

Digoxin Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased. Intervention: Monitor patients taking digoxin appropriately.

Pregnancy Risk Summary Discontinue atorvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.

Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data).

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus.

There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. 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 at the MRHD based on surface area (mg/m 2 ).

In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. 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).

Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma.

Pediatric Use The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of atorvastatin calcium for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls.

The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH. The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH).

Acute liver failure or decompensated cirrhosis Hypersensitivity to atorvastatin or any excipients in atorvastatin calcium. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported. Acute liver failure or decompensated cirrhosis.

Hypersensitivity to atorvastatin or any excipient in atorvastatin calcium.

No specific antidotes for atorvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.