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LIPITOR Atorvastatin Calcium Tablets Warnings And Precautions

Warnings And Precautions

General
Before instituting therapy with LIPITOR (atorvastatin calcium), an attempt should be made to control elevated serum lipoprotein levels with appropriate diet, exercise, and weight reduction in overweight patients, and to treat other underlying medical problems (see INDICATIONS AND CLINICAL USE). Patients should be advised to inform subsequent physicians of the prior use of LIPITOR or any other lipid-lowering agents.

Pharmacokinetic Interactions
The use of HMG- CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are co-administered with drugs that inhibit the cytochrome P-450 enzyme system. Atorvastatin is metabolized by cytochrome P-450 isoform 3A4 and as such may interact with agents that inhibit this enzyme (see WARNINGS AND PRECAUTIONS, Muscle effects, and DRUG INTERACTIONS).

Muscle Effects
Effects on skeletal muscle such as myalgia, myositis, myopathy and rarely, rhabdomyolysis have been reported in patients treated with LIPITOR.

Rare cases of rhabdomyolysis, with acute renal failure secondary to myoglobinuria, have been reported with LIPITOR and with other HMG-CoA reductase inhibitors.

Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. LIPITOR therapy should be discontinued if markedly elevated CK levels are measured or myopathy is diagnosed or suspected.

Pre-disposing Factors for Myopathy/Rhabdomyolysis: LIPITOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:

  • Personal or family history of hereditary muscular disorders
  • Previous history of muscle toxicity with another HMG-CoA reductase inhibitor
  • Concomitant use of a fibrate, or niacin
  • Hypothyroidism
  • Alcohol abuse
  • Excessive physical exercise
  • Age > 65 years
  • Renal impairment
  • Hepatic impairment
  • Diabetes with hepatic fatty change
  • Surgery and trauma
  • Frailty
  • Situations where an increase in plasma levels of active ingredient may occur

The risk of myopathy and rhabdomyolysis is increased with concurrent administration of drugs that increase the systemic concentration of atorvastatin via CYP 3A4, such as cyclosporin, fibric acid derivatives, erythromycin, clarithromycin, letermovir, niacin (nicotinic acid), azole antifungals, nefazodone, colchicine, hepatitis C (HCV) protease inhibitors telaprevir, boceprevir, elbasvir/grazoprevir, glecaprevir/pibrentasvir and simeprevir, other human immunodeficiency virus (HIV) protease inhibitor fosamprenavir and each of the following HIV protease inhibitor combinations: saquinavir/ritonavir, lopinavir/ritonavir, tipranavir/ritonavir, darunavir/ritonavir and fosamprenavir/ritonavir. Concomitant use of LIPITOR with glecaprevir/pibrentasvir or cyclosporine is contraindicated. The combined therapy with LIPITOR and gemfibrozil, telaprevir or tipranavir/ritonavir should be avoided. LIPITOR dose restriction or caution is recommended for combined therapy with other CYP 3A4 inhibitors (see CONTRAINDICATIONS, Pharmacokinetic Interactions; DRUG INTERACTIONS, Drug-Drug Interactions; DETAILED PHARMACOLOGY, Human Pharmacokinetics).

The concurrent use of atorvastatin and fusidic acid should be avoided, therefore, temporary suspension of atorvastatin during fusidic acid therapy is advised (see DRUG INTERACTIONS, Drug-Drug Interactions).

Although patients with renal impairment are known to be predisposed to the development of rhabdomyolysis with administration of HMG-CoA reductase inhibitors (also known as statins), those with a history of renal impairment may also be predisposed to the development of rhabdomyolysis. Such patients merit close monitoring for skeletal muscle effects.

LIPITOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (such as sepsis, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use. IMNM is characterized by:

  • proximal muscle weakness and elevated creatine kinase, which persist despite discontinuation of statin treatment
  • muscle biopsy showing necrotizing myopathy without significant inflammation
  • improvement with immunosuppressive agents.

Cardiovascular

Hemorrhagic Stroke in Patients with Recent Stroke or Transient Ischemic Attack (TIA)
A post-hoc analysis of a clinical study in 4,731 patients without coronary heart disease (CHD) who had a stroke or TIA within the preceding six months revealed a higher incidence of hemorrhagic stroke in the atorvastatin 80mg group compared to placebo. Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke. The potential risk of hemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin in patients with recent (1-6 months) stroke or TIA.

Effect on Ubiquinone (CoQ10) Levels
Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term statin- induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure (see REFERENCES).

Endocrine and Metabolism

Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with atorvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with atorvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g. ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.

Increases in fasting glucose and HbA1c levels have been reported with inhibitors of HMG-CoA reductase as a class. For some patients, at high risk of diabetes mellitus, hyperglycemia was sufficient to shift them to the diabetes status. The benefit of treatment continues to outweigh the small increased risk. Periodic monitoring of these patients is recommended.

Effect on Lipoprotein (a)
In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in Lp(a) lipoprotein concentrations. Present knowledge suggests the importance of high Lp(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high risk patients placed on atorvastatin therapy (see REFERENCES).

Patients with Severe Hypercholesterolemia
Higher drug dosages (80 mg/day) required for some patients with severe hypercholesterolemia (including familial hypercholesterolemia) are associated with increased plasma levels of atorvastatin. Caution should be exercised in such patients who are also severely renally impaired, elderly, or are concomitantly being administered digoxin or CYP 3A4 inhibitors (see WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions, Muscle Effects; DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION).

Hepatic/Biliary/Pancreatic

Hepatic Effects
In clinical trials, persistent increases in serum transaminases greater than three times the upper limit of normal occurred in <1% of patients who received LIPITOR. When the dosage of LIPITOR was reduced, or when drug treatment was interrupted or discontinued, serum transaminase levels returned to pretreatment levels. The increases were generally not associated with jaundice or other clinical signs or symptoms. Most patients continued treatment with a reduced dose of LIPITOR without clinical sequelae. If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, particularly if they rise to greater than 3 times the upper limit of normal and are persistent, the dosage should be reduced or the drug discontinued.

Liver function tests should be performed before the initiation of treatment, and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIPITOR, promptly interrupt therapy. If an alternate etiology is not found, do not restart LIPITOR.

LIPITOR, as well as other HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of LIPITOR; if such a condition should develop during therapy, the drug should be discontinued.

Ophthalmologic

Effect on the Lens
Current long-term data from clinical trials do not indicate an adverse effect of atorvastatin on the human lens.

Renal

Renal Insufficiency
Plasma concentrations and LDL-C lowering efficacy of LIPITOR was shown to be similar in patients with moderate renal insufficiency compared with patients with normal renal function. However, since several cases of rhabdomyolysis have been reported in patients with a history of renal insufficiency of unknown severity, as a precautionary measure and pending further experience in renal disease, the lowest dose (10 mg/day) of LIPITOR should be used in these patients. Similar precautions apply in patients with severe renal insufficiency [creatinine clearance <30 mL/min (<0.5 mL/sec)]; the lowest dosage should be used and implemented cautiously (see WARNINGS AND PRECAUTIONS, Muscle Effects; DRUG INTERACTIONS). Refer also to DOSAGE AND ADMINISTRATION.

Sensitivity/Resistance

Hypersensitivity
An apparent hypersensitivity syndrome has been reported with other HMG-CoA reductase inhibitors which has included 1 or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. Although to date hypersensitivity syndrome has not been described as such, LIPITOR should be discontinued if hypersensitivity is suspected.

Special Populations

Use in Pregnancy: LIPITOR is contraindicated during pregnancy (see CONTRAINDICATIONS).

There are no data on the use of LIPITOR during pregnancy. LIPITOR 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 LIPITOR, the drug should be discontinued and the patient apprised of the potential risk to the fetus.

There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or fetuses. In rats, rabbits and dogs atorvastatin had no effect on fertility and was not teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of atorvastatin. In rats, there is evidence of placental transfer.

Use in Nursing Mothers: In rats, milk concentrations of atorvastatin are similar to those in plasma. It is not known whether this drug is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking LIPITOR should not breast-feed (see CONTRAINDICATIONS).

Pediatric Use: Safety and effectiveness of LIPITOR in patients 10-17 years of age (N=140) 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 LIPITOR had a safety and tolerability profile generally similar to that of placebo. Doses greater than 20 mg have not been studied in this patient population.

Safety and effectiveness of LIPITOR in pediatric patients has not been determined in the prevention of myocardial infarction.

LIPITOR had no effect on growth or sexual maturation in boys and in girls. The effects on menstrual cycle were not assessed [see PHARMACOLOGY, Clinical Studies section; ADVERSE REACTIONS, Pediatric Patients; and DOSAGE AND ADMINISTRATION for Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age)].

Adolescent females should be counselled on appropriate contraceptive methods while on LIPITOR therapy (see CONTRAINDICATIONS and PRECAUTIONS, Use in Pregnancy).

LIPITOR has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. For this patient population, there are limited data available from uncontrolled, open label studies (see ADVERSE REACTIONS, Heterozygous Familial Hypercholesterolemia in pediatric patients and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions: Pediatrics).

Doses of LIPITOR up to 80 mg/day for 1 year have been evaluated in 8 pediatric patients with homozygous familial hypercholesterolemia (see Clinical Studies - Heterozygous Familial Hypercholesterolemia in pediatric patients).

Geriatric Use: Treatment experience in adults 70 years or older (N=221) with doses of LIPITOR up to 80 mg/day has demonstrated that the safety and effectiveness of atorvastatin in this population was similar to that of patients <70 years of age. Pharmacokinetic evaluation of atorvastatin in subjects over the age of 65 years indicates an increased AUC. As a precautionary measure, the lowest dose should be administered initially (see DETAILED PHARMACOLOGY, Human Pharmacokinetics; REFERENCES).

Elderly patients may be more susceptible to myopathy (see WARNINGS – Muscle Effects – Pre- disposing Factors for Myopathy/Rhabdomyolysis).

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