Lipitor

/ Dexcel Pharma Technologies Ltd

General: Before instituting therapy with this product , an attempt should be made to control hypercholesterolemia with appropriate diet, exercise and weight reduction in obese patients, and to treat underlying medical problems. patient should continue on a standard cholesterol lowering diet during treatment withthis product. The usual starting dose is 10 mg or 20 mg once daily. The dosage range is 10 to 80 mg once daily. Starting and maintenance doses should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response. Adjustment of dosage should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Doses may be given at any time of day with or without food. After initiation and/or upon titration of this product, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. Therapy with lipid-altering agents should be a component of multiple-risk-factor intervention in individuals at increased risk for atherosclerotic vascular disease due to hypercholesterolemia. For full details see prescribing information.

Hypercholesterolemia: Adjunct to diet for the treatment of elevated total and LDL cholesterol, apolipoprotein B and triglycerides and to increase HDL-cholesterol in patients with primary hypercholesterolemia including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb) when response to diet and other non-pharmaceutical measures alone has been inadequate. To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments.
Pediatric patients (10-17 years of age): As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains equal to or higher than 190 mg/dL, or b. LDL-C remains equal to or higher than 160 mg/dL and there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient.
Prevention of cardiovascular disease: Prevention of cardiovascular and/or cerebrovascular events such as MI or stroke: As an adjunct to correction of other risk factors such as hypertension in patients with three or more additional risk factors or diabetes with one additional risk factor.

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

Myopathy and Rhabdomyolysis:
This medicinal product may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK] and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin.
Risk Factors for Myopathy: Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher dosage.
Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis: Atorvastatin exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with this medicinal product is not recommended. Dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications. Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis.
Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin.
Discontinue atorvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if atorvastatin is discontinued. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).
Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Atorvastatin should be discontinued in case of de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia.
Immune-Mediated Necrotizing Myopathy:
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase, that persists despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue atorvastatin if IMNM is suspected.
Hepatic Dysfunction:
Increases in serum transaminases have been reported. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving this product in clinical trials.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin.
Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.
Consider liver enzyme testing before initiation and when clinically indicated thereafter. This medicinal product is contraindicated in patients with acute liver failure or decompensated cirrhosis. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin.
Increases in HbA1c and Fasting Serum Glucose Levels:
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.
Increased Risk of Hemorrhagic Stroke in Patients on LIPITOR 80 mg with Recent Hemorrhagic Stroke:
Consider the risk/benefit of use of LIPITOR 80 mg in patients with recent hemorrhagic stroke
See prescribing information for full details.

Common adverse reaction: Nasopharyngitis, arthralgia, diarrhea, pain in extremity, urinary tract infection, dyspepsia, nausea, musculoskeletal pain, muscle spasms, myalgia, insomnia, pharyngolaryngeal pain.
Other important adverse reactions: Myopathy and rhabdomyolysis, immune-mediated necrotizing myopathy, hepatic dysfunction, increases in HbA1c and fasting serum glucose levels.
See prescribing information for full details.

Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with this drug:
This drug is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Its plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters.
Cyclosporine or Gemfibrozil
Atorvastatin plasma levels were significantly increased with concomitant administration of this drug and cyclosporine, an inhibitor of CYP3A4 and OATP1B1. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with this drug. Concomitant use of cyclosporine or gemfibrozil with this drug is not recommended.
Anti-Viral Medications
Atorvastatin plasma levels were significantly increased with concomitant administration of this drug with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2). Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with this drug.
• Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with this drug is not recommended.
• In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.
• In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed 20 mg.
• In patients taking nelfinavir, do not exceed 40 mg.
• Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with this drug.
• Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
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:
Atorvastatin plasma levels were significantly increased with concomitant administration of this drug with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters.
In patients taking clarithromycin or itraconazole, do not exceed 20 mg.  Consider the risk/benefit of concomitant use of other azole antifungals or
macrolide antibiotics with this drug. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:
Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (>1 gram/day niacin) with this drug.
Consider if the benefit of using lipid modifying dosages of niacin concomitantly with this drug outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with this drug.
Consider if the benefit of using fibrates concomitantly with this drug outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with this drug.
Consider the risk/benefit of concomitant use of colchicine with this drug. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking this drug.
Drug Interactions that may Decrease Exposure to this drug
Rifampin
Concomitant administration of this drug with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of this drug after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Administer this drug and rifampin simultaneously.
Effects on Other Drugs
Oral Contraceptives
Co-administration of this drug and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol.
Consider this when selecting an oral contraceptive for patients taking this drug.
Digoxin
When multiple doses of this drug and digoxin were co-administered, steady state plasma digoxin concentrations increased.
Monitor patients taking digoxin appropriately.
For full details see prescribing information.

pregnancy:
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. 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/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD.
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 2-4% and 15-20%, respectively.
See prescribing information for full details.
Lactation:
There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in. animal milk, it is likely that the drug will be present in human milk. Statins, including atorvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with this medicinal product.
See prescribing information for full details.

No specific antidotes for atorvastatin are known. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.