Atozet

Atozet

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ezetimibe, atorvastatin.
Description
ATOZET is available for oral use as tablets containing 10 mg of ezetimibe and: 10.9 mg of atorvastatin calcium, equivalent to 10 mg of atorvastatin (ATOZET 10 mg/10 mg); 21.7 mg of atorvastatin calcium, equivalent to 20 mg of atorvastatin (ATOZET 10 mg/20 mg); 43.4 mg of atorvastatin calcium, equivalent to 40 mg of atorvastatin (ATOZET 10 mg/40 mg); or 86.8 mg of atorvastatin calcium, equivalent to 80 mg of atorvastatin (ATOZET 10 mg/80 mg).
Action
Therapeutic Class: ATOZET (ezetimibe/atorvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.
Pharmacology: Pharmacodynamics: Mechanism of Action: ATOZET: Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. ATOZET contains ezetimibe and atorvastatin, two lipid-lowering compounds with complementary mechanisms of action. ATOZET reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe: Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol-reducing compounds (e.g., statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.
Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.
In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.
A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.
Atorvastatin: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
Pharmacokinetics: General Introduction: ATOZET: ATOZET has been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets.
Absorption: ATOZET The effects of a high-fat meal on the pharmacokinetics of ezetimibe and atorvastatin when administered as ATOZET tablets are comparable to those reported for the individual tablets.
Ezetimibe: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe 10-mg tablets.
Atorvastatin: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is approximately 12% 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.
Distribution: Ezetimibe: Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Atorvastatin: Mean volume of distribution of atorvastatin is approximately 381 l. Atorvastatin is ≥ 98% bound to plasma proteins.
Metabolism: Ezetimibe: Ezetimibe is metabolized primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.
Atorvastatin: Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. 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.
Elimination: Ezetimibe: Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Atorvastatin: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, the medicinal product does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.
Special Populations: Renal Impairment: Ezetimibe: After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 ml/min/1.73 m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9).
An additional patient in this study (post-renal transplant and receiving multiple medications, including cyclosporine) had a 12-fold greater exposure to total ezetimibe.
Atorvastatin: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Hepatic Impairment: Ezetimibe: After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic impairment. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score >9) hepatic impairment, ezetimibe is not recommended in these patients (see Hepatic Impairment under Precautions).
Atorvastatin: Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).
Pediatric: Ezetimibe: The pharmacokinetics of ezetimibe are similar between children ≥ 6 years and adults. Pharmacokinetic data in the pediatric population < 6 years of age are not available.
Atorvastatin: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.
Geriatric: Ezetimibe: Plasma concentrations for total ezetimibe are about 2-fold higher in the elderly (≥65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe.
Atorvastatin: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Race: Based on a meta analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between Blacks and Caucasians.
Gender: Ezetimibe: Plasma concentrations for total ezetimibe are slightly higher (<20 %) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe.
Atorvastatin: Concentrations of atorvastatin and its active metabolites in women differ from those in men (women: approx. 20% higher for Cmax and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
Hemodialysis: Atorvastatin 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.
Indications/Uses
Prevention of Cardiovascular Disease: ATOZET is indicated to reduce the risk of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, or need for revascularization) in patients with coronary heart disease (CHD).
Primary Hypercholesterolemia: ATOZET is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH): ATOZET is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).
Dosage/Direction for Use
General: The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with ATOZET. The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response. ATOZET can be administered as a single dose at any time of the day, with or without food.
Adults: Primary Hypercholesterolemia and/or Coronary Heart Disease: The dosage range of ATOZET is 10/10 to 10/80 mg once daily. The recommended starting dose of ATOZET is 10/10 or 10/20 mg once daily. Patients who require a larger reduction in LDL-C (more than 55%) may be started at 10/40 mg once daily. After initiation and/or upon titration of ATOZET, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly.
Dosage in Patients with Homozygous Familial Hypercholesterolemia: The dosage of ATOZET in patients with homozygous familial hypercholesterolemia is 10/40 or 10/80 mg daily. ATOZET should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Pediatric Patients: Treatment with ATOZET is not recommended.
Geriatric Patients: No dosage adjustment is required for elderly patients.
Renal Impairment: No dosage adjustment is required for renally impaired patients.
Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh score 5 to 6). Treatment with ATOZET is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score >9) liver dysfunction. (See Hepatic Impairment under Precautions.)
Coadministration with Bile Acid Sequestrants: Dosing of ATOZET should occur either ≥ 2 hours before or ≥ 4 hours after administration of a bile acid sequestrant.
Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents: In patients taking cyclosporine or the HIV protease inhibitors tipranavir plus ritonavir or the hepatitis C protease inhibitor telaprevir, therapy with ATOZET should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing ATOZET and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or the hepatitis C antiviral agents boceprevir, elbasvir, grazoprevir or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with ATOZET should be limited to 10/20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed. In patients taking the HIV protease inhibitor nelfinavir, therapy with ATOZET should be limited to 10/40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of ATOZET is employed. (See Myopathy/Rhabdomyolysis under Precautions.)
Other Concomitant Lipid-Lowering Therapy: The combination of ATOZET and fibrates is not recommended (see Fibrates under Precautions and Other Interactions under Interactions).
Overdosage
ATOZET: No specific treatment of overdosage with ATOZET can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed.
Ezetimibe: In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks, was generally well tolerated.
A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.
Atorvastatin: Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.
Contraindications
ATOZET is contraindicated in patients with hypersensitivity to ezetimibe, atorvastatin, or any of its inactive ingredients.
Active liver disease or unexplained persistent elevations of serum transaminases.
Pregnancy and nursing (see Use in Pregnancy & Lactation).
Warnings
Contraindication in pregnancy and breastfeeding.
Contraindication in patients with liver disease.
This drug should be discontinued and physicians should be consulted if patients develop symptoms of myalgia at calf, back or body.
Liver function tests should be performed before treatment begins and 6 and 12 weeks thereafter. Patients who take this drug regularly should have Liver function test every 6 months or as recommended by physicians. If transaminase levels rise to > 3 times the upper limit of normal, patients should stop taking the drug and consult a physician.
Caution should be exercised when taken concomitantly with digoxin or warfarin because serum concentration of digoxin or warfarin will be elevated and may be harmful.
The risk of myopathy or rhabdomyolysis may be increased when concomitant use of statin drug with the following drugs: azole antifungals e.g. ketoconazole, itraconazole etc., macrolide antibiotics e.g. erythromycin, clarithromycin etc., HIV protease inhibitors e.g. indinavir, ritonavir, nelfinavir, saquinavir etc., verapamil, diltiazem, gemfibrozil, nicotinic acid, cyclosporine, amiodarone, etc.
The risk of rhabdomyolysis may be increased in patients who are taking higher doses, elderly, have hepatic or renal impairment, alcoholism, hypothyroidism etc.
Caution should be exercised when statins are taken concomitantly with colchicine especially in elderly or patients with renal impairment because the risk of myopathy or rhabdomyolysis may occur.
The risk of higher levels of blood sugar may be increased.
Special Precautions
Myopathy/Rhabdomyolysis: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CPK values >10 times ULN. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ATOZET. ATOZET therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected (see Adverse Reactions).
The risk of myopathy during treatment with statins is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C antiviral agents telaprevir, elbasvir, grazoprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with ATOZET and fibric acid derivatives, erythromycin, clarithromycin, elbasvir, grazoprevir, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of ATOZET should be considered when taken concomitantly with the aforementioned drugs. (See CYP3A4 Interactions under Interactions.) Periodic CPK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in the table (see Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents under Dosage & Administration, and CYP3A4 Interactions under Interactions). (See table.)

Click on icon to see table/diagram/image

Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ATOZET with colchicine (see Other Interactions under Interactions).
Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA reductase inhibitors coadministered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to suspending ATOZET temporarily in patients taking daptomycin (see Other Interactions under Interactions).
ATOZET therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Liver Enzymes: In controlled coadministration trials in patients receiving ezetimibe with atorvastatin, consecutive transaminase elevations (≥3 X the upper limit of normal [ULN]) have been observed. (See Adverse Reactions.)
Atorvastatin, like some other lipid-lowering therapies, has been associated with biochemical abnormalities of liver function.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with ATOZET 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 ATOZET, promptly interrupt therapy. If an alternate etiology is not found, do not restart ATOZET.
ATOZET should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin (see Contraindications).
Endocrine Function: Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins 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. Caution should be exercised if ATOZET is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Hepatic Impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ATOZET is not recommended in these patients.
Fibrates (see Other Interactions under Interactions): Gemfibrozil: Concomitant administration of ATOZET with gemfibrozil should be avoided.
Fenofibrate: Caution should be used when prescribing ATOZET and fenofibrate, as fenofibrate can cause myopathy when give alone.
If cholelithiasis is suspected in a patient receiving ATOZET and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see the product labeling for fenofibrate and fenofibric acid).
Other fibrates: The coadministration of ezetimibe with other fibrates has not been studied. Therefore, coadministration of ATOZET and other fibrates is not recommended.
Fusidic acid: Patients on fusidic acid treated concomitantly with ATOZET may have an increased risk of myopathy/rhabdomyolysis (see Other Interactions under Interactions). Coadministration with fusidic acid is not recommended. In patients where the use of systemic fusidic acid is considered essential, ATOZET should be discontinued throughout the duration of fusidic acid treatment. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g. for the treatment of severe infections, the need for coadministration of ATOZET and fusidic acid should only be considered on a case-by-case basis under close medical supervision.
Anticoagulants: If ATOZET is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored (see Other Interactions under Interactions).
Use in Patients with Recent Stroke or TIA: In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo. The incidence of fatal hemorrhagic stroke was similar across treatment groups. The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group as compared to the placebo group. Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
Effects on ability to drive and use machines: No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects that have been reported with ATOZET may affect some patients' ability to drive or operate machinery. Individual responses to ATOZET may vary. (See Adverse Reactions.)
Use in Children: There are insufficient data for the safe and effective use of ATOZET in pediatric patients.
Use In Pregnancy & Lactation
Pregnancy: 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.
ATOZET: ATOZET is contraindicated during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ATOZET may cause fetal harm when administered to pregnant women. ATOZET should be discontinued as soon as pregnancy is recognized (see Contraindications). Advise females of reproductive potential to use effective contraception during treatment with ATOZET.
Ezetimibe: No clinical data on exposed pregnancies are available. Animal studies of ezetimibe administered alone do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
When ezetimibe was given with statins, no teratogenic effects were observed in embryo-fetal development studies in pregnant rats. In pregnant rabbits, a low incidence of skeletal malformations was observed.
Atorvastatin: Limited published data on atorvastatin from observational studies, meta-analyses and case reports have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a greater than or equal to three-to-four-fold increase in congenital anomalies over background incidence. In 89% of theprospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses 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 was observed at doses ≥ 6 times the MRHD.
Nursing Mothers: ATOZET: ATOZET is contraindicated in nursing mothers. Because of the potential for serious adverse reactions in a breastfed infant, women who are nursing should not take ATOZET.
Ezetimibe: Studies in rats have shown that ezetimibe and atorvastatin are excreted in milk. It is not known whether ezetimibe is excreted into human breast milk.
Atorvastatin: There is no available information on the effects of atorvastatin on the breastfed infant or the effects of atorvastatin on milk production. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk.
Adverse Reactions
Clinical Trials Experience: Adults: ATOZET: ATOZET (or coadministration of ezetimibe and atorvastatin equivalent to ATOZET) has been evaluated for safety in more than 2400 patients in 7 clinical trials. ATOZET was generally well tolerated.
The following common (≥1/100, <1/10) or uncommon (≥1/1000, <1/100) drug-related adverse experiences were reported in patients taking ATOZET: Infections and Infestations: Uncommon: influenza.
Psychiatric disorders: Uncommon: depression; insomnia; sleep disorder.
Nervous system disorders: Uncommon: dizziness; dysgeusia; headache; paresthesia.
Cardiac disorders: Uncommon: sinus bradycardia.
Vascular disorders: Uncommon: hot flush.
Respiratory, thoracic and mediastinal disorders: Uncommon: dyspnea.
Gastrointestinal disorders: Common: diarrhea.
Uncommon: abdominal discomfort; abdominal distension; abdominal pain; abdominal pain lower; abdominal pain upper; constipation; dyspepsia; flatulence; frequent bowel movements; gastritis; nausea; stomach discomfort.
Skin and subcutaneous tissue disorders: Uncommon: acne; urticarial.
Musculoskeletal and connective tissue disorders: Common: myalgia.
Uncommon: arthralgia; back pain; muscle fatigue; muscle spasms; muscular weakness; pain in extremity.
General disorders and administration site conditions: Uncommon: asthenia; fatigue; malaise; edema.
Investigations: Uncommon: ALT and/or AST increased; alkaline phosphatase increased; blood CK increased; gamma-glutamyltransferase increased; hepatic enzyme increased; liver function test abnormal; weight increased.
In controlled clinical trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 X ULN, consecutive) was 0.6% for patients treated with ATOZET. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline spontaneously or after discontinuation of therapy. (See Liver Enzymes under Precautions.)
None of the patients treated with ATOZET had CK levels ≥10 X ULN.
Post-marketing Experience and Other Clinical Trial Experience: The following additional adverse reactions have been reported in post-marketing use with ATOZET or in clinical studies or post-marketing use with ezetimibe or atorvastatin: Infections and infestations: nasopharyngitis.
Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.
Metabolism and nutrition disorders: decreased appetite; anorexia; hyperglycemia; hypoglycemia.
Psychiatric disorders: nightmares.
Nervous system disorders: hypesthesia; peripheral neuropathy.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Eye disorders: vision blurred; vision disturbance.
Ear and labyrinth disorders: tinnitus; hearing loss.
Vascular disorders: hypertension.
Respiratory, thoracic, and mediastinal disorders: cough; pharyngolaryngeal pain; epistaxis.
Gastrointestinal disorders: dry mouth; pancreatitis; gastroesophageal reflux disease; eructation; vomiting.
Hepatobiliary disorders: hepatitis; cholelithiasis; cholecystitis; cholestasis.
Skin and subcutaneous tissue disorders: alopecia; pruritus; skin rash; erythema multiforme; angioneurotic oedema; dermatitis bullous including erythema multiforme; Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: myopathy/rhabdomyolysis (see Myopathy/Rhabdomyolysis under Precautions); neck pain; joint swelling; myositis; tendonopathy, sometimes complicated by rupture.
There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents (see Myopathy/Rhabdomyolysis under Precautions).
Reproductive system and breast disorders: gynecomastia.
General disorders and administration site conditions: chest pain; pain; edema peripheral; pyrexia.
Investigations: white blood cells urine positive.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
The following adverse events have been reported with some statins: sexual dysfunction; depression; exceptional cases of interstitial lung disease, especially with long term therapy; diabetes mellitus: frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension).
Drug Interactions
ATOZET: No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with atorvastatin.
Multiple mechanisms may contribute to potential interactions with HMG Co-A reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase atorvastatin plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with atorvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
CYP3A4 Interactions: In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.
Inhibitors of cytochrome P3A4 increase the risk of myopathy by reducing the elimination of the atorvastatin component of ATOZET (see Myopathy/Rhabdomyolysis under Precautions): Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of 80 mg atorvastatin with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone. Therefore, in patients taking clarithromycin, caution should be used when the ATOZET dose exceeds 10/20 mg (see Myopathy/Rhabdomyolysis under Precautions, and Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents under Dosage & Administration).
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of ATOZET should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing ATOZET, and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, or the hepatitis C protease inhibitor boceprevir, the dose of ATOZET should not exceed 10/20 mg and should be used with caution (see Myopathy/Rhabdomyolysis under Precautions, and Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents under Dosage & Administration). In patients taking the HIV protease inhibitor nelfinavir, the dose of ATOZET should not exceed 10/40 mg and close clinical monitoring is recommended.
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg. Therefore, in patients taking itraconazole, caution should be used when the ATOZET dose exceeds 10/20 mg.
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).
Cyclosporine: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of cyclosporine, a single 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3- to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see Myopathy/Rhabdomyolysis under Precautions).
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 atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone. The coadministration of ATOZET with cyclosporine should be avoided (see Myopathy/Rhabdomyolysis under Precautions).
Other Interactions: Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant. Coadministration of atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased plasma concentrations of atorvastatin and its active metabolites approximately 35%; however, LDL-C reduction was not altered.
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.
Fibrates (see Fibrates under Precautions): Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of ATOZET with gemfibrozil should be avoided.
In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available.
Fenofibrate: Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fenofibrate, ATOZET should be administered with caution when used concomitantly with fenofibrate.
In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.
Other fibrates: The safety and effectiveness of ezetimibe administered with other fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, coadministration of ATOZET with other fibrates is not recommended until use in patients is studied.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid (see Myopathy/Rhabdomyolysis under Precautions).
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased INR in patients who had ezetimibe added to warfarin or fluindione. Most of these patients were also on other medications. (See Anticoagulants.)
Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
The effect of ATOZET on the prothrombin time has not been studied.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Atorvastatin is a substrate of the efflux transporter BCRP. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin may be necessary. Coadministration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin by 1.9-fold due in part to CYP3A and/or BCRP inhibition; therefore, the dose of ATOZET should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Myopathy/Rhabdomyolysis under Precautions).
Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin 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 coadministration 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.
Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.
Colestipol: Plasma concentrations of atorvastatin decreased approximately 25% when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.
Digoxin: When multiple doses of atorvastatin and digoxin were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Amlodipine: In a drug-drug interaction study in healthy subjects, coadministration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin that was not clinically meaningful.
Niacin: The risk of skeletal muscle effects may be enhanced when ATOZET is used in combination with niacin; a reduction in ATOZET dosage should be considered in this setting (see Myopathy/Rhabdomyolysis under Precautions).
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ATOZET with colchicine.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin (see Myopathy/Rhabdomyolysis under Precautions).
Storage
Store below 30°C. Store in the original package.
ATC Classification
C10BA05 - atorvastatin and ezetimibe ; Belongs to the class of HMG CoA reductase inhibitors in combination with other lipid modifying agents. Used in the treatment of hyperlipidemia.
Presentation/Packing
10/10 mg FC tab (white to off-white capsule-shaped, biconvex with code "257" on one side) 30's. 10/20 mg FC tab (white to off-white capsule-shaped, biconvex, with code "333" on one side) 30's. 10/40 mg FC tab (white to off-white capsule-shaped, biconvex with code "337" on one side.) 30's. 10/80 mg FC tab (white to off-white capsule-shaped, biconvex with code "357" on one side) 30's.
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