Liptruzet(atorvastatin/ezetimibe)TH

Liptruzet
(atorvastatin/ezetimibe)
THERAPEUTIC CLASS

Cholesterol absorption inhibitor/HMG-CoA reductase inhibitor (statin)
DEA CLASS

RX
INDICATIONS

Adjunct to diet to reduce elevated total cholesterol (total-C), LDL-C, apolipoprotein B, TGs, and non-HDL-C, and to increase HDL-C in patients w/ primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. Reduce elevated total-C and LDL-C in patients w/ homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.
ADULT DOSAGE
Primary Hyperlipidemia/Mixed Hyperlipidemia

Initial: 10mg/10mg/day or 10mg/20mg/day as a single dose at any time of the day
Range: 10mg/10mg to 10mg/80mg qd
Titrate: After initiation and/or upon titration, analyze lipid levels w/in ≥2 weeks and adjust dose, if needed

Patients Requiring Larger LDL Reduction (>55%):
Initial: 10mg/40mg/day
Homozygous Familial Hypercholesterolemia

10mg/40mg/day or 10mg/80mg/day
DOSING CONSIDERATIONS

Concomitant Medications
Bile Acid Sequestrants: Take either ≥2 hrs before or ≥4 hrs after bile acid sequestrant
Cyclosporine, Tipranavir Plus Ritonavir (RTV), Telaprevir, Gemfibrozil: Avoid therapy w/ Liptruzet
Lopinavir Plus RTV: Use caution; use lowest dose of Liptruzet necessary
Clarithromycin, Itraconazole, Saquinavir Plus RTV, Darunavir Plus RTV, Fosamprenavir, Fosamprenavir Plus RTV:
Max: 10mg/20mg/day
Nelfinavir, Boceprevir:
Max: 10mg/40mg/day
ADMINISTRATION

Oral route

Take w/ or w/o food
Swallow tab whole; do not crush, dissolve, or chew
HOW SUPPLIED

Tab: (Ezetimibe/Atorvastatin) 10mg/10mg, 10mg/20mg, 10mg/40mg, 10mg/80mg
CONTRAINDICATIONS

Active liver disease or unexplained persistent elevations in hepatic transaminase levels, women who are or may become pregnant, nursing mothers.
WARNINGS/PRECAUTIONS

Has not been studied in Fredrickson type I, III, IV, and V dyslipidemias. Myopathy (including immune-mediated necrotizing myopathy [IMNM]) and rhabdomyolysis reported; d/c if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Temporarily withhold or d/c therapy in any patient w/ an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic/endocrine/electrolyte disorders, uncontrolled seizures). Liver enzyme elevations and fatal and nonfatal hepatic failure (rare) reported; obtain LFTs prior to initiating therapy and repeat as clinically indicated; promptly interrupt therapy if serious liver injury w/ clinical symptoms and/or hyperbilirubinemia or jaundice occurs and do not restart if no alternative etiology found. Caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Increases in HbA1c and FPG levels reported. May blunt adrenal and/or gonadal steroid production. Increased risk of hemorrhagic stroke in patients w/ recent stroke or transient ischemic attack (TIA). Caution in elderly.
ADVERSE REACTIONS

Increased ALT/AST, musculoskeletal pain, abdominal pain, nausea, arthralgia.
DRUG INTERACTIONS

See Dosing Considerations. Caution w/ drugs that decrease levels or activity of endogenous steroid hormones (eg, ketoconazole, spironolactone, cimetidine). Increased risk of myopathy w/ fibric acid derivatives, erythromycin, lipid-modifying doses of niacin, strong CYP3A4 inhibitors (eg, clarithromycin, HIV protease inhibitors), and azole antifungals; consider lower initial and maint doses. Monitor INR levels when used w/ warfarin. Atorvastatin: Strong CYP3A4 inhibitors, grapefruit juice, saquinavir plus ritonavir, diltiazem, and amlodipine may increase levels. Itraconazole may increase exposure. Myopathy, including rhabdomyolysis, reported w/ colchicine; use w/ caution. OATP1B1 inhibitors may increase bioavailability. May increase levels of digoxin; monitor appropriately. May increase exposure of norethindrone and ethinyl estradiol. CYP3A4 inducers (eg, efavirenz, rifampin) may decrease levels; simultaneous coadministration w/ rifampin is recommended. Ezetimibe: Cholestyramine may decrease exposure of total ezetimibe.
PREGNANCY AND LACTATION

Category X, not for use in nursing.
MECHANISM OF ACTION

Atorvastatin: HMG-CoA reductase inhibitor; 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; also reduces LDL production and the number of LDL particles. Ezetimibe: Cholesterol absorption inhibitor; localizes at the brush border of the small intestine and inhibits absorption of cholesterol and decreases intestinal cholesterol delivery to the liver.
PHARMACOKINETICS

Absorption: Atorvastatin: Absolute bioavailability (14%); Tmax=1-2 hrs. Distribution: Atorvastatin: Vd=381L; plasma protein binding (≥98%). Ezetimibe: Plasma protein binding (>90%). Metabolism: Atorvastatin: CYP3A4 (extensive); ortho- and parahydroxylated derivatives (metabolites). Ezetimibe: Small intestine and liver via glucuronide conjugation; ezetimibe-glucuronide (active metabolite). Elimination: Atorvastatin: Bile (major), urine (1L) of grapefruit juice may increase this risk. Advise to discuss w/ physician all medications, both prescription and OTC, currently taking. Instruct to report to physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if signs/symptoms persist after discontinuing therapy. Advise to report promptly any signs of liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Counsel women of childbearing age to use an effective method of birth control while using the drug and to discuss future pregnancy plans; instruct to d/c therapy and contact physician if pregnancy occurs. Advise not to breastfeed during treatment.
STORAGE

20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). Store in foil pouch until use. Protect from moisture and light and store in a dry place after the foil pouch is opened. Once a tab is removed, slide blister card back into case. Discard any unused tab 30 days after pouch is opened.

Hasil (Bahasa Indonesia) 1:

Liptruzet(atorvastatin/ezetimibe)THERAPEUTIC CLASSCholesterol absorption inhibitor/HMG-CoA reductase inhibitor (statin)DEA CLASSRXINDICATIONSAdjunct to diet to reduce elevated total cholesterol (total-C), LDL-C, apolipoprotein B, TGs, and non-HDL-C, and to increase HDL-C in patients w/ primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. Reduce elevated total-C and LDL-C in patients w/ homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.ADULT DOSAGEPrimary Hyperlipidemia/Mixed HyperlipidemiaInitial: 10mg/10mg/day or 10mg/20mg/day as a single dose at any time of the dayRange: 10mg/10mg to 10mg/80mg qdTitrate: After initiation and/or upon titration, analyze lipid levels w/in ≥2 weeks and adjust dose, if neededPatients Requiring Larger LDL Reduction (>55%):Initial: 10mg/40mg/dayHomozygous Familial Hypercholesterolemia10mg/40mg/day or 10mg/80mg/dayDOSING CONSIDERATIONSConcomitant MedicationsBile Acid Sequestrants: Take either ≥2 hrs before or ≥4 hrs after bile acid sequestrantCyclosporine, Tipranavir Plus Ritonavir (RTV), Telaprevir, Gemfibrozil: Avoid therapy w/ LiptruzetLopinavir Plus RTV: Use caution; use lowest dose of Liptruzet necessaryClarithromycin, Itraconazole, Saquinavir Plus RTV, Darunavir Plus RTV, Fosamprenavir, Fosamprenavir Plus RTV:Max: 10mg/20mg/dayNelfinavir, Boceprevir:Max: 10mg/40mg/dayADMINISTRATIONOral routeTake w/ or w/o foodSwallow tab whole; do not crush, dissolve, or chewHOW SUPPLIEDTab: (Ezetimibe/Atorvastatin) 10mg/10mg, 10mg/20mg, 10mg/40mg, 10mg/80mgCONTRAINDICATIONSActive liver disease or unexplained persistent elevations in hepatic transaminase levels, women who are or may become pregnant, nursing mothers.WARNINGS/PRECAUTIONSHas not been studied in Fredrickson type I, III, IV, and V dyslipidemias. Myopathy (including immune-mediated necrotizing myopathy [IMNM]) and rhabdomyolysis reported; d/c if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Temporarily withhold or d/c therapy in any patient w/ an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic/endocrine/electrolyte disorders, uncontrolled seizures). Liver enzyme elevations and fatal and nonfatal hepatic failure (rare) reported; obtain LFTs prior to initiating therapy and repeat as clinically indicated; promptly interrupt therapy if serious liver injury w/ clinical symptoms and/or hyperbilirubinemia or jaundice occurs and do not restart if no alternative etiology found. Caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Increases in HbA1c and FPG levels reported. May blunt adrenal and/or gonadal steroid production. Increased risk of hemorrhagic stroke in patients w/ recent stroke or transient ischemic attack (TIA). Caution in elderly.ADVERSE REACTIONSIncreased ALT/AST, musculoskeletal pain, abdominal pain, nausea, arthralgia.DRUG INTERACTIONSSee Dosing Considerations. Caution w/ drugs that decrease levels or activity of endogenous steroid hormones (eg, ketoconazole, spironolactone, cimetidine). Increased risk of myopathy w/ fibric acid derivatives, erythromycin, lipid-modifying doses of niacin, strong CYP3A4 inhibitors (eg, clarithromycin, HIV protease inhibitors), and azole antifungals; consider lower initial and maint doses. Monitor INR levels when used w/ warfarin. Atorvastatin: Strong CYP3A4 inhibitors, grapefruit juice, saquinavir plus ritonavir, diltiazem, and amlodipine may increase levels. Itraconazole may increase exposure. Myopathy, including rhabdomyolysis, reported w/ colchicine; use w/ caution. OATP1B1 inhibitors may increase bioavailability. May increase levels of digoxin; monitor appropriately. May increase exposure of norethindrone and ethinyl estradiol. CYP3A4 inducers (eg, efavirenz, rifampin) may decrease levels; simultaneous coadministration w/ rifampin is recommended. Ezetimibe: Cholestyramine may decrease exposure of total ezetimibe.PREGNANCY AND LACTATIONCategory X, not for use in nursing.MECHANISM OF ACTIONAtorvastatin: HMG-CoA reductase inhibitor; 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; also reduces LDL production and the number of LDL particles. Ezetimibe: Cholesterol absorption inhibitor; localizes at the brush border of the small intestine and inhibits absorption of cholesterol and decreases intestinal cholesterol delivery to the liver.PHARMACOKINETICSAbsorption: Atorvastatin: Absolute bioavailability (14%); Tmax=1-2 hrs. Distribution: Atorvastatin: Vd=381L; plasma protein binding (≥98%). Ezetimibe: Plasma protein binding (>90%). Metabolism: Atorvastatin: CYP3A4 (extensive); ortho- and parahydroxylated derivatives (metabolites). Ezetimibe: Small intestine and liver via glucuronide conjugation; ezetimibe-glucuronide (active metabolite). Elimination: Atorvastatin: Bile (major), urine (<2%); T1/2=approx 14 hrs. Ezetimibe: Feces (78%, 69% unchanged drug), urine (11%, 9% metabolite); T1/2=approx 22 hrs.ASSESSMENTAssess for history of or active liver disease, unexplained persistent elevations in hepatic transaminases, risk factors for developing myopathy (eg, advanced age, hypothyroidism, renal impairment), recent stroke or TIA, hypersensitivity to the drug, pregnancy/nursing status, and possible drug interactions. Assess use in patients who consume substantial quantities of alcohol. Obtain baseline lipid profile (total-C, LDL, HDL, TGs) and LFTs (eg, AST, ALT).MONITORING

Monitor for signs/symptoms of myopathy, rhabdomyolysis, liver dysfunction, and other adverse reactions. Analyze lipid levels w/in 2 or more weeks after initiation and/or upon titration. Monitor LFTs as clinically indicated, and for increases in HbA1c and FPG levels.
PATIENT COUNSELING

Advise to adhere to the National Cholesterol Education Program recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Counsel about risk of myopathy and inform that consuming large quantities (>1L) of grapefruit juice may increase this risk. Advise to discuss w/ physician all medications, both prescription and OTC, currently taking. Instruct to report to physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if signs/symptoms persist after discontinuing therapy. Advise to report promptly any signs of liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Counsel women of childbearing age to use an effective method of birth control while using the drug and to discuss future pregnancy plans; instruct to d/c therapy and contact physician if pregnancy occurs. Advise not to breastfeed during treatment.
STORAGE

20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). Store in foil pouch until use. Protect from moisture and light and store in a dry place after the foil pouch is opened. Once a tab is removed, slide blister card back into case. Discard any unused tab 30 days after pouch is opened.