Atorvastatin/Ezetimibe

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[edit] BRAND NAMES

[edit] STRUCTURE

[edit] MECHANISM OF ACTION

Atorvastatin is a hypolipidemic belonging to the class of drugs called Statins. Cholesterol is made mainly in the liver. Statins work by blocking a key liver enzyme involved in this process, thereby slowing down the production of cholesterol in the liver. This encourages the liver to take extra cholesterol, LDL cholesterol in particular, out of the bloodstream, by increasing the number of hepatic LDL receptors on the cell-surface and thus, causing the LDL cholesterol level to decrease.

Atorvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase.
As HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, this results in a decrease in mevalonate, a precursor of cholesterol. Atorvastatin reduces total-cholesterol, LDL-cholesterol, VLDL-cholesterol and TG and increases HDL-cholesterol (good cholesterol).


Ezetimibe is a hypolipidemic drug that selectively inhibits the intestinal absorption of cholesterol and related phytosterols leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

Ezetimibe molecular target has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. This distinct mechanism of action is complementary to that of statins

[edit] INDICATIONS

Hyperlipidemia:

  • Patients with primary hypercholesterolemia and mixed dyslipidemia (elevated LDL-cholesterol and triglyceride) as an adjunct to diet.
  • Patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid lowering treatments

No incremental benefit of Atorvastatin/Ezetimibe combination on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established.

[edit] DOSAGE

The recommended starting dose is (ezetimibe mg/atorvastatin mg): 10/10 mg/day or 10/20 mg/day. It can be administered as a single dose at any time of the day, with or without food. The recommended starting dose for patients who require a larger reduction in LDL-C (greater than 55%) is 10/40 mg/day. After initiation and/or upon titration, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly

The dosage in patients with homozygous familial hypercholesterolemia is 10/40 mg/day or 10/80 mg/day.

[edit] DOSAGE FORMS AND STRENGTHS

  • Tablets (ezetimibe mg/atorvastatin mg): 10/10, 10/20, 10/40, 10/80

[edit] CONTRAINDICATIONS

  • Known hypersensitivity to Atorvastatin or Ezetimibe
  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
  • Women who may become pregnant, pregnancy and breastfeeding

[edit] WARNINGS AND PRECAUTIONS

  • Skeletal Muscle Effects: Myalgia, myopathy and, rarely, rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Atorvastatin. These risks can occur at any dose level, but are increased at the highest dose.
    Atorvastatin should be prescribed with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated hypothyroidism, renal impairment, personal or family history of hereditary muscular disorders, alcohol abuse).

    Concomitant use of cyclosporine, Fibrates, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, 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 antifungal (e.g. Itraconazole, Ketoconazole), may increase the risk of myopathy. (see Interaction).

    Whilst on treatment, patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. Creatine Kinase levels should be measured in these patients. Therapy should be discontinued if Creatine Kinase levels are markedly elevated.
  • Liver enzyme abnormalities and monitoring: As with other HMG-CoA reductase inhibitors, persistent elevations in hepatic transaminases can occur. Monitor liver enzymes prior to initiating therapy and repeat it when clinically indicated.

[edit] INTERACTIONS

Drug Interactions Associated with Increased Risk of 
Myopathy/Rhabdomyolysis with Atorvastatin
Interacting Agents
Prescribing Recommendations 
for Atorvastatin/Ezetimibe combination (LIPTRUZET)
Cyclosporine, HIV protease inhibitors (Tipranavir plus Ritonavir), hepatitis C protease inhibitor (Telaprevir), Gemfibrozil Avoid Atorvastatin/Ezetimibe combination
HIV protease inhibitor (Lopinavir plus Ritonavir) Use with caution and lowest dose necessary.
Clarithromycin, Itraconazole, HIV protease inhibitors (Saquinavir plus Ritonavir, Darunavir plus Ritonavir, Fosamprenavir, Fosamprenavir plus Ritonavir) Do not exceed (ezetimibe mg/atorvastatin mg): 10/20 mg daily
HIV protease inhibitor (Nelfinavir),hepatitis C protease inhibitor (Boceprevir) Do not exceed (ezetimibe mg/atorvastatin mg) 10/40 mg daily.
  • Other lipid-lowering medications: Use with Fenofibrates or lipid modifying doses (≥1 g/day) of Niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with Atorvastatin/Ezetimibe combination.
  • Fenofibrates: Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.
  • Cholestyramine: Combination decreases exposure of ezetimibe.
  • 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: Values for norethindrone and ethinyl estradiol may be increased. These increases should be considered when selecting an oral contraceptive for a woman taking Atorvastatin/Ezetimibe combination.
  • Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category X (US). Atorvastatin/Ezetimibe combination is contraindicated in women who are or may become pregnant
  • Women taking Atorvastatin/Ezetimibe combination should not breast-feed

[edit] SIDE EFFECTS

Common adverse reactions (incidence ≥2% and greater than placebo) are: increased ALT, increased AST, and musculoskeletal pain.

See also WARNINGS AND PRECAUTIONS section

[edit] RELATED LINKS

[edit] BIBLIOGRAPHY

[edit] REFERENCES