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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 fibrates, erythromycin, immunosuppressive drugs, azole antifungals, or lipid-modifying doses of niacin (≥1g/day) 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. Therefore, lower starting and maintenance doses of ATOZET should also be considered when taken concomitantly with the aforementioned drugs. Temporary suspension of ATOZET may be appropriate during fusidic acid therapy. [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 Table 4 [see Cyclosporine, Clarithromycin, Itraconazole, or Certain HIV/HCV Antiviral Agents under Dosage & Administration and CYP3A4 Interactions under Interactions]. (See Table 4.)
Click on icon to see table/diagram/imageCases 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).
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by: persistent 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.
Myasthenia Gravis/Ocular Myasthenia: In few cases, statins have been reported to induce new onset or aggravate pre-existing myasthenia gravis or ocular myasthenia [see Adverse Reactions]. ATOZET should be discontinued in case these conditions occur. There have been reports of recurrences of these conditions when the same or a different statin was (re-) administered.
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.
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 given 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.]
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.
Use in Children: There are insufficient data for the safe and effective use of ATOZET in pediatric patients.
