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| __NOTOC__
| | #REDIRECT [[Atorvastatin#Warnings]] |
| {{Atorvastatin}}
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| {{CMG}} ; {{AE}} {{PB}}
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| ==WARNINGS AND PRECAUTIONS==
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| ===Skeletal Muscle===
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| 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.
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| [[Atorvastatin]], like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in [[creatine phosphokinase]] ([[CPK]]) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., [[clarithromycin]], [[itraconazole]], and HIV protease inhibitors) increases the risk of [[myopathy]]/[[rhabdomyolysis]]. | |
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| There have been 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.
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| [[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 atorvastatin. atorvastatin therapy should be discontinued if markedly elevated [[CPK]] levels occur or [[myopathy]] is diagnosed or suspected.
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| The risk of [[myopathy]] during treatment with drugs in this class is increased with concurrent administration of [[cyclosporine]], fibric acid derivatives, [[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]] antifungals. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, [[erythromycin]], [[clarithromycin]], 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 poten[[TIA]]l benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the ini[[TIA]]l months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (see Drug Interactions (7)). Periodic [[creatine phosphokinase]] ([[CPK]]) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe [[myopathy]].
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| Prescribing recommendations for interacting agents are summarized in Table 1
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| {|
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| |[[Image:Pharmacokinetics of Atorvastatin1.PNG|thumb|800px]]
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| <div>
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| Cases of [[myopathy]], including [[rhabdomyolysis]], have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interaction.
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| atorvastatin 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).
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| ===Liver Dysfunction===
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| Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum [[transaminases]] occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
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| One patient in clinical trials developed [[jaundice]]. Increases in liver function tests ([[LFT]]) in other patients were not associated with [[jaundice]] or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent [[LFT]] elevations continued treatment with a reduced dose of atorvastatin.
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| It is recommended that liver enzyme tests be obtained prior to ini[[TIA]]ting therapy with atorvastatin 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 atorvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin.
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| atorvastatin should be used with caution in patients who consume substan[[TIA]]l 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 (4.1)].
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| ===Endocrine Function===
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| Increases in HbA1c and fasting serum glucose levels have been reported with [[HMG-CoA reductase]] inhibitors, including atorvastatin.
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| 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 a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous [[steroid]] hormones, such as [[ketoconazole]], [[spironolactone]], and [[cimetidine]].
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| ===CNS Toxicity===
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| Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0–24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No [[CNS]] lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose of 80 mg/day.
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| [[CNS]] vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
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| ===Use in Patients with Recent stroke or TIA===
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| 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 (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic [[stroke]] was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic [[stroke]] was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar [[stroke]] on study entry, were associated with a higher incidence of hemorrhagic [[stroke]] in the atorvastatin group [see Adverse Reactions. <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = atorvastatin (ATORVASTATIN CALCIUM) TABLET, FILM COATED [PARKE-DAVIS DIV OF PFIZER INC] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c6e131fe-e7df-4876-83f7-9156fc4e8228#nlm34089-3 | publisher = | date = | accessdate = }}</ref>
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| </div>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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