Atorwin

Atorwin

atorvastatin

Manufacturer:

sanofi-aventis

Distributor:

sanofi-aventis
Full Prescribing Info
Contents
Atorvastatin calcium.
Description
Each 10-mg, 20-mg and 40-mg film-coated tablet contains atorvastatin as calcium 10 mg, 20 mg and 40 mg, respectively.
Action
Pharmacotherapeutic Group: HMG-CoA reductase inhibitors. ATC Code: C10AA05.
Pharmacology: Pharmacodynamics: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein LDL is formed from VLDL and is catabolised primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medication.
Atorvastatin has been shown to reduce concentrations of total-C (30%-46%), LDL-C (41% -61%), apolipoprotein B (34% -50%), and triglycerides (14% -33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality. Mortality and morbidity studies with atorvastatin have not yet completed.
Atherosclerosis: In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomized, double-blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n = 253), there was no progression of atherosclerosis.
The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p = 0.98) in the atorvastatin group and + 2.7% (p = 0.001) in the pravastatin group (n = 249). When compared to pravastatin the effects of atorvastatin were statistically significant (p = 0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e.g. need for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 26) (p <0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin : -18.4%, p <0.0001), mean TG levels by 20% (pravastatin : -6.8%, p <0.0009), and mean apolipoprotein B by 39.1% (pravastatin : -22.%, p <0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin : +5.6%, p = NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p <0.0001).
Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.
The safety and tolerability profiles of the two treatment groups were comparable.
Acute Coronary Syndrome: In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients (atorvastatin n = 1,538; placebo n = 1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina). Treatment was initiated during the acute phase after hospital admission and lasted for a period of 16 weeks. Treatment with atorvastatin 80 mg/day increased the time to occurrence of the combined primary endpoint, defined as death from any cause, nonfatal MI, resuscitated cardiac arrest, or angina pectoris with evidence of myocardial ischaemia requiring hospitalization, indicating a risk reduction by 16% (p = 0.048). this was mainly due to a 26% reduction in re-hospitalization for angina pectoris with evidence of myocardial ischaemia (p=0.018). The other secondary endpoints did not reach statistical significance on their own (overall: Placebo: 22.2%, Atorvastatin: 22.4%).
The safety profile of atorvastatin in the MIRACL study was consistent with what is described in Adverse Reactions.
Prevention of Cardiovascular Disease: The effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed in a randomized, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40-79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/l (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors : male gender, age ≥55 years, smoking, diabetes, history of CHD in a first-degree relative, TC : HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/ albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.
Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137).
The absolute and relative risk reduction effect of atorvastatin was as follows: See Table 1.

Click on icon to see table/diagram/image

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p = 0.17 and 74 vs. 82 events, p = 0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly due to the low event rate in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients treated with Amlodipine (HR 0.47 (0.32-0.69), p = 0.00008), but not in those treated with Atenolol (HR 0.83 (0.59-1.17), p = 0.287).
The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/l (160 mg/dl) and TG ≤6.78 mmol/l (600 mg/dl). All patients had at least 1 of the following risk factors : hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.
Patients were treated with either atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410) for a median follow-up of 3.9 years. The absolute and relative risk reduction effect of atorvastatin was as follows: See Table 2.

Click on icon to see table/diagram/image

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the atorvastatin group, p = 0.0592). Pharmacotherapeutic category: HMG-CoA reductase inhibitors, ATC code: C10AA 05. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. This rate-limiting enzyme catalyses the conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In the liver, triglycerides and cholesterol are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and catabolised predominantly by the receptor with high affinity for LDL (LDL receptor).
Atorvastatin lowers concentrations of plasma cholesterol and lipoproteins in serum by inhibiting HMG-CoA reductase and hence cholesterol biosynthesis in the liver, and increases the number of hepatic LDL receptors on the cell surface resulting in accelerated uptake and catabolism of LDL. Atorvastatin reduces LDL production and the number of LDL particles. It produces a profound and sustained increase in LDL receptor activity coupled with an improvement in the quality of circulating LDL particles. Atorvastatin reduces LDL cholesterol in patients with homozygous familial hypercholesterolaemia, a patient population that does not usually respond to lipid-lowering medicinal products.
In a dose-response study, atorvastatin was shown to reduce concentrations of total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (by 34-50%) and triglycerides (by 14-33%) and, at the same time, produce variable increases in the concentrations of HDL cholesterol and apolipoprotein A1. These results apply equally to patients with heterozygous familial hypercholesterolaemia, non-familial forms of hypercholesterolaemia and mixed hyperlipidaemia, including patients with non-insulin dependent diabetes mellitus.
The reduction in total cholesterol, LDL cholesterol and apolipoprotein B provided demonstrable evidence of a reduction in the risk of cardiovascular events and cardiovascular deaths.
Prevention of Cardiovascular Disease: In the ASCOT-LLA study (Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm), a randomised, double-blind, placebo-controlled study, the effect of atorvastatin on fatal and non-fatal coronary heart disease was assessed.
The patients received antihypertensive therapy (based on either amlodipine or atenolol) and either 10 mg of atorvastatin daily (n=5168) or placebo (n=5137).
The primary endpoint (fatal coronary heart disease and non-fatal myocardial infarction) was significantly reduced by atorvastatin in patients treated with amlodipine (HR 0.47 (0.32 to 0.69), p=0.00008) but not in those treated with atenolol (HR 0.83 (0.59 to 1.17), p=0.287).
Pharmacokinetics: Absorption: 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 bioavailibity 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: Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins.
Metabolism: Atorvastatin is metabolized by cytochrome P450 3A4 to ortho-and parahydroxylated derivates 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.
Excretion: 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: Geriatric: 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 patients' populations.
Paediatric: pharmacokinetic data in the paediatric population are not available.
Gender: 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.
Renal Insufficiency: renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Hepatic insufficiency: 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 (Childs-Pugh B).
Toxicology: Preclinical Safety Data: Atorvastatin was not carcinogenic in rats. The maximum dose used was 63-fold higher than the highest human dose (80 mg/day) on a mg/kg body-weight basis and 8-to 16fold higher based on AUC(0-24) values as determined by total inhibitory activity. In a 2-year study in mice, incidences of hepatocellular adenoma in males and hepatocellular carcinomas in females were increased at the maximum dose used and the maximum dose used was 250-fold higher than the highest human dose on a mg/kg body-weight basis. Systemic exposure was 6-to11-fold higher based on AUC(0-24). Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro tests with and without metabolic activation and in 1 in vitro assay. In animal studies atorvastatin had no effect on male or female fertility at doses up to 175 and 225 mg/kg/day, respectively, and was not teratogenic.
Indications/Uses
Hypercholesterolemia: Atorvastatin is indicated s an adjunct to diet for the reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides in patients with primary hypercholesterolemia, including familial hypercholesterolemia (heterozygous variant) or combined (mixed) hyperlipidemia (corresponding to types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.
Atorvastatin is also indicated to reduce the total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering-treatments (eg, LDL apheresis) or if such treatment are unavailable.
Prevention of Cardiovascular Disorders: Prevention of cardiovascular events in patients estimated to have a high risk for a first cardiovascular event (see Pharmacology: Pharmacodynamics under Actions), as an adjunct to correction of other risk factors.
Dosage/Direction for Use
The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin.
Dosage should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response.
The usual starting dose is 10 mg once a day. Adjustment of dosage should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Each daily dose of atorvastatin is given all at once and may be given at any time of day with or without food.
For patients with established coronary heart disease or other patients at increased risk of ischemic events, the treatment goal is LDL-C <3 mmol/l (or <115 mg/dl) and total cholesterol <5 mmol/l (or <190 mg/dl).
Adapted from "Prevention of coronary heart disease in clinical practice: Recommendations of the Second Joint Task Force of European and Other Societies on Coronary Prevention" in Atherosclerosis.
Primary Hypercholesterolaemia and Combined (mixed) Hyperlipidaemia: The majority of patients are controlled with Atorvastatin 10 mg once a day. A therapeutic response is evident within 2 weeks, and the maximum therapeutic response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Heterozygous Familial Hypercholesterolaemia: Patients should be started with Atorvastatin 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg atorvastatin once daily.
Homozygous Familial Hypercholesterolaemia: In a compassionate-use study of 64 patients there were 46 patients for whom confirmed LDL receptor information was available. From these 46 patients, the mean percent reduction in LDL-C was approximately 21%. Atorvastatin was administrated at doses up to 80 mg/day.
The dosage of atorvastatin in patients with homozygous familial hypercholesterolaemia is 10 to 80 mg daily. Atorvastatin should be used as an adjunct to other lipidlowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.
Prevention of Cardiovascular Disorders: In the primary prevention trials the dose was 10 mg/day. Higher dosages may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines.
Dosage in Patients with Renal Insufficiency: Renal disease has no influence on the atorvastatin plasma concentrations nor lipid effects of Atorvastatin; thus, no adjustment of dose is required.
Pediatric Use: Pediatric use should only be carried out by specialists. Experience in pediatrics is limited to a small number of patients (age 4-17 years) with severe dyslipidemias, such as homozygous familial hypercholesterolaemia. The recommended starting dose in this population is 10 mg of atorvastatin per day. The dose may be increased to 80 mg daily, according to the response and tolerability.
Developmental safety data in this population have not been evaluated.
Geriatric Use: Efficacy and safety in patients older than 70 using recommended doses are similar to that seen in the general population.
Overdosage
Specific treatment is not available for Atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CPK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysisis not expected to significantly enhance atorvastatin clearance.
Contraindications
Atorvastatin is contraindicated in patients: With hypersensitivity to the active substance or to any of the excipients of this medication; with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal; with myopathy; during pregnancy; while breast-feeding; in women of child-bearing potential not using appropriate contraceptive measures.
Special Precautions
Liver Effects: Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality (ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal persist, reduction of dose or withdrawal of Atorvastatin is recommended (see Adverse Reactions).
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Skeletal Muscle Effects: Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated CPK levels (>10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
Before the Treatment: Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A creatine phosphokinase (CPK) level should be measured before starting statin treatment in the following situations: Renal impairment; hypothyroidism; personal or familial history of hereditary muscular disorders; previous history of muscular toxicity with a statin or fibrate; previous history of liver disease and/or where substantial quantities of alcohol are consumed; in elderly (age >70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis.
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.
If CPK levels are significantly elevated (>5 times ULN) at baseline, treatment should not be started.
Creatine Phosphokinase Measurement: Creatine phosphokinase (CPK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CPK increase as this makes value interpretation difficult. If CPK levels are significantly elevated at baseline (>5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.
Whilst on Treatment: Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.
If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CPK levels should be measured. If these levels are found to be significantly elevated (>5 times ULN), treatment should be stopped.
If muscular symptoms are severe and cause daily discomfort, even if the CPK levels are elevated to ≤5 x ULN ; treatment discontinuation should be considered.
If symptoms resolve and CPK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.
Atorvastatin must be discontinued if clinically significant elevation of CPK levels (>10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.
Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicaments such as: ciclosporin, erythromycin, clarithromycin, itraconazole, ketoconazole, nefazodone, niacin, gemfibrozil, other fibric acid derivates or HIV-protease inhibitors (see Interactions and Adverse Reactions).
This product contains Lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
There have been very rare reports of an immune-mediated necrotizsing myopathy (IMNM) during or after treatment with some statins, including atorvastatin. IMNM is clinically characterizsed by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
Effects on Ability to Drive and Use Machines: Atorvastatin has negligible influence on the ability to drive and use machines.
Use In Pregnancy & Lactation
Atorvastatin is contraindicated in pregnancy and while breast feeding. Women of child-bearing potential should use appropriate contraceptive measures.
The safety of atorvastatin in pregnancy and lactation has not yet been proven.
There is evidence from animal studies that HMG-CoA reductase inhibitors may influence the development of embryos or foetuses. The development of rat offspring was delayed and post-natal survival reduced during exposure of the dams to atorvastatin at doses above 20 mg/kg/day (the clinical systemic exposure).
In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. It is not known whether this medicinal product or its metabolites are excreted in human milk.
Adverse Reactions
The most commonly expected adverse events are mainly gastrointestinal, including constipation, flatulence, dyspepsia, abdominal pain and usually ameliorate on continued treatment.
Less than 2% of patients were discontinued from clinical trials due to adverse effects attributed to atorvastatin. Based on data from clinical studies and extensive post-marketing experience, the following presents the adverse event profile for atorvastatin.
Estimated frequencies of events are ranked according to following convention: Common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (≤1/10,000).
Gastrointestinal Disorders: Common: Constipation, flatulence, dyspepsia, nausea, diarrhea. Uncommon: Anorexia, vomiting.
Blood and Lymphatic System Disorders: Uncommon: Thrombocytopenia.
Immune System Disorders: Common: Allergic reactions. Very Rare: Anaphylaxis.
Endocrine Disorders: Uncommon: Alopecia, hyperglycemia, pancreatitis.
Psychiatric: Common: Insomnia. Uncommon: Amnesia.
Nervous System Disorders: Common: Headache, dizziness, paresthesia, hypoesthesia. Uncommon: Peripheral neuropathy.
Hepatobiliary Disorders: Rare: Hepatitis, cholestatic jaundice.
Skin/Appendages: Common: Skin rash, pruritus. Uncommon: Urticaria. Very Rare: Angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).
Ear and Labyrinth Disorders: Uncommon: Tinnitus.
Musculoskeletal Disorders: Common: Myalgia, arthralgia. Uncommon: Myopathy. Rare: Myositis, rhabdomyolysis. Not Known: Immune-mediated necrotizing myopathy.
Reproductive System Disorders: Uncommon: Impotence.
General Disorders: Common: Asthenia, chest pain, back pain, peripheral edema. Uncommon: Malaise, weight gain.
Investigations: As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving atorvastatin. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (>3 times ULN) elevations in serum transaminases occurred in 0.8% patients on atorvastatin. These elevations were dose related and were reversible in all patients.
Elevated serum creatinine phosphokinase (CPK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels >10 times the normal upper range occurred in 0.4% atorvastatin-treated patients (see Precautions).
The following adverse events have been reported with some statins: Sexual dysfunction; depression; exceptional cases of interstitial lung disease, especially with long term therapy (see Precautions); 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
The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of ciclosporin, fibric acid derivates, boceprevir, macrolide antibiotics including erythromycin, azole antifungals, or niacin, telaprevir, or the combination of tipranavir/ritonavir and on rare occasions has resulted in rhabdomyolysis with renal dysfunction secondary to myoglobinuria. Therefore, the benefit and the risk of concurrent treatment should be carefully weighed (see Precautions).
Inhibitors of Cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Interaction may occur when Atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. ciclosporin, macrolide antibiotics including erythromycin and clarithromycin, nefazodone, azole antifungals including itraconazole and HIV protease inhibitors). Concomitant administration can lead to increased plasma concentrations of atorvastatin. Therefore, special caution should be exercised when atorvastatin is used in combination with such medicinal agents (see Precautions).
Inhibitors of P-glycoprotein: Atorvastatin and atorvastatin-metabolites are substrates of P-glycoprotein. Inhibitors of the P-glycoprotein (e.g. ciclosporin) can increase the bioavailability of atorvastatin.
Erythromycin, Clarithromycin: Coadministration of atorvastatin 10 mg OD and erythromycin (500 mg QID), or atorvastatin 10 mg OD and clarithromycin (500 mg BID), known inhibitors of cytochromeP450 3A4, were associated with higher plasma concentrations of atorvastatin. Clarythromycin increased the Cmax and AUC of atorvastatin by 56% and 80% respectively.
Itraconazole: Concomitant administration of atorvastatin 40 mg and itraconazole 200 mg daily resulted in a 3-fold increase in atorvastatin AUC.
Protease Inhibitors: Coadministration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin.
Grapefruit Juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of medicinal products metabolized by CYP3A4. Intake of one 240 mL glass of grapefruit juice resulted in an increase in atorvastatin AUC of 37% and a decreased AUC of 20.4% for the active orthohydroxy metabolite. However, large quantities of grapefruit juice (over 1.2 L daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors 1.3 fold. Concomitant intake of large quantities of grapefruit juice and atorvastatin is therefore not recommended.
Inducers of Cytochrome P450 3A4: The effect of inducers of cytochrome P450 3A4 (e.g. rifampicin or phenytoin) on Atorvastatin is unknown. The possible interaction with other substrates of this isozyme is unknown but should be considered for other medicinal products with narrow therapeutic index, for example, antiarrhythmic agents Class III including amiodarone.
Other Concomitant Therapy: Gemfibrozil/Fibric Acid Derivatives: The risk of atorvastatin-induced myopathy may be increased with the concomitant use of fibric acid derivatives. According to results of in vitro studies the metabolic pathway of atorvastatin via glucuronidation is inhibited by Gemfibrozil. This may possibly lead to increased plasma levels of atorvastatin (see Precautions).
Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were coadministered, steady-state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with 80 mg atorvastatin daily. This interaction may be explained by an inhibition of the membrane transport protein, P-glycoprotein. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives: Coadministration of Atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol. These increased concentrations should be considered when selecting oral contraceptive doses.
Colestipol: Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) when colestipol was coadministered with Atorvastatin. However, lipid effects were greater when Atorvastatin and colestipol were coadministered than when either medicinal product was given alone.
Antacid: Coadministration of Atorvastatin with an oral antacid suspension containing magnesium and aluminium hydroxides decreased plasma concentrations of atorvastatin and its active metabolites approx. 35%; however, LDL-C reduction was not altered.
Warfarin: Coadministration of Atorvastatin and warfarin caused a small decrease in prothrombin time during the first days of dosing which returned to normal within 15 days of Atorvastatin treatment. Nevertheless, patients receiving warfarin should be closely monitored when Atorvastatin is added to their therapy.
Phenazone: Coadministration of multiple doses of Atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone.
Cimetidine: An interaction study with cimetidine and Atorvastatin was conducted, and no interaction was seen.
Amlodipine: Atorvastatin pharmacokinetics were not altered by the coadministration of atorvastatin 80 mg and amlodipine 10 mg at steady state.
Colchicine: Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
Other: In clinical studies in which Atorvastatin was administered with antihypertensives or hypoglycaemic agents no clinically significant interactions were seen.
Paediatric Population: Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The above mentioned interactions for adults and the warnings should be taken into account for the paediatric population.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 25°C.
ATC Classification
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
Presentation/Packing
FC tab (white to off-white, oblong-shaped, biconvex) 10 mg x 30's. 20 mg x 30's. 40 mg x 30's.
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