Active Ingredient: Crystalline Atorvastatin Calcium.
Pharmacotherapeutic group: Lipid modifying agents, 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 medicinal products.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.
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 bioavailability 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.
Biotransformation: Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolised 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.
Elimination: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, atorvastatin 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.
Atorvastatin is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin.
Special populations: Elderly: 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 patient populations.
Paediatric population: Apparent oral clearance of atorvastatin in paediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of atorvastatin and o-hydroxyatorvastatin exposures.
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 impairment: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Hepatic impairment: 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 (Child-Pugh B).
SLOC1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis (see Precautions). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients. Possible consequences for the efficacy are unknown.
Atorvastatin is indicated as an adjunct to diet for the treatment of patients with elevated total cholesterol, LDL-Cholesterol, apolipoprotein B and triglycerides and to increase HDL-Cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson Types IIa and IIb), elevated serum triglyceride levels (Fredrickson Type IV) and for patients with dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
Atorvastatin is also indicated for the reduction to total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia.
Prevention of Cardiovascular Disease: In adult patients without clinically evident coronary heart disease but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, CRYSTORVAS is indicated to: Reduce the risk of myocardial infarction, Reduce the risk of stroke, Reduce the risk for revascularization procedures and angina.
In patients with type 2 diabetes, without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking or hypertension, CRYSTORVAS is indicated to: Reduce the risk of myocardial infarction, Reduce the risk of stroke.
In patients with clinically evident coronary heart disease, atorvastatin is indicated to: Reduce the risk of non-fatal myocardial infarction, Reduce the risk of fatal and non-fatal stroke, Reduce the risk for revascularization procedures, Reduce the risk of hospitalization for CHF, Reduce the risk of angina.
Pediatric Patient (10-17 years of age): Atorvastatin is indicated as an adjunct to diet to reduce total-C and apo B levels in boys and postmenarchal girls 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains ≥ 190 mg/dl or; b. LDL-C remains ≥ 160 mg/dl and: There is a positive family history of premature cardiovascular disease or Two or more other CVD risk factors are present in the pediatric patient.
ROUTE OF ADMINISTRATION: ORAL.
General: Before instituting therapy with atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise and weight reduction in obese patients, and to treat the underlying medical problems. The patient should continue on a standard cholesterol-lowering diet during treatment with atorvastatin. The dosage range is 10mg to 80mg once daily. Doses may be given any time of the day with or without food. Starting and maintenance dosage should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within 2-4 weeks and dosage adjusted accordingly.
Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia: The majority of patients are controlled with 10mg atorvastatin once daily. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.
Homozygous Familial Hypercholesterolemia: In a compassionate-use study of patients with homozygous familial hypercholesterolemia, most patients responded to 80mg atorvastatin with a greater than 15% reduction in LDL-C (18%-45%).
Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age): The recommended starting dose of atorvastatin is 10mg/day; the usual dose range is 10 to 20mg orally once daily. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.
Severe Dyslipidemias in Pediatric Patients: For patients aged 10 years and above, the recommended starting dose is 10mg atorvastatin once daily. The dose may be increased to 80mg daily, according to the response and tolerability. Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.
Use in Patients with Renal Insufficiency: Renal disease has no influence on plasma concentration or on LDL-C reduction with atorvastatin. Thus, no dose adjustment is required.
Use in Elderly: No differences in safety, efficacy or lipid treatment goal attainment were observed between elderly patients and the overall population.
Dosage in Patients taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protein Inhibitors: In patients taking cyclosporine or the human immunodeficiency virus (HIV) protease inhibitors (tipanivir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with atorvastatin should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin and the lowest dose necessary is employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin should be limited to 20mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin should be limited to 40mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed.
Use in Children (Homozygous Familial Hypercholesterolemia): Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80mg/day for one year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients.
Specific treatment is not available for Crystorvas overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.
Crystorvas is contraindicated in patients: with hypersensitivity to the active substance or to any of the excipients present in this product; with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal; during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see Use in Pregnancy & Lactation); treated with the hepatitis C antivirals glecaprevir/pibrentasvir.
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 (ULN) persist, reduction of dose or withdrawal of Crystorvas is recommended (see Side Effects).
Crystorvas should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL): In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of haemorrhagic stroke in patients initiated on atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior haemorrhagic stroke or lacunar infarct at study entry. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment (see Pharmacology: Pharmacodynamics under Actions).
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 creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised 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.
Physicians considering combined therapy with atorvastatin 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 and 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 atorvastatin should also be considered when taken concomitantly with the aforementioned drugs. Temporary suspension of atorvastatin may be appropriate during fusidic acid therapy.
Before the treatment: Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK 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; Situations where an increase in plasma levels may occur, such as interactions (see Interactions) and special populations including genetic subpopulations (see Pharmacology: Pharmacokinetics under Actions).
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.
If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.
Creatine kinase measurement: Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK 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 CK 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 CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.
If symptoms resolve and CK 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 CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other medicinal products: Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin, or ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.
In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a lower maximum dose of atorvastatin is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended (see Interactions).
Atorvastatin must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see Interactions). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.
Statin therapy may be re-introduced seven days after the last dose of fusidic acid.
In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Crystorvas and fusidic acid should only be considered on a case by case basis and under close medical supervision.
Interstitial lung disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see Side Effects). Presenting features can include dyspnoea, nonproductive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus: Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI >30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
Excipients: Crystorvas contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effect on Ability to Drive and Use Machines: Crystorvas has negligible influence on the ability to drive and use machines.
Use in Children: No clinically significant effect on growth and sexual maturation was observed in a 3-year study based on the assessment of overall maturation and development, assessment of Tanner Stage, and measurement of height and weight (see Side Effects).
Women of childbearing potential: Women of child-bearing potential should use appropriate contraceptive measures during treatment (see Contraindications).
Pregnancy: Crystorvas is contraindicated during pregnancy (see Contraindications). Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Studies in animals have shown toxicity to reproduction.
Maternal treatment with atorvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.
For these reasons, Crystorvas should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Crystorvas should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see Contraindications).
Breast-feeding: It is unknown whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking Crystorvas should not breast-feed their infants (see Contraindications). Atorvastatin is contraindicated during breast-feeding (see Contraindications).
Fertility: In animal studies atorvastatin had no effect on male or female fertility.
Following information presents the adverse reaction profile for Crystorvas.
Infections and infestations: Common: nasopharyngitis.
Blood and lymphatic system disorders: Rare: thrombocytopenia.
Immune system disorders: Common: allergic reactions. Very rare: anaphylaxis.
Metabolism and nutrition disorders: Common: hyperglycaemia. Uncommon: hypoglycaemia, weight gain, anorexia.
Psychiatric disorders: Uncommon: nightmare, insomnia.
Nervous system disorders: Common: headache. Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia. Rare: peripheral neuropathy.
Eye disorders: Uncommon: vision blurred. Rare: visual disturbance.
Ear and labyrinth disorders: Uncommon: tinnitus. Very rare: hearing loss.
Respiratory, thoracic and mediastinal disorders: Common: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders: Common: constipation, flatulence, dyspepsia, nausea, diarrhoea. Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.
Hepatobiliary disorders: Uncommon: hepatitis. Rare: cholestasis. Very rare: hepatic failure.
Skin and subcutaneous tissue disorders: Uncommon: urticaria, skin rash, pruritus, alopecia. Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain. Uncommon: neck pain, muscle fatigue. Rare: myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture. Very rare: lupus-like syndrome. Frequency not known: immune mediated necrotizing myopathy (see Precautions).
Reproductive system and breast disorders: Very rare: gynecomastia.
General disorders and administration site conditions: Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
Investigations: Common: liver function test abnormal, blood creatine kinase increased. Uncommon: white blood cells urine positive.
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. These elevations were dose related and were reversible in all patients.
Paediatric population: The safety and tolerability profile in paediatric patients was similar to the known safety profile of atorvastatin in adult patients.
Based on the data available, the frequency, type and severity of adverse reactions in children is similar to adults.
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).
There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median 3 weeks). Increases in HbA1c and fasting blood glucose have been reported with statins. The risk of hyperglycemia, however, is outweighed by the reduction in vascular risk with statins.
Effect of co-administered medicinal products on atorvastatin:
Atorvastatin is metabolised by cytochrome P450 3A4 (CYP3A4) and is a substrate of the hepatic transporters, organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the multi-drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see Pharmacology: Pharmacokinetics under Actions). Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. The risk might also be increased at concomitant administration of atorvastatin with other medicinal products that have a potential to induce myopathy, such as fibric acid derivates and ezetimibe (see Contraindications and Precautions).
Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 1 and specific information as follows). Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, some antivirals used in the treatment of HCV (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 1).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor.
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A (e.g. efavirenz, rifampin, St. John's Wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1).
Gemfibrozil/fibric acid derivatives:
The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin to achieve the therapeutic objective should be used and the patients should be appropriately monitored (see Precautions).
Concurrent use of fibrates may cause severe myositis and myoglobinuria.
The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended.
Plasma concentrations of atorvastatin and its active metabolites were lower (ratio of atorvastatin concentration: 0.74) when colestipol was co-administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either medicinal product was given alone.
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination.
If treatment with systemic fusidic acid is necessary, atorvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment (see Precautions).
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.
Effect of atorvastatin on co-administered medicinal products: Digoxin:
When multiple doses of digoxin and 10 mg atorvastatin were co-administered, steady-state digoxin concentrations increased slightly. Patients taking digoxin should be monitored appropriately.
Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.
In a clinical study in patients receiving chronic warfarin therapy, co-administration of atorvastatin 80 mg daily with warfarin caused a small decrease of about 1.7 seconds in prothrombin time during the first 4 days of dosing which returned to normal within 15 days of atorvastatin treatment. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before starting atorvastatin in patients taking coumarin anticoagulants and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of atorvastatin is changed or discontinued, the same procedure should be repeated. Atorvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The previously mentioned interactions for adults and the warnings should be taken into account for the paediatric population.
(See Tables 1 and 2.)
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Click on icon to see table/diagram/image
Store below 30°C, protected from moisture.
C10AA05 - atorvastatin ; Belongs to the class of HMG CoA reductase inhibitors. Used in the treatment of hyperlipidemia.
FC tab 20 mg (white to off-white, 7 mm round, biconvex, with "20" marking on one side and plain on the other side) x 3 x 10's. 40 mg (white to off-white, 10 mm round, biconvex, with "40" marking on one side and plain on the other side) x 3 x 10's.