Chemical formula: C₃₃H₃₅FN₂O₅ Molecular mass: 558.64 g/mol PubChem compound: 60823
Atorvastatin interacts in the following cases:
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 coadministration 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.
Atorvastatin should be used with caution in patients with hepatic impairment.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended.
Grapefruit Juice, 240 mL once daily: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of medicinal products metabolised by CYP3A4. Intake of one 240 ml glass of grapefruit juice also resulted in a decreased AUC of 20.4% for the active orthohydroxy metabolite. 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.
Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin. 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
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. 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 coadministration 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.
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.
Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethindrone and ethinyl oestradiol.
Lower starting dose and clinical monitoring of these patients is recommended. The dose of atorvastatin should not exceed a daily dose of 20 mg during co-administration with boceprevir.
Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic exposure of atorvastatin. 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.
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.
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 coadministered than when either medicinal product was given alone.
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.
After initiation or following dose adjustments of diltiazem, appropriate clinical monitoring of these patients is recommended.
In patients taking the hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for cytomegalovirus infection prophylaxis concomitantly with atorvastatin, the dose of atorvastatin should not exceed 20 mg/day.
Lower maximum dose and clinical monitoring of these patients is recommended.
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.
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.
In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. At atorvastatin doses exceeding 20 mg, clinical monitoring of these patients is recommended.
Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin.
Consider if the benefit of using lipid modifying dosages of niacin concomitantly with LIPITOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
In cases where co-administration with atorvastatin is necessary, lower maintenance doses of atorvastatin are recommended. At atorvastatin doses exceeding 40 mg, clinical monitoring of these patients is recommended.
In cases where co-administration with atorvastatin is necessary, do not exceed 10 mg atorvastatin daily. Clinical monitoring of these patients is recommended.
In a clinical study in patients receiving chronic warfarin therapy, coadministration 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.
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.
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:
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.
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.
Atorvastatin is contraindicated during pregnancy. 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, Atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
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 Lipitor should not breast-feed their infants. Atorvastatin is contraindicated during breast-feeding.
Women of child-bearing potential should use appropriate contraceptive measures during treatment.
In animal studies atorvastatin had no effect on male or female fertility.
Atorvastatin has negligible influence on the ability to drive and use machines.
In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755 atorvastatin vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
Based on data from clinical studies and extensive post-marketing experience, the following list presents the adverse reaction profile for atorvastatin.
Estimated frequencies of reactions are ranked according to the 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), not known (cannot be estimated from the available data).
Common: nasopharyngitis.
Rare: thrombocytopenia.
Common: allergic reactions.
Very rare: anaphylaxis.
Common: hyperglycaemia.
Uncommon: hypoglycaemia, weight gain, anorexia.
Uncommon: nightmare, insomnia.
Common: headache.
Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.
Rare: peripheral neuropathy.
Uncommon: vision blurred.
Rare: visual disturbance.
Uncommon: tinnitus.
Very rare: hearing loss.
Common: pharyngolaryngeal pain, epistaxis.
Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.
Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.
Uncommon: hepatitis.
Rare: cholestasis.
Very rare: hepatic failure.
Uncommon: urticaria, skin rash, pruritus, alopecia.
Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
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.
Not known: immune mediated necrotizing myopathy
Very rare: gynecomastia.
Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
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. Clinically important (>3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on atorvastatin. These elevations were dose related and were reversible in all patients.
Elevated serum creatine kinase (CK) 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 above 10 times the normal upper range occurred in 0.4% atorvastatin-treated patients.
Paediatric patients aged from 10 to 17 years of age treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo, the most common adverse experiences observed in both groups, regardless of causality assessment, were infections. 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. The safety and tolerability profile in paediatric patients was similar to the known safety profile of atorvastatin in adult patients.
The clinical safety database includes safety data for 520 paediatric patients who received atorvastatin, among which 7 patients were <6 years old, 121 patients were in the age range of 6 to 9, and 392 patients were in the age range of 10 to 17. 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:
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