Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Atorstan is contraindicated in patients:
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 Atorstan is recommended (see section 4.8).
Atorstan should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
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 hemorrhagic 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 infract at study entry. For patients with prior hemorrhagic stroke or lacunar infract, the balance of risks and benefits of atorvastatin 80 mg is uncertain. As such, the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment (see section 5.1).
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 characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.
Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting 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.
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.
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. ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, intraconazole, posaconazole, letermovir 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 derivatives, 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 section 4.5).
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 section 4.5). 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 Atorstan and fusidic acid should only be considered on a case by case basis and under close medical supervision.
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 section 4.8).
Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive 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.
Some evidence suggests that statins as a class raise blood glucose. 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.
This product contains lactose.
Patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption should not take this medicine.
This product contains sodium.
This medicine contains less than 1mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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 section 5.2). 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 derivatives and ezetimibe (see section 4.3 and 4.4).
Potent CYP3A4 inhibitors have been shown to lead to markedly increased concentrations of atorvastatin (see Table 1 and specific information below). 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. elbasivir/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. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor or following dose adjustments of the CYP3A4 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. If concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Inhibitors of transport proteins can increase the systemic exposure of atorvastatin. Both ciclosporin and letermovir are inhibitors of transporters involved in the elimination of atorvastatin, such as OATP1B1 / 1B3, P-gp and BCRP, resulting in increased systemic exposure to 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).
The use of fibrates alone is occasionally associated with muscle related events, including rhabdomyolysis. The risk of these events may be increased with 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 section 4.4).
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 when colestipol was co-administered with atorvastatin (ratio of atorvastatin concentration: 0.74). However, lipid effects were greater when atorvastatin and colestipol were co-administered together 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 section 4.4).
Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine. Caution should be exercised when prescribing atorvastatin with colchicine.
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 above mentioned interactions for adults and the warnings in section 4.4 should be taken into account for the paediatric population.
Table 1. Effect of co-administered medicinal products on the pharmacokinetics of atorvastatin:
| Co-administered medicinal product and dosing regimen | Atorvastatin | ||
|---|---|---|---|
| Dose (mg) | Ratio of AUC& | Clinical Recommendation# | |
| Glecaprevir 400 mg OD/Pibrentasvir 120 mg OD, 7 days | ?10 mg OD for 7 days | 8.3 | Co-administration with products containing glecaprevir or pibrentasvir is contraindicated (see section 4.3). |
| Tipranavir 500 mg BID/Ritonavir 200 mg BID, 8 days (days 14 to 21) | 40 mg on day 1, 10 mg on day 20 | 9.4 | In cases where co-administration with atorvastatin is necessary, do not exceed 10 mg atorvastatin daily. Clinical monitoring of these patients is recommended. |
| Telaprevir 750 mg q8h, 10 days | 20 mg, SD | 7.9 | |
| Ciclosporin 5.2 mg/kg/day, stable dose | 10 mg OD for 28 days | 8.7 | |
| Lopinavir 400 mg BID/Ritonavir 100 mg BID, 14 days | 20 mg OD for 4 days | 5.9 | 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. |
| Clarithromycin 500 mg BID, 9 days | 80 mg OD for 8 days | 4.5 | |
| Saquinavir 400 mg BID/Ritonavir (300 mg BID from days 5-7, increased to 400 mg BID on day 8), days 4-18, 30 min after atorvastatin dosing | 40 mg OD for 4 days | 3.9 | 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. |
| Darunavir 300 mg BID/ Ritonavir 100 mg BID, 9 days | 10 mg OD for 4 days | 3.4 | |
| Itraconazole 200 mg OD, 4 days | 40 mg SD | 3.3 | |
| Fosamprenavir 700 mg BID/Ritonavir 100 mg BID, 14 days | 10 mg OD for 4 days | 2.5 | |
| Fosamprenavir 1400 mg BID, 14 days | 10 mg OD for 4 days | 2.3 | |
| Elbasvir 50 mg OD/ Grazoprevir 200 mg OD, 13 days | 10 mg SD | 1.95 | The dose of atorvastatin should not exceed a daily dose of 20 mg during co‑administration with products containing elbasvir or grazoprevir. |
| Letermovir 480 mg OD, 10 days | 20 mg SD | 3.29 | The dose of atorvastatin should not exceed a daily dose of 20 mg during co‑administration with products containing letermovir. |
| Nelfinavir 1250 mg BID, 14 days | 10 mg OD for 28 days | 1.74 | No specific recommendation. |
| Grapefruit Juice, 240 mL OD | 40 mg, SD | 1.37 | Concomitant intake of large quantities of grapefruit juice and atorvastatin is not recommended. |
| Diltiazem 240 mg OD, 28 days | 40 mg, SD | 1.51 | After initiation or following dose adjustments of diltiazem, appropriate clinical monitoring of these patients is recommended. |
| Erythromycin 500 mg QID, 7 days | 10 mg, SD | 1.33 | Lower maximum dose and clinical monitoring of these patients is recommended. |
| Amlodipine 10 mg, single dose | 80 mg, SD | 1.18 | No specific recommendation. |
| Cimetidine 300 mg QID, 2 weeks | 10 mg OD for 2 weeks | 1.00 | No specific recommendation. |
| Colestipol 10 g BID, 24 weeks | 40 mg OD for 8 weeks | 0.74** | No specific recommendation. |
| Antacid suspension of magnesium and aluminium hydroxides, 30 mL QID, 17 days. | 10 mg OD for 15 days | 0.66 | No specific recommendation. |
| Efavirenz 600 mg OD, 14 days | 10 mg for 3 days | 0.59 | No specific recommendation. |
| Rifampin 600 mg OD, 7 days (co-administered) | 40 mg SD | 1.12 | If co-administration cannot be avoided, simultaneous co-administration of atorvastatin with rifampin is recommended, with clinical monitoring. |
| Rifampin 600 mg OD, 5 days (doses separated) | 40 mg SD | 0.20 | |
| Gemfibrozil 600 mg BID, 7 days | 40mg SD | 1.35 | Lower starting dose and clinical monitoring of these patients is recommended. |
| Fenofibrate 160 mg OD, 7 days | 40mg SD | 1.03 | Lower starting dose and clinical monitoring of these patients is recommended. |
| Boceprevir 800 mg TID, 7 days | 40mg SD | 2.3 | 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. |
& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).
# See sections 4.4 and 4.5 for clinical significance.
* 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 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.
** Ratio based on a single sample taken 8-16 h post dose.
OD = once daily; SD = single dose; BID = twice daily; TID = three times daily; QID = four times daily.
Table 2. Effect of atorvastatin on the pharmacokinetics of co-administered medicinal products:
| Atorvastatin and dosing regimen | Co-administered medicinal product | ||
|---|---|---|---|
| Medicinal product/Dose (mg) | Change in AUC& | Clinical Recommendation | |
| 80 mg OD for 10 days | Digoxin 0.25 mg OD, 20 days | 1.15 | Patients taking digoxin should be monitored appropriately. |
| 40 mg OD for 22 days | Oral contraceptive OD, 2 months - norethindrone 1 mg - ethinyl estradiol 35 µg | 1.28 1.19 | No specific recommendation. |
| 80 mg OD for 15 days | *Phenazone, 600 mg SD | 1.03 | No specific recommendation |
| 10 mg, SD | Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days | 1.08 | No specific recommendation |
| 10 mg, OD for 4 days | Fosamprenavir 1400 mg BID, 14 days | 0.73 | No specific recommendation |
| 10 mg OD for 4 days | Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days | 0.99 | No specific recommendation |
& Represents ratio of treatments (co-administered drug plus atorvastatin versus atorvastatin alone).
* Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone.
OD = once daily; SD = single dose; BID = twice daily
Women of child-bearing potential should use appropriate contraceptive measures during treatment (see section 4.3).
Atorvastatin is contraindicated during pregnancy (see section 4.3). 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 (see section 5.3).
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, Atorstan should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Atorstan should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).
It is not known 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 (see section 5.3). Because of the potential for serious adverse reactions, women taking Atorstan should not breast-feed their infants (see section 4.3). Atorvastatin is contraindicated during breastfeeding (see section 4.3).
In animal studies atorvastatin had no effect on male or female fertility (see section 5.3).
Atorstan 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 table presents the adverse reaction profile for atorvastatin.
Estimated frequencies of reactions are ranked according to the following convention: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000), very rare (<1/10000), 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, muscle rupture, tendonopathy, sometimes complicated by rupture.
Very rare: lupus-like syndrome.
Not known: immune-mediated necrotizing myopathy (see section 4.4).
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 (see section 4.4).
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:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continue monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Tel: +357 22608607, Fax: +357 22608669, Website: www.moh.gov.cy/phs.
Not applicable.
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