Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: N.V. Organon, Kloosterstraat 6, NL-5349 AB Oss, The Netherlands
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Therapy with ATOZET is contraindicated during pregnancy and breast-feeding, and in women of child-bearing potential not using appropriate contraceptive measures (see section 4.6).
ATOZET is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases exceeding 3 times the upper limit of normal (ULN).
ATOZET is contraindicated in patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir.
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.
ATOZET contains atorvastatin. 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 phosphokinase (CPK) levels (>10 times ULN), myoglobinaemia and myoglobinuria, which may lead to renal failure.
ATOZET should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CPK 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 CPK levels are significantly elevated (>5 times ULN) at baseline, treatment should not be started.
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.
Due to the atorvastatin component of ATOZET, the risk of rhabdomyolysis is increased when ATOZET 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 derivatives, antivirals for the treatment of hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, or niacin. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products (see section 4.8).
In cases where co-administration of these medicinal products with ATOZET 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 ATOZET is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of ATOZET 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 ATOZET and fusidic acid should only be considered on a case by case basis and under close medical supervision.
Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. atorvastatin and ezetimibe/atorvastatin) co-administered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to temporarily suspend ATOZET in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. Consult the prescribing information of daptomycin to obtain further information about this potential interaction with HMG-CoA reductase inhibitors (e.g. atorvastatin and ezetimibe/atorvastatin) and for further guidance related to monitoring (See section 4.5.).
In few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8). TRADEMARK should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.
In controlled co-administration trials in patients receiving ezetimibe and atorvastatin, consecutive transaminase elevations (≥ 3 times the upper limit of normal [ULN]) have been observed (see section 4.8).
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 ULN persist, reduction of dose or withdrawal of ATOZET is recommended.
ATOZET should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ATOZET is not recommended (see section 5.2).
The safety and efficacy of ezetimibe administered with fibrates have not been established; therefore, co-administration of ATOZET and fibrates is not recommended (see section 4.5).
Caution should be exercised when initiating ATOZET in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving ATOZET and ciclosporin (see section 4.5).
If ATOZET is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).
In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischaemic 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 section 5.1).
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 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.
ATOZET contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
ATOZET contains less than 1 mmol (23 mg) sodium per tablet and is considered to be essentially sodium-free.
Multiple mechanisms may contribute to potential interactions with HMG CoA reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase atorvastatin plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with atorvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
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 ATOZET with other medicinal products that have a potential to induce myopathy, such as fibric acid derivatives and ezetimibe (see section 4.4).
No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with atorvastatin.
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant. Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe-glucuronide) approximately 55%. The incremental low-density lipoprotein cholesterol (LDL-C) reduction due to adding ATOZET to cholestyramine may be lessened by this interaction (see section 4.2).
Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of ciclosporin, a single 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3 to 7.9 fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency who was receiving ciclosporin and multiple other medicinal products demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of ciclosporin on Day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating ATOZET in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving ATOZET and ciclosporin (see section 4.4).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5 and 1.7 fold, respectively. Although these increases are not considered clinically significant, co-administration of ATOZET with fibrates is not recommended (see section 4.4).
CYP3A4 inhibitors: 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. 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 ATOZET cannot be avoided, lower starting and maximum doses of ATOZET 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 ATOZET may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of ATOZET 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.
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of products that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin 1.9-fold (see Table 1); therefore, the dose of ATOZET should not exceed 10/20 mg daily in patients receiving concomitant medications with products containing elbasvir or grazoprevir (see sections 4.2 and 4.4).
Inducers of cytochrome P450 3A4: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin, St. John’s wort) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of ATOZET with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations. The effect of rifampicin on atorvastatin concentrations in hepatocytes is, however, unknown and if concomitant administration cannot be avoided, patients should be carefully monitored for efficacy.
Transport inhibitors: 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 of ATOZET and clinical monitoring for efficacy is recommended (see Table 1).
Gemfibrozil/fibric acid derivatives: The use of fibrates alone is occasionally associated with musclerelated events, including rhabdomyolysis. The risk of these events may be increased with the concomitant use of fibric acid derivatives and atorvastatin.
Ezetimibe: 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.
Colestipol: Plasma concentrations of atorvastatin and its active metabolites were lower (by approx. 25%) 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.
Fusidic acid: 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. Also see section 4.4.
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.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin. Consideration should be given to suspending ATOZET temporarily in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk (see section 4.4).
Boceprevir: Exposure to atorvastatin was increased when administered with boceprevir. When coadministration with ATOZET is required, starting with the lowest possible dose of ATOZET should be considered with titration up to desired clinical effect while monitoring for safety, without exceeding a daily dose of 10/20 mg. For patients currently taking ATOZET, the dose of ATOZET should not exceed a daily dose of 10/20 mg during co-administration with boceprevir.
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If ATOZET is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).
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.
Oral contraceptives: Co-administration of atorvastatin with an oral contraceptive produced increases in plasma concentrations of norethisterone and ethinyl estradiol.
Warfarin: 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 ATOZET 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 ATOZET 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.
Table 1. Effect of Co-administered Medicinal Products on the Pharmacokinetics of Atorvastatin:
| Co-administered Medicinal Product and Dosing Regimen | Atorvastatin | ATOZET | |
|---|---|---|---|
| Dose (mg) | Change in AUC& | Clinical Recommendation# | |
| 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-fold | In cases where co- administration with ATOZET is necessary, do not exceed 10/10 mg ATOZET daily. Clinical monitoring of these patients is recommended. |
| Ciclosporin 5.2 mg/kg/day, stable dose | 10 mg OD for 28 days | ↑ 8.7-fold | |
| Lopinavir 400 mg BID/ Ritonavir 100 mg BID, 14 days | 20 mg OD for 4 days | ↑ 5.9-fold | In cases where co- administration with ATOZET is necessary, lower maintenance doses of ATOZET are recommended. At ATOZET doses exceeding 10/20 mg, clinical monitoring of these patients is recommended. |
| Clarithromycin 500 mg BID, 9 days | 80 mg OD for 8 days | ↑ 4.4-fold | |
| Saquinavir 400 mg BID/ Ritonavir 300 mg BID from Days 5-7, increased to 400 mg BID on Day 8), Days 5-18, 30 min after atorvastatin dosing | 40 mg OD for 4 days | ↑ 3.9-fold | In cases where co- administration with ATOZET is necessary, lower maintenance doses of ATOZET are recommended. At ATOZET doses exceeding 10/40 mg, clinical monitoring of these patients is recommended. |
| Darunavir 300 mg BID/ Ritonavir 100 mg BID, 9 days | 10 mg OD for 4 days | ↑ 3.3-fold | |
| Itraconazole 200 mg OD, 4 days | 40 mg SD | ↑ 3.3-fold | |
| Fosamprenavir 700 mg BID/ Ritonavir 100 mg BID, 14 days | 10 mg OD for 4 days | ↑ 2.5-fold | |
| Fosamprenavir 1,400 mg BID, 14 days | 10 mg OD for 4 days | ↑ 2.3-fold | |
| Nelfinavir 1250 mg BID, 14 days | 10 mg OD for 28 days | ↑ 1.7-fold^ | No specific recommendation. |
| Grapefruit juice, 240 mL OD* | 40 mg SD | ↑ 37% | Concomitant intake of large quantities of grapefruit juice and ATOZET is not recommended. |
| Diltiazem 240 mg OD, 28 days | 40 mg SD | ↑ 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 ↑ | 33%^ | Lower maximum dose and clinical monitoring of these patients is recommended. |
| Amlodipine 10 mg, single dose | 80 mg SD | ↑ 18% | No specific recommendation. |
| Cimetidine 300 mg QID, 2 weeks | 10 mg OD for 4 weeks | ↓ less than 1%^ | No specific recommendation. |
| Antacid suspension of magnesium and aluminium hydroxides, 30 mL QID, 2 weeks | 10 mg OD for 4 weeks | ↓ 35%^ | No specific recommendation. |
| Efavirenz 600 mg OD, 14 days | 10 mg for 3 days | ↓ 41% | No specific recommendation. |
| Rifampicin 600 mg OD, 7 days (co-administered) | 40 mg SD | ↑ 30% | If co-administration cannot be avoided, simultaneous co- administration of ATOZET with rifampicin is recommended, with clinical monitoring. |
| Rifampicin 600 mg OD, 5 days (doses separated) | 40 mg SD | ↓ 80% | |
| Gemfibrozil 600 mg BID, 7 days | 40 mg SD | ↑ 35% | Not recommended. |
| Fenofibrate 160 mg OD, 7 days | 40 mg SD | ↑ 3% | Not recommended. |
| Boceprevir 800 mg TID, 7 days | 40 mg SD | ↑ 2.3-fold | Lower starting dose and clinical monitoring of these patients is recommended. The dose of ATOZET should not exceed a daily dose of 10/20 mg during co- administration with boceprevir. |
| Elbasvir 50 mg OD/Grazoprevir 200 mg OD, 13 days | 10 mg SD | ↑ 1.94-fold | The dose of ATOZET should not exceed a daily dose of 10/20 mg during co-administration with products containing elbasvir or grazoprevir. |
| Glecaprevir 400 mg OD/Pibrentasvir 120 mg OD, 7 days | 10 mg OD for 7 days | ↑ 8.3-fold | Co-administration with products containing glecaprevir or pibrentasvir is contraindicated (see section 4.3). |
& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change)
# 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 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)
^ Total atorvastatin equivalent activity
Increase is indicated as “↑”, decrease as "↓"
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 | ATOZET | |
|---|---|---|---|
| Medicinal Product/ Dose (mg) | Change in AUC& | Clinical Recommendation | |
| 80 mg OD for 10 days | Digoxin 0.25 mg OD, 20 days | ↑ 15% | Patients taking digoxin should be monitored appropriately. |
| 40 mg OD for 22 days | Oral contraceptive OD, 2 months -norethisterone 1 mg -ethinyl estradiol 35 μg | ↑ 28% ↑ 19% | No specific recommendation. |
| 80 mg OD for 15 days | *Phenazone, 600 mg SD | ↑ 3% | No specific recommendation |
| 10 mg OD for 4 days | Fosamprenavir 1,400 mg BID, 14 days | ↓ 27% | No specific recommendation |
& Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change)
* Co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone
Increase is indicated as “↑”, decrease as "↓"
OD = once daily; SD = single dose; BID = twice daily
Women of childbearing potential should use appropriate contraceptive measures during treatment (see section 4.3).
Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.
ATOZET is contraindicated during pregnancy (see section 4.3). No clinical data are available on the use of ATOZET during pregnancy. ATOZET should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with ATOZET should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see section 4.3).
The co-administration of ezetimibe and atorvastatin in pregnant rats indicated that there was a test article-related increase in the skeletal variation “reduced ossification of the sternebrae” in the high dose ezetimibe/atorvastatin group. This may be related to the observed decrease in foetal body weights. In pregnant rabbits a low incidence of skeletal deformities (fused sternebrae, fused caudal vertebrae and asymmetrical sternebrae variation) were observed.
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. Animal studies 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.
No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see section 5.3).
ATOZET is contraindicated during breast-feeding. Because of the potential for serious adverse reactions, women taking ATOZET should not breast-feed their infants. Studies on rats have shown that ezetimibe is secreted into breast milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. It is not known if the active components of ATOZET are secreted into human breast milk (see section 4.3).
No fertility studies were conducted with ATOZET.
In animal studies atorvastatin had no effect on male or female fertility.
Ezetimibe had no effect on the fertility of male or female rats.
ATOZET has negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.
ATOZET (or co-administration of ezetimibe and atorvastatin equivalent to ATOZET) has been evaluated for safety in more than 2,400 patients in 7 clinical trials.
Adverse reactions observed in clinical studies of ATOZET (or co-administration of ezetimibe and atorvastatin equivalent to ATOZET) or ezetimibe or atorvastatin or reported from post-marketing use with ATOZET or ezetimibe or atorvastatin are listed in Table 3. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common ≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); and not known (cannot be estimated from the available data).
Table 3. Adverse Reactions:
| System organ class Frequency | Adverse reaction |
|---|---|
| Infections and infestations | |
| Uncommon | influenza |
| Not known | nasopharyngitis |
| Blood and lymphatic system disorders | |
| Not known | thrombocytopenia |
| Immune system disorders | |
| Not known | hypersensitivity, including anaphylaxis, angioedema, rash, and urticaria\ |
| Metabolism and nutrition disorders | |
| Not known | decreased appetite; anorexia; hyperglycaemia; hypoglycaemia |
| Psychiatric disorders | |
| Uncommon | depression; insomnia; sleep disorder |
| Not known | nightmares |
| Nervous system disorders | |
| Uncommon | dizziness; dysgeusia; headache; paraesthesia |
| Not known | hypoesthesia; amnesia; peripheral neuropathy; myasthenia gravis |
| Eye disorders | |
| Not known | vision blurred; visual disturbance; ocular myasthenia |
| Ear and labyrinth disorders | |
| Not known | tinnitus; hearing loss |
| Cardiac disorders | |
| Uncommon | sinus bradycardia |
| Vascular disorders | |
| Uncommon | hot flush |
| Not known | hypertension |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon | dyspnoea |
| Not known | cough; pharyngolaryngeal pain; epistaxis |
| Gastrointestinal disorders | |
| Common | diarrhoea |
| Uncommon | abdominal discomfort; abdominal distension; abdominal pain; abdominal pain lower; abdominal pain upper; constipation; dyspepsia; flatulence; frequent bowel movements; gastritis; nausea; stomach discomfort |
| Not known | pancreatitis; gastro-oesophageal reflux disease; eructation; vomiting; dry mouth |
| Hepatobiliary disorders | |
| Not known | hepatitis; cholelithiasis; cholecystitis; cholestasis; fatal and non-fatal hepatic failure |
| Skin and subcutaneous tissue disorders | |
| Uncommon | acne; urticaria |
| Not known | alopecia; skin rash; pruritus; erythema multiforme; angioneurotic oedema; dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders | |
| Common | myalgia |
| Uncommon | arthralgia; back pain; muscle fatigue; muscle spasms; muscular weakness; pain in extremity |
| Not known | myopathy/rhabdomyolysis; muscle rupture; tendinopathy, sometimes complicated by rupture; neck pain; joint swelling; myositis; lupus-like syndrome; immune-mediated necrotizing myopathy (see section 4.4) |
| Reproductive system and breast disorders | |
| Not known | gynaecomastia |
| General disorders and administration site conditions | |
| Uncommon | asthenia; fatigue; malaise; oedema |
| Not known | chest pain; pain; peripheral oedema; pyrexia |
| Investigations | |
| Uncommon | ALT and/or AST increased; alkaline phosphatase increased; blood creatine phosphokinase (CPK) increased; gamma-glutamyltransferase increased; hepatic enzyme increased; liver function test abnormal; weight increased |
| Not known | white blood cells urine positive |
In controlled clinical trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 X ULN, consecutive) was 0.6% for patients treated with ATOZET. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline spontaneously or after discontinuation of therapy (see section 4.4).
The following adverse events have been reported with some statins:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via ADR Reporting at www.medicinesauthority.gov.mt/adrportal.
Not applicable.
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