Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Lupin Australia Pty Ltd, Suite 2, Level 2, 19-23 Prospect Street, Box Hill, VIC, 3128 Distributor: Arrotex Pharmaceuticals Pty Ltd, 15-17 Chapel Street, Cremorne, VIC, 3121, Australia
As with other lipid-lowering agents of the same class, moderate (>3 x upper limit of normal [ULN]) elevations of serum transaminases have been reported following therapy with atorvastatin.
Persistent increases in serum transaminases >3 x ULN occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2, 0.2, 0.6, and 2.3% for 10, 20, 40, and 80 mg respectively. Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced or drug treatment interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
In controlled clinical studies, the incidence of consecutive elevations (≥3 X the upper limit of normal [ULN]) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%).
In controlled co-administration trials in patients receiving ezetimibe with atorvastatin, the incidence of consecutive elevations (≥3 X ULN) in hepatic transaminase levels was 0.6% for patients treated with ezetimibe administered with atorvastatin (see Section 4.8 Adverse Effects (Undesirable Effects)).
Liver function tests should be performed before the initiation of treatment and periodically thereafter. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of > 3 times ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.
EZETAST should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of EZETAST (see Section 4.3 Contraindications).
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of CPK > 10 X ULN was 4 of 1,674 (0.2%) patients administered ezetimibe alone vs. 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ezetimibe and a statin vs. 4 of 929 (0.4%) patients administered a statin alone.
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis.
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CK values > 10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as ciclosporin and strong CYP3A4 inhibitors (eg., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterised by: proximal muscle weakness and elevated serum creatinine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Ezetimibe/Atorvastatin. Ezetimibe/Atorvastatin therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with statins is increased with concurrent administration of ciclosporin, fibric acid derivatives, erythromycin, clarithromycin, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, azole antifungals, colchicine, or hepatitis C antiviral agents such as, telaprevir, boceprevir, elbasvir and grazoprevir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Physicians considering combined therapy with EZETAST and fibric acid derivatives, erythromycin, clarithromycin, elbasvir, grazoprevir, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, colchicine, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or 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. Lower starting and maintenance doses of EZETAST should be considered when taken concomitantly with the aforementioned drugs (see Section 4.2 Dose and Method of Administration – Use in Combination with Other Medicinal Compounds). Periodic CK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarised in Table 1 (see Section 4.2 Dose and Method of Administration – Ciclosporin, Clarithromycin, Itraconazole, or Certain HIV/HCV antiviral agents, and Section 4.5 Interactions with Other Medicines and Other Forms of Interactions – CYP3A4Interactions).
Table 1. Atorvastatin Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis:
| Interacting Agents | Prescribing Recommendations for EZETAST |
|---|---|
| Ciclosporin, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil | Avoid EZETAST |
| Other fibrates (except fenofibrate), fusidic acid | Not recommended with EZETAST |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir), hepatitis C antiviral agents (boceprevir, elbasvir, grazoprevir) | Do not exceed 10/20 mg of EZETAST daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 10/40 mg of EZETAST daily |
* Use with caution and with the lowest dose necessary.
There have been reports of rhabdomyolysis (including some fatalities) in patients receiving concomitant fusidic acid and statins (see Section 4.3 Contraindications and Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of the fusidic acid treatment. 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.
Reports of myopathy and/or rhabdomyolysis have been observed with HMG-CoA reductase inhibitors coadministered with daptomycin. Caution should be used when prescribing HMGCoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to suspending EZETAST temporarily in patients taking daptomycin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other Drug Interactions).
EZETAST therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, (eg. severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
The co-administration of ezetimibe with fibrates, other than fenofibrate, has not been studied. Therefore, co-administration of EZETAST and fibrates is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Fibrates may increase cholesterol excretion from the bile, and ezetimibe increased cholesterol in the gallbladder bile in a preclinical study in dogs. Given the potential for cholelithiasis, and the numerically higher incidence of cholecystectomies in patients administered ezetimibe and fenofibrate in a clinical study (see Section 5.1 Pharmacodynamic Properties – Clinical Trials and Section 4.8 Adverse Effects (Undesirable Effects)), co-administration of EZETAST and fenofibrate is not recommended in patients with pre-existing gallbladder disease (see Section 4.3 Contraindications).
In patients taking ciclosporin, therapy with EZETAST should be avoided (see Table 1, Section 4.5 Interactions with Other Medicines and Other Forms of Interactions and Section 4.2 Dose and Method of Administration).
If EZETAST is added to warfarin, another coumarin anticoagulant or fluindione the International Normalised Ratio (INR) should be appropriately monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
A post-hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or TIA, showed a higher incidence of haemorrhagic stroke in patients on atorvastatin 80 mg (55/2365, 2.3%) compared to placebo (33/2366, 1.4%), (p=0.02). Throughout the study, all cause mortality was numerically higher in the atorvastatin arm than the placebo arm. At study end all cause mortality was 9.1% on atorvastatin vs. 8.9 % on placebo.
The increased risk of haemorrhagic stroke was observed in patients who entered the study with prior haemorrhagic stroke (15.6% for atorvastatin vs. 4.2% for placebo, HR 4.06; 95% CI 0.84-19.57) or prior lacunar infarct (2.8% for atorvastatin vs. 0.6% for placebo, HR 4.99; 95%CI 1.71-14.61). All cause mortality was also increased in these patients with prior haemorrhagic stroke (15.6% for atorvastatin vs. 10.4% for placebo) or prior lacunar infarct (10.9% for atorvastatin vs. 9.1% for placebo). The potential risk of haemorrhagic stroke should be carefully considered before initiating treatment with EZETAST in patients with recent (1-6 months) stroke or TIA.
In 68% of patients who entered the study with neither a haemorrhagic stroke nor lacunar infarct, the risk of haemorrhagic stroke on atorvastatin vs. placebo was 2% vs. 1.8% (large vessel), 1.7% vs. 1.6% (TIA), 1.6% vs. 1.7% (unknown cause).
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if EZETAST is administered concomitantly with other drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Exceptional cases of interstitial lung disease have been reported with some statins, especially with longterm therapy (see Section 4.8 Adverse Effects (Undesirable Effects)). 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, EZETAST therapy should be discontinued.
Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term, statin-induced deficiency of ubiquinone has not been established.
Like other HMG-CoA reductase inhibitors, atorvastatin has variable effects on lipoprotein (a) (Lp (a)). It is unclear whether the beneficial effects of lowering LDL-C and total cholesterol in some patients may be blunted by raised Lp (a) levels.
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, EZETAST is not recommended in these patients (see Section 5 2 Pharmacokinetic Properties – Characteristics in Patients, (Special Populations)).
No dosage adjustment is required for elderly patients. Because advanced age (≥ 65 years) is a predisposing factor for myopathy, Ezetimibe and Atorvastatin tablets should be prescribed with caution in the elderly (see Section 5 2 Pharmacokinetic Properties – Characteristics in Patients, (Special Populations)).
Co-administration of ezetimibe and atorvastatin was studied in 1,053 patients ≥ 65 years of age with hypercholesterolaemia and high risk for CHD. Patients received ezetimibe 10 mg and atorvastatin doses from 10 to 40 mg daily. The treatments were well tolerated, with a similar safety profile to that observed in younger patients.
Treatment experience in adults aged ≥70 years with doses of atorvastatin up to 80 mg/day has been evaluated in 221 patients. The safety and efficacy of atorvastatin in this population were similar to those of patients <70 years of age.
There are insufficient data for the safe and effective administration of ezetimibe and atorvastatin in paediatric patients.
Ezetimibe and atorvastatin tablets can cause elevations in ALT/AST, alkaline phosphatase, GGT, bilirubin and creatine kinase.
No clinically significant pharmacokinetic interaction was seen when ezetimibe was co- administered with atorvastatin.
Multiple mechanisms may contribute to potential interactions with HMG-CoA reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (eg. CYP3A4) and/or transporter (eg. 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.
Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4. Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have been noted with HIV protease inhibitors (fosamprenavir and combinations of lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole. In patients taking ciclosporin, the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of EZETAST should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing EZETAST and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir or fosamprenavir plus ritonavir, or the hepatitis C protease inhibitor boceprevir, the dose of EZETAST should not exceed 10/20 mg and should be used with caution (see Section 4.4 Special Warnings and Precautions for Use – Skeletal Muscle and Section 4.2 Dose and Method of Administration – Ciclosporin, Clarithromycin, Itraconazole or Certain HIV/HCV antiviral agents). In patients taking the HIV protease inhibitor nelfinavir, the dose of EZETAST should not exceed 10/40 mg and close clinical monitoring is recommended. Based on experience with other HMGCoA reductase inhibitors caution should be exercised when atorvastatin is administered with inhibitors of cytochrome P450 3A4 (eg. macrolide antibiotics including erythromycin and clarithromycin, and azole antifungals including itraconazole). The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is increased with concurrent administration of ciclosporin, fibric acid derivatives, erythromycin, azole antifungals or niacin:
Erythromycin/Clarithromycin: In healthy individuals, co-administration of atorvastatin (10 mg QD) and erythromycin (500 mg QID), or clarithromycin (500 mg BID), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin. In patients taking clarithromycin the dose of EZETAST should not exceed 10/20 mg (see Section 4.4 Special Warnings and Precautions for Use – Skeletal Muscle).
Protease Inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin.
Itraconazole: Concomitant administration of atorvastatin (20 to 40mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC. In patients taking itraconazole the dose of EZETAST should not exceed 10/20 mg.
Diltiazem Hydrochloride: Co-administration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin.
Cimetidine: Atorvastatin plasma concentrations and LDL-C reduction were not altered by coadministration of cimetidine.
Grapefruit Juice: Contains one or more components that inhibit cytochrome P450 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 L per day).
Cimetidine: Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.
Atorvastatin is metabolised by cytochrome P450 3A4.
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg. efavirenz, rifampicin, phenytoin, 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 atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations.
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.
Ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyloestradiol and levonorgestrel), glipizide, tolbutamide or midazolam during coadministration.
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.
Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides with atorvastatin decreased atorvastatin plasma concentrations approximately 35%, however, LDL-C reduction was not altered.
Dosing of Ezetimibe and Atorvastatin tablets and a bile acid binding sequestrant should take place several hours apart. However, efficacy of such combination has not been studied.
Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol and atorvastatin were co-administered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.
Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.
The safety and effectiveness of ezetimibe and atorvastatin administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co- administration of ezetimibe and atorvastatin with fibrates is not recommended until use in patients is studied.
Caution should be used when prescribing EZETAST and fenofibrate, as fenofibrate can cause myopathy when given alone. In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.
Concomitant administration of EZETAST with gemfibrozil should be avoided.
In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. No clinical data are available.
The effect of Ezetimibe and Atorvastatin tablets on the prothrombin time has not been studied.
Concurrent administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability and prothrombin time in a study of twelve healthy adult males administered a single dose of warfarin. There have been post-marketing reports of increased International Normalised Ratio in patients who had ezetimibe added to warfarin or fluindione. Most of these patients were also on other medications (see Section 4.4 Special Warnings and Precautions for Use).
Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Co-administration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown.
Although interaction studies with atorvastatin and fusidic acid have not been conducted, there have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, EZETAST treatment should be discontinued throughout the duration of the fusidic acid treatment (see Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use – Skeletal Muscle).
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 EZETAST with colchicine (see Section 4.4 Special Warnings and Precautions for Use).
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (eg. ciclosporin) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and ciclosporin 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin. The co-administration of EZETAST with ciclosporin should be avoided (see Section 4.4 Special Warnings and Precautions for Use – Skeletal Muscle and Section 4.2 Dose and Method of Administration).
The effect of ciclosporin on ezetimibe was studied in eight post-renal transplant patients with creatinine clearance of >50 mL/min who were 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 group of historical healthy volunteers (n=17) who had taken a single 10 mg dose of ezetimibe alone.
In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including ciclosporin, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls.
In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single dose 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 (see Section 4.4 Special Warnings and Precautions for Use).
Atorvastatin is a substrate of the efflux transporter BCRP. Concomitant administration of products that are inhibitors of BCRP (eg., elbasvir and grazoprevir) may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin may be necessary. Co-administration of elbasvir and grazoprevir with atorvastatin increased atorvastatin exposure (AUC0-∞) by 1.9-fold, whereas the maximum plasma drug concentration (Cmax) increased by 4.3-fold. This was due in part to CYP3A and/or BCRP inhibition; therefore, the dose of EZETAST should not exceed 10/20 mg daily in patients receiving concomitant medication with products containing elbasvir or grazoprevir (see Section 4.4 Special Warnings and Precautions for Use – Skeletal muscle).
When multiple doses of digoxin (0.25 mg QD) and 10 mg atorvastatin were co-administered, steadystate plasma digoxin concentrations were unaffected. However, steady-state plasma digoxin concentrations increased by approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Co-administration of atorvastatin with an oral contraceptive containing norethindrone and ethinyloestradiol increased AUC values for norethindrone and ethinyloestradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking EZETAST.
The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMGCoA reductase inhibitors and daptomycin (see Section 4.4 Special Warnings and Precautions for Use, Skeletal muscle).
Atorvastatin pharmacokinetics were not altered by the co-administration of atorvastatin 80 mg daily and amlodipine 10 mg daily at steady-state. In a drug-drug interaction study in healthy subjects, coadministration of atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to atorvastatin, which was not clinically meaningful.
Co-administration of atorvastatin 10 mg daily and azithromycin (500 mg QD) did not alter the plasma concentrations of atorvastatin.
In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and oestrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with all specific agents have not been conducted.
Ezetimibe had no effects on fertility in male and female rats at doses up to 1000 mg/kg/day by oral gavage, corresponding to exposures of approximately 1 and 7 times the adult human exposure for ezetimibe and total ezetimibe respectively.
The effects of atorvastatin on spermatogenesis and human fertility have not been investigated in clinical studies. Dietary administration of 100 mg atorvastatin/kg/day to rats caused a decrease in spermatid concentration in the testes, a decrease in sperm motility and an increase in sperm abnormalities. Similar effects, however, were not observed in male rats dosed by gavage to 175 mg/kg/day (plasma AUC for HMG-CoA reductase inhibitory activity 14 times higher than in humans dosed at 80 mg/day) and male fertility was not affected in either study. No adverse effects on fertility or reproduction were observed in female rats given doses up to 225 mg/kg/day (plasma AUC for enzyme inhibitory activity 56 times higher than in humans dosed at 80 mg/day). Atorvastatin caused no adverse effects on sperm or semen parameters, or on reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years (Plasma AUC for enzyme inhibitory activity 13 times higher than in humans).
Category D
The definition of Pregnancy Category D is drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
EZETAST is contraindicated in pregnancy. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolaemia. Cholesterol and other products of cholesterol biosynthesis are essential components for foetal development (including synthesis of steroids and cell membranes).
EZETAST should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential. If the patient becomes pregnant while taking this drug, therapy should be discontinued and the patient apprised of the potential hazard to the foetus (see Section 4.3 Contraindications).
No clinical data on exposed pregnancies are available. Ezetimibe crossed the placenta in rats and rabbits. There was no evidence of foetal abnormalities in rats dosed with up to 1000 mg/kg/day of ezetimibe by oral gavage during organogenesis, corresponding to exposures of about 1 and 7 times the adult human exposure for ezetimibe and total ezetimibe respectively, based on AUC. There was an increase in the incidence of extra thoracic ribs in rabbits at doses of 250 to 1000 mg/kg/day, corresponding to exposures of 0.5 to 1 times and 100 to 150 times the adult human exposure for ezetimibe and total ezetimibe, respectively. The relevance of this finding to humans is not known.
Ezetimibe in combination with statins, including atorvastatin, in rats and rabbits resulted in higher exposures to ezetimibe and/or statins than either drug administered alone. Skeletal malfunctions (hemivertebrae in rats and shortened /filamentous tail associated with fused and reduced number of caudal vertebrae in rabbits) and other less severe foetal abnormalities were observed in rats and rabbits dosed with ezetimibe/statin combinations during organogenesis.
Embryofoetal studies in rats showed no adverse foetal effects of oral ezetimibe/fenofibrate doses corresponding to 5 times (total ezetimibe) and 38 times (fenofibric acid) the anticipated human plasma exposure at the maximum recommended doses. In similar studies in rabbits, a No Effect Level for embryotoxicity was established at ca. 90 times (total ezetimibe) and 32 times (fenofibric acid) anticipated human exposure levels.
Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women.
HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
Atorvastatin crosses the rat placenta and reaches a level in foetal liver equivalent to that in maternal plasma. Animal reproduction studies showed no evidence of teratogenic activity in rats or rabbits at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Increased post-implantation loss, decreased foetal weight and increased skeletal variations were observed in rats dosed at 100–300 mg/kg/day and rabbits dosed at 50–100 mg/kg/day. In a peri/post-natal study, rats dosed at 225 mg/kg/day showed an increased incidence of stillbirths, decreases in birthweight, an increased incidence of dilated renal pelvis, increased postnatal mortality, suppression of pup growth, retardation of physical development and abnormal behavioural development; some of these effects were also observed at the non-maternotoxic dose of 100 mg/kg/day; the plasma AUC for HMG-CoA reductase inhibitory activity at the no effect dose level of 20 mg/kg/day was similar to that in humans dosed at 80 mg/day.
In two series of 178 and 143 cases where pregnant women took a HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy serious foetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetus occurring after a pregnant woman is exposed to HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in women exposed to HMG-CoA reductase inhibitors is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist.
Ezetimibe/Atorvastatin is contraindicated in nursing mothers. Because of the potential for serious adverse reactions in a breastfed infant, women who are nursing should not take Ezetimibe/Atorvastatin (see Section 4.3 Contraindications). No studies in lactating animals have been conducted with the combination of ezetimibe and atorvastatin.
Studies in rats have shown that ezetimibe is excreted in milk. Ezetimibe had no effects on pup development in rats treated with up to 1000 mg/kg/day of ezetimibe during late pregnancy and lactation. Drug exposures (based on AUC) in pups were approximately 1.5% and 50% of maternal exposures for ezetimibe and total ezetimibe respectively. It is not known whether ezetimibe is excreted into human breast milk.
In rats, plasma concentrations of atorvastatin are similar to those in milk. It is not known whether atorvastatin is excreted in human milk.
No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects that have been reported with ezetimibe and atorvastatin tablets may affect some patients' ability to drive or operate machinery. Individual responses to EZETAST may vary (see Section 4.8 Adverse Effects (Undesirable Effects)).
Co-administration of ezetimibe and atorvastatin has been evaluated for safety in more than 2,400 patients in 7 clinical trials. Co-administration of ezetimibe and atorvastatin was generally well-tolerated. Table 2 summarises the common (≥1.0% in any group) drug-related adverse events by system organ class and preferred term.
Table 2. Drug-related Adverse Events Occurring in ≥1.0% in Patients Receiving Atorvastatin or Co-Administered Ezetimibe and Atorvastatina:
| Atorvastatina (%) N=2521 | Co-administered ezetimibe and atorvastatina (%) N=2523 | |
|---|---|---|
| Gastrointestinal disorders | ||
| Diarrhoea | 0.7 | 1.0 |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 1.2 | 1.5 |
a All doses.
In a placebo-controlled clinical trial in 628 patients with hyperlipidaemia (P0692), in which patients were treated for up to 12 weeks, the most commonly reported adverse reactions (incidence ≥2% and greater than placebo) were:
Table 3. Clinical and Selected Laboratory Adverse Reactions Occurring in ≥2% of Patients Treated with Co-Administered Ezetimibe and Atorvastatin* and at an Incidence Greater then Placebo, Regardless of Causality:
| Body System/Organ Class Adverse Reaction | Placebo (%) N=60 | Ezetimibe 10 mg (%) N=65 | Atorvastatin† (%) N=248 | Eze/Atorva† (%) N=255 |
|---|---|---|---|---|
| Nervous system disorders | ||||
| Dizziness | 0 | 6 | <1 | 2 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Coughing | 0 | 3 | <1 | 2 |
| Gastrointestinal disorders | ||||
| Abdominal pain | 2 | 2 | 4 | 3 |
| Nausea | 0 | 2 | 5 | 3 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 0 | 5 | 6 | 3 |
| Muscle weakness | 0 | 2 | 0 | 2 |
| Musculoskeletal pain | 3 | 8 | 5 | 4 |
| Metabolism and nutrition disorders | ||||
| Hyperkalaemia | 0 | 0 | <1 | 2 |
| Infections and infestations | ||||
| Bronchitis | 0 | 2 | 2 | 2 |
| Sinusitis | 0 | 3 | 2 | 2 |
| Vascular disorders | ||||
| Hot flushes | 0 | 0 | <1 | 2 |
| Investigations | ||||
| ALT increased | 0 | 0 | 2 | 5 |
| AST increased | 0 | 0 | <1 | 4 |
* Equivalent to EZETAST.
† All doses.
The following other uncommon (≥1/1000, <1/100) drug-related adverse experiences by system organ class and preferred term were reported in patients taking co-administered ezetimibe and atorvastatin:
Uncommon: influenza.
Uncommon: depression, insomnia, sleep disorder.
Uncommon: dysgeusia, paraesthesia, dizziness, headache.
Dyspnoea
Uncommon: sinus bradycardia.
Uncommon: hot flush.
Uncommon: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, frequent bowel movements, stomach discomfort, upset stomach, abdominal distension, constipation, dyspepsia, flatulence, gastritis, nausea.
Uncommon: acne; urticaria.
Uncommon: arthralgia, back pain, muscle fatigue, muscular weakness, pain in extremity, muscle spasms, musculoskeletal stiffness.
Uncommon: asthenia, oedema, fatigue, malaise.
Uncommon: ALT and/or AST increased, alkaline phosphatase increased, gammaglutamyltransferase increased, hepatic enzyme increased, liver function test abnormal, weight increased, blood CK increased.
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 co-administered ezetimibe and atorvastatin. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline spontaneously or after discontinuation of therapy (see Section 4.4 Special Warnings and Precautions for Use).
Persistent increases in serum transaminases >3 x ULN occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2, 0.2, 0.6, and 2.3% for 10, 20, 40, and 80 mg respectively. Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced or drug treatment interrupted or discontinued, transaminase levels returned to pre-treatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
In controlled clinical studies, the incidence of consecutive elevations (≥3 X the upper limit of normal [ULN]) in hepatic transaminase levels was similar between ezetimibe (0.5%) and placebo (0.3%).
Gastrointestinal disorders and musculoskeletal and connective tissue disorders contributed to the majority of adverse experiences which lead to discontinuation in clinical trials. A total of 37 (0.7%) of 5,169 patients discontinued due to gastrointestinal adverse experiences; 2 (3.3%) of 60 patients in the placebo group, 0 of 65 patients in the ezetimibe monotherapy group, 20 (0.8%) of 2,521 patients in the atorvastatin monotherapy group, and 15 (0.6%) of 2,523 patients in the ezetimibe + atorvastatin co-administration group. A total of 28 (0.5%) of 5,169 patients discontinued due to musculoskeletal adverse experiences; 13 (0.5%) of 2,521 patients on atorvastatin monotherapy and 15 (0.6%) of 2,523 patients on ezetimibe + atorvastatin. The most frequently reported adverse experiences causing discontinuation were nausea; 7 (0.3%) and 3 (0.1%) patients, respectively, and myalgia, 8 (0.3%) and 8 (0.3%) patients, respectively, in the atorvastatin monotherapy and ezetimibe + atorvastatin treatment groups.
In a ezetimibe and atorvastatin placebo-controlled clinical trial, 628 patients (age range 18-86 years, 59% women, 85% Caucasians, 6% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 12 weeks, 6% of patients on ezetimibe and atorvastatin tablets and 5% of patients on placebo discontinued due to adverse reactions.
The most common adverse reactions in the group treated with ezetimibe and atorvastatin tablets that led to treatment discontinuation and occurred at a rate greater than placebo were:
The following additional adverse reactions have been reported in post-marketing use with coadministered ezetimibe and atorvastatin or in clinical studies or post-marketing use with ezetimibe or atorvastatin. Not all effects listed have been causally associated with ezetimibe or atorvastatin.
Eye disorders: vision blurred, visual disturbance.
Infections and infestations: nasopharyngitis, urinary tract infection, infection, sinusitis, pharyngitis.
Blood and lymphatic system disorders: thrombocytopenia.
Immune system disorders: hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.
Metabolism and nutrition disorders: decreased appetite, anorexia, hyperglycaemia; hypoglycaemia.
Nervous system disorders: hypoesthesia, dysgeusia, amnesia, peripheral neuropathy.
Psychiatric disorders: nightmare.
Ear and labyrinth disorders: tinnitus, deafness.
Vascular disorders: hypertension, haemorrhagic stroke.
Respiratory, thoracic, and mediastinal disorders: cough, pharyngolaryngeal pain, epistaxis, asthma.
Gastrointestinal disorders: pancreatitis, gastroesophageal reflux disease, eructation, vomiting, dry mouth.
Hepatobiliary disorders: hepatitis, cholelithiasis, cholecystitis, hepatic failure, cholestasis.
Skin and subcutaneous tissue disorders: pruritus, skin rash, angioneurotic oedema, dermatitis bullous (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrosis), alopecia.
Musculoskeletal and connective tissue disorders: immune mediated necrotising myopathy, myopathy/rhabdomyolysis which may be fatal (examples of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure and cardiac arrhythmia (see Section 4.4 Special Warnings and Precautions for Use), neck pain, joint swelling, musculoskeletal pain, myositis, tendonopathy (sometimes complicated by rupture).
Reproductive system and breast disorders: gynaecomastia, erectile dysfunction.
General disorders and administration site conditions: chest pain, pain, oedema peripheral, pyrexia.
Injury, poisoning and procedural complications: tendon rupture, injury.
Investigations: white blood cells urine positive.
The following adverse events have been reported with some statins:
A post-hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or TIA, showed an increased risk of haemorrhagic stroke in patients with prior haemorrhagic stroke or prior lacunar infarct (see Section 4.4 Special Warnings and Precautions for Use).
In ASCOT (see Section 5.1 Pharmacodynamic Properties – Clinical Trials, Prevention of Cardiovascular Disease) involving 10,305 participants treated with atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.
There has been rare post-marketing reports of cognitive impairment (eg. 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 of 3 weeks).
In a co-administration study with fenofibrate (see Section 5.1 Pharmacodynamic Properties – Clinical Trials), in which 292 patients were exposed for ≥24 weeks and 120 exposed for ≥52 weeks, the incidence rate of cholecystectomy in the co-administration group was 1.7% (95% CI 0.6, 4.0) per 100 patient years (PY) compared to 0 (95% CI 0, 9.2) per 100 PY for the ezetimibe group and 0.6% (95% CI 0, 3.1) per 100 PY for the fenofibrate group. Longer term safety outcomes have not been studied.
Please see the individual Product Information documents for atorvastatin and ezetimibe for further information on adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
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