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.
Ezetimibe/atorvastatin combination is contraindicated during pregnancy. No clinical data are available on the use of ezetimibe/atorvastatin during pregnancy. Ezetimibe/atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with ezetimibe/atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
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. 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.
Ezetimibe/atorvastatin combination is contraindicated during breast-feeding. Because of the potential for serious adverse reactions, women taking ezetimibe/atorvastatin 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 ezetimibe/atorvastatin are secreted into human breast milk.
Women of childbearing potential should use appropriate contraceptive measures during treatment.
No fertility studies were conducted with ezetimibe/atorvastatin.
In animal studies atorvastatin had no effect on male or female fertility.
Ezetimibe had no effect on the fertility of male or female rats.
Ezetimibe/atorvastatin combination 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.
Ezetimibe/atorvastatin fixed-dose combination has been evaluated for safety in more than 2,400 patients in 7 clinical trials.
Adverse reactions observed in clinical studies of ezetimibe/atorvastatin or ezetimibe or atorvastatin or reported from post-marketing use with ezetimibe/atorvastatin or ezetimibe or atorvastatin are listed in the table below. 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).
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 |
| 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 ezetimibe/atorvastatin. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline spontaneously or after discontinuation of therapy.
The following adverse events have been reported with some statins:
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