The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension.
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. No information is available regarding the use of amlodipine/valsartan during breast-feeding, therefore administration is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
There are no clinical studies on fertility with amlodipine/valsartan.
Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.
Patients taking amlodipine/valsartan and driving vehicles or using machines should take into account that dizziness or weariness may occasionally occur.
Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.
The safety of amlodipine/valsartan has been evaluated in five controlled clinical studies with 5,175 patients, 2,613 of whom received valsartan in combination with amlodipine. The following adverse reactions were found to be the most frequently occurring or the most significant or severe: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia and hot flush.
Adverse reactions have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
| MedDRA System organ class | Adverse reactions | Frequency | ||
|---|---|---|---|---|
| Amlodipine/valsartan combination | Amlodipine | Valsartan | ||
| Infections and infestations | Nasopharyngitis | Common | -- | -- |
| Influenza | Common | -- | -- | |
| Blood and lymphatic system disorders | Haemoglobin and haematocrit decreased | -- | -- | Not known |
| Leukopenia | -- | Very rare | -- | |
| Neutropenia | -- | -- | Not known | |
| Thrombocytopenia, sometimes with purpura | -- | Very rare | Not known | |
| Immune system disorders | Hypersensitivity | Rare | Very rare | Not known |
| Metabolism and nutrition disorders | Anorexia | Uncommon | -- | -- |
| Hypercalcaemia | Uncommon | -- | -- | |
| Hyperglycaemia | -- | Very rare | -- | |
| Hyperlipidaemia | Uncommon | -- | -- | |
| Hyperuricaemia | Uncommon | -- | -- | |
| Hypokalaemia | Common | -- | -- | |
| Hyponatraemia | Uncommon | -- | -- | |
| Psychiatric disorders | Depression | -- | Uncommon | -- |
| Anxiety | Rare | -- | -- | |
| Insomnia/sleep disorders | -- | Uncommon | -- | |
| Mood swings | -- | Uncommon | -- | |
| Confusion | -- | Rare | -- | |
| Nervous system disorders | Coordination abnormal | Uncommon | -- | -- |
| Dizziness | Uncommon | Common | -- | |
| Dizziness postural | Uncommon | -- | -- | |
| Dysgeusia | -- | Uncommon | -- | |
| Extrapyramidal syndrome | -- | Not known | -- | |
| Headache | Common | Common | -- | |
| Hypertonia | -- | Very rare | -- | |
| Paraesthesia | Uncommon | Uncommon | -- | |
| Peripheral neuropathy, neuropathy | -- | Very rare | -- | |
| Somnolence | Uncommon | Common | -- | |
| Syncope | -- | Uncommon | -- | |
| Tremor | -- | Uncommon | -- | |
| Hypoesthesia | -- | Uncommon | -- | |
| Eye disorders | Visual disturbance | Rare | Uncommon | -- |
| Visual impairment | Uncommon | Uncommon | -- | |
| Ear and labyrinth disorders | Tinnitus | Rare | Uncommon | -- |
| Vertigo | Uncommon | -- | Uncommon | |
| Cardiac disorders | Palpitations | Uncommon | Common | -- |
| Syncope | Rare | -- | -- | |
| Tachycardia | Uncommon | -- | -- | |
| Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) | -- | Very rare | -- | |
| Myocardial infarction | -- | Very rare | -- | |
| Vascular disorders | Flushing | -- | Common | -- |
| Hypotension | Rare | Uncommon | -- | |
| Orthostatic hypotension | Uncommon | -- | -- | |
| Vasculitis | -- | Very rare | Not known | |
| Respiratory, thoracic and mediastinal disorders | Cough | Uncommon | Very rare | Uncommon |
| Dyspnoea | -- | Uncommon | -- | |
| Pharyngolaryngeal pain | Uncommon | -- | -- | |
| Rhinitis | -- | Uncommon | -- | |
| Gastrointestinal disorders | Abdominal discomfort, abdominal pain upper | Uncommon | Common | Uncommon |
| Change of bowel habit | -- | Uncommon | -- | |
| Constipation | Uncommon | -- | -- | |
| Diarrhoea | Uncommon | Uncommon | -- | |
| Dry mouth | Uncommon | Uncommon | -- | |
| Dyspepsia | -- | Uncommon | -- | |
| Gastritis | -- | Very rare | -- | |
| Gingival hyperplasia | -- | Very rare | -- | |
| Nausea | Uncommon | Common | -- | |
| Pancreatitis | -- | Very rare | -- | |
| Vomiting | -- | Uncommon | -- | |
| Hepatobiliary disorders | Liver function test abnormal, including blood bilirubin increase | -- | Very rare* | Not known |
| Hepatitis | -- | Very rare | -- | |
| Intrahepatic cholestasis, jaundice | -- | Very rare | -- | |
| Skin and subcutaneous tissue disorders | Alopecia | -- | Uncommon | -- |
| Angioedema | -- | Very rare | Not known | |
| Dermatitis bullous | -- | -- | Not known | |
| Erythema | Uncommon | -- | -- | |
| Erythema multiforme | -- | Very rare | -- | |
| Exanthema | Rare | Uncommon | -- | |
| Hyperhidrosis | Rare | Uncommon | -- | |
| Photosensitivity reaction | -- | Uncommon | -- | |
| Pruritus | Rare | Uncommon | Not known | |
| Purpura | -- | Uncommon | -- | |
| Rash | Uncommon | Uncommon | Not known | |
| Skin discolouration | -- | Uncommon | -- | |
| Urticaria and other forms of rash | -- | Very rare | -- | |
| Exfoliative dermatitis | -- | Very rare | -- | |
| Stevens-Johnson syndrome | -- | Very rare | -- | |
| Quincke oedema | -- | Very rare | -- | |
| Toxic Epidermal Necrolysis | -- | Not known | -- | |
| Musculoskeletal and connective tissue disorders | Arthralgia | Uncommon | Uncommon | -- |
| Back pain | Uncommon | Uncommon | -- | |
| Joint swelling | Uncommon | -- | -- | |
| Muscle spasm | Rare | Uncommon | -- | |
| Myalgia | -- | Uncommon | Not known | |
| Ankle swelling | -- | Common | -- | |
| Sensation of heaviness | Rare | -- | -- | |
| Renal and urinary disorders | Blood creatinine increased | -- | -- | Not known |
| Micturition disorder | -- | Uncommon | -- | |
| Nocturia | -- | Uncommon | -- | |
| Pollakiuria | Rare | Uncommon | -- | |
| Polyuria | Rare | -- | -- | |
| Renal failure and impairment | -- | -- | Not known | |
| Reproductive system and breast disorders | Impotence | -- | Uncommon | -- |
| Erectile dysfunction | Rare | -- | -- | |
| Gynaecomastia | -- | Uncommon | -- | |
| General disorders and administration site conditions | Asthenia | Common | Uncommon | -- |
| Discomfort, malaise | -- | Uncommon | -- | |
| Fatigue | Common | Common | Uncommon | |
| Facial oedema | Common | -- | -- | |
| Flushing, hot flush | Common | -- | -- | |
| Non cardiac chest pain | -- | Uncommon | -- | |
| Oedema | Common | Common | -- | |
| Oedema peripheral | Common | -- | -- | |
| Pain | -- | Uncommon | -- | |
| Pitting oedema | Common | -- | -- | |
| Investigations | Blood potassium increased | -- | -- | Not known |
| Weight increase | -- | Uncommon | -- | |
| Weight decrease | -- | Uncommon | -- | |
* Mostly consistent with cholestasis
Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower incidence in patients who received the amlodipine/valsartan combination than in those who received amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by dose was as follows:
| % of patients who experienced peripheral oedema | Valsartan (mg) | |||||
| 0 | 40 | 80 | 160 | 320 | ||
| Amlodipine (mg) | 0 | 3,0 | 5,5 | 2,4 | 1,6 | 0,9 |
| 2,5 | 8,0 | 2,3 | 5,4 | 2,4 | 3,9 | |
| 5 | 3,1 | 4,8 | 2,3 | 2,1 | 2,4 | |
| 10 | 10,3 | NA | NA | 9,0 | 9,5 | |
The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the amlodipine/valsartan combination.
Adverse reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential adverse reactions with amlodipine/valsartan as well, even if not observed in clinical trials or during the post-marketing period.
Common: Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.
Uncommon: Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnoea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, increased urinary frequency, impotence, gynaecomastia, chest pain, malaise, weight increase, weight decrease.
Rare: Confusion.
Very rare: Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycaemia, hypertonia, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, hepatic enzymes increased*, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, StevensJohnson syndrome, Quincke oedema, photosensitivity.
Not known: Toxic Epidermal Necrolysis
* mostly consistent with cholestasis
Exceptional cases of extrapyramidal syndrome have been reported.
Not known: Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia, increase of serum potassium, elevation of liver function values including increase of serum bilirubin, renal failure and impairment, elevation of serum creatinine, angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.
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