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 AIIRAs 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.
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
There is no experience on the use of amlodipine/valsartan/hydrochlorothiazide in pregnant women. Based on the existing data with the components, the use of amlodipine/valsartan/hydrochlorothiazide is not recommended during first trimester and contraindicated during the second and third trimester of pregnancy.
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 valsartan during breastfeeding. Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit milk production.
The use of amlodipine/valsartan/hydrochlorothiazide during breast-feeding is not recommended. If amlodipine/valsartan/hydrochlorothiazide is used during breast-feeding, doses should be kept as low as possible. 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/hydrochlorothiazide.
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/hydrochlorothiazide 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/valsartan/hydrochlorothiazide suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.
The safety profile of amlodipine/valsartan/hydrochlorothiazide presented below is based on clinical studies performed with amlodipine/valsartan/hydrochlorothiazide and the known safety profile of the individual components amlodipine, valsartan and hydrochlorothiazide.
The safety of amlodipine/valsartan/hydrochlorothiazide has been evaluated at its maximum dose of 10 mg/320 mg/25 mg in one controlled short-term (8 weeks) clinical study with 2,271 patients, 582 of whom received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient in nature and only infrequently required discontinuation of therapy. In this active controlled clinical trial, the most common reasons for discontinuation of therapy with amlodipine/valsartan/hydrochlorothiazide were dizziness and hypotension (0.7%).
In the 8-week controlled clinical study, no significant new or unexpected adverse reactions were observed with triple therapy treatment compared to the known effects of the monotherapy or dual therapy components.
In the 8-week controlled clinical study, changes in laboratory parameters observed with the combination of amlodipine/valsartan/hydrochlorothiazide were minor and consistent with the pharmacological mechanism of action of the monotherapy agents. The presence of valsartan in the triple combination attenuated the hypokalaemic effect of hydrochlorothiazide.
The following adverse reactions, listed by MedDRA System Organ Class and frequency, concern amlodipine/valsartan/hydrochlorothiazide combination and amlodipine, valsartan and HCT individually. 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/ hydrochlorothiazide | Amlodipine | Valsartan | HCT | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma) | -- | -- | -- | Not known |
| Blood and lymphatic system disorders | Agranulocytosis, bone marrow failure | -- | -- | -- | Very rare |
| Haemoglobin and haematocrit decreased | -- | -- | Not known | -- | |
| Haemolytic anaemia | -- | -- | -- | Very rare | |
| Leukopenia | -- | Very rare | -- | Very rare | |
| Neutropenia | -- | -- | Not known | -- | |
| Thrombocytopenia, sometimes with purpura | -- | Very rare | Not known | Rare | |
| Aplastic anaemia | -- | -- | -- | Not known | |
| Immune system disorders | Hypersensitivity | -- | Very rare | Not known | Very rare |
| Metabolism and nutrition disorders | Anorexia | Uncommon | -- | -- | -- |
| Hypercalcaemia | Uncommon | -- | -- | Rare | |
| Hyperglycaemia | -- | Very rare | -- | Rare | |
| Hyperlipidaemia | Uncommon | -- | -- | -- | |
| Hyperuricaemia | Uncommon | -- | -- | Common | |
| Hypochloraemic alkalosis | -- | -- | -- | Very rare | |
| Hypokalaemia | Common | -- | -- | Very common | |
| Hypomagnesaemia | -- | -- | -- | Common | |
| Hyponatraemia | Uncommon | -- | -- | Common | |
| Worsening of diabetic metabolic state | -- | -- | -- | Rare | |
| Psychiatric disorders | Depression | -- | Uncommon | -- | Rare |
| Insomnia/sleep disorders | Uncommon | Uncommon | -- | Rare | |
| Mood swings | -- | Uncommon | -- | -- | |
| Confusion | -- | Rare | -- | -- | |
| Nervous system disorders | Coordination abnormal | Uncommon | -- | -- | -- |
| Dizziness | Common | Common | -- | Rare | |
| Dizziness postural, dizziness exertional | Uncommon | -- | -- | -- | |
| Dysgeusia | Uncommon | Uncommon | -- | -- | |
| Extrapyramidal syndrome | -- | Not known | -- | -- | |
| Headache | Common | Common | -- | Rare | |
| Hypertonia | -- | Very rare | -- | -- | |
| Lethargy | Uncommon | -- | -- | -- | |
| Paraesthesia | Uncommon | Uncommon | -- | Rare | |
| Peripheral neuropathy, neuropathy | Uncommon | Very rare | -- | -- | |
| Somnolence | Uncommon | Common | -- | -- | |
| Syncope | Uncommon | Uncommon | -- | -- | |
| Tremor | -- | Uncommon | -- | -- | |
| Hypoesthesia | -- | Uncommon | -- | -- | |
| Eye disorders | Acute angle-closure glaucoma | -- | -- | -- | Not known |
| Visual disturbance | -- | Uncommon | -- | -- | |
| Visual impairment | Uncommon | Uncommon | -- | Rare | |
| Choroidal effusion | -- | -- | -- | Not Known | |
| Ear and labyrinth disorders | Tinnitus | -- | Uncommon | -- | -- |
| Vertigo | Uncommon | -- | Uncommon | -- | |
| Cardiac disorders | Palpitations | -- | Common | -- | -- |
| Tachycardia | Uncommon | -- | -- | -- | |
| Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) | -- | Very rare | -- | Rare | |
| Myocardial infarction | -- | Very rare | -- | -- | |
| Vascular disorders | Flushing | -- | Common | -- | -- |
| Hypotension | Common | Uncommon | -- | -- | |
| Orthostatic hypotension | Uncommon | -- | -- | Common | |
| Phlebitis, thrombophlebitis | Uncommon | -- | -- | -- | |
| Vasculitis | -- | Very rare | Not known | -- | |
| Respiratory, thoracic and mediastinal disorders | Cough | Uncommon | Very rare | Uncommon | -- |
| Dyspnoea | Uncommon | Uncommon | -- | -- | |
| Acute respiratory distress syndrome (ARDS) | -- | -- | -- | Very rare | |
| Respiratory distress, pulmonary oedema, pneumonitis | -- | -- | -- | Very rare | |
| Rhinitis | -- | Uncommon | -- | -- | |
| Throat irritation | Uncommon | -- | -- | -- | |
| Gastrointestinal disorders | Abdominal discomfort, abdominal pain upper | Uncommon | Common | Uncommon | Rare |
| Breath odour | Uncommon | -- | -- | -- | |
| Change of bowel habit | -- | Uncommon | -- | -- | |
| Constipation | -- | -- | -- | Rare | |
| Decreased appetite | -- | -- | -- | Common | |
| Diarrhoea | Uncommon | Uncommon | -- | Rare | |
| Dry mouth | Uncommon | Uncommon | -- | -- | |
| Dyspepsia | Common | Uncommon | -- | -- | |
| Gastritis | -- | Very rare | -- | -- | |
| Gingival hyperplasia | -- | Very rare | -- | -- | |
| Nausea | Uncommon | Common | -- | Common | |
| Pancreatitis | -- | Very rare | -- | Very rare | |
| Vomiting | Uncommon | Uncommon | -- | Common | |
| Hepatobiliary disorders | Liver function test abnormal, including blood bilirubin increase | -- | Very rare** | Not known | -- |
| Hepatitis | -- | Very rare | -- | -- | |
| Intrahepatic cholestasis, jaundice | -- | Very rare | -- | Rare | |
| Skin and subcutaneous tissue disorders | Alopecia | -- | Uncommon | -- | -- |
| Angioedema | -- | Very rare | Not known | -- | |
| Dermatitis bullous | -- | -- | Not known | -- | |
| Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus | -- | -- | -- | Very rare | |
| Erythema multiforme | -- | Very rare | -- | Not known | |
| Exanthema | -- | Uncommon | -- | -- | |
| Hyperhidrosis | Uncommon | Uncommon | -- | -- | |
| Photosensitivity reaction | -- | Very rare | -- | Rare | |
| Pruritus | Uncommon | Uncommon | Not known | -- | |
| Purpura | -- | Uncommon | -- | Rare | |
| Rash | -- | Uncommon | Not known | Common | |
| Skin discoloration | -- | Uncommon | -- | -- | |
| Urticaria and other forms of rash | -- | Very rare | -- | Common | |
| Vasculitis necrotising and toxic epidermal necrolysis | -- | Not known | -- | Very rare | |
| Exfoliative dermatitis | -- | Very rare | -- | -- | |
| Stevens-Johnson syndrome | -- | Very rare | -- | -- | |
| Quincke oedema | -- | Very rare | -- | -- | |
| Musculoskeletal and connective tissue disorders | Arthralgia | -- | Uncommon | -- | -- |
| Back pain | Uncommon | Uncommon | -- | -- | |
| Joint swelling | Uncommon | -- | -- | -- | |
| Muscle spasm | Uncommon | Uncommon | -- | Not known | |
| Muscular weakness | Uncommon | -- | -- | -- | |
| Myalgia | Uncommon | Uncommon | Not known | -- | |
| Pain in extremity | Uncommon | -- | -- | -- | |
| Ankle swelling | -- | Common | -- | -- | |
| Renal and urinary disorders | Blood creatinine increased | Uncommon | -- | Not known | -- |
| Micturition disorder | -- | Uncommon | -- | -- | |
| Nocturia | -- | Uncommon | -- | -- | |
| Pollakiuria | Common | Uncommon | -- | -- | |
| Renal dysfunction | -- | -- | -- | Not known | |
| Acute renal failure | Uncommon | -- | -- | Not known | |
| Renal failure and impairment | -- | -- | Not known | Rare | |
| Reproductive system and breast disorders | Impotence | Uncommon | Uncommon | -- | Common |
| Gynaecomastia | -- | Uncommon | -- | -- | |
| General disorders and administration site conditions | Abasia, gait disturbance | Uncommon | -- | -- | -- |
| Asthenia | Uncommon | Uncommon | -- | Not known | |
| Discomfort, malaise | Uncommon | Uncommon | -- | -- | |
| Fatigue | Common | Common | Uncommon | -- | |
| Non cardiac chest pain | Uncommon | Uncommon | -- | -- | |
| Oedema | Common | Common | -- | -- | |
| Pain | -- | Uncommon | -- | -- | |
| Pyrexia | -- | -- | -- | Not known | |
| Investigations | Lipids increased | -- | -- | -- | Very common |
| Blood urea nitrogen increased | Uncommon | -- | -- | -- | |
| Blood uric acid increased | Uncommon | -- | -- | -- | |
| Glycosuria | -- | -- | -- | Rare | |
| Blood potassium decreased | Uncommon | -- | -- | -- | |
| Blood potassium increased | -- | -- | Not known | -- | |
| Weight increase | Uncommon | Uncommon | -- | -- | |
| Weight decrease | -- | Uncommon | -- | -- | |
** Mostly consistent with cholestasis
Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed.
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