Ramipril and Amlodipine interacts in the following cases:
The maximum daily dose is 2.5 mg ramipril.
To find the optimal starting dose and maintenance dose of patients with renal impairment, the patients should be individually titrated using the individual components of amlodipine and ramipril.
Ramipril is slightly dialysable, the medicinal product should be administered few hours after haemodialysis is performed.
Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.
Renal function and serum potassium levels should be monitored during therapy with ramipril/amlodipine. In the case of renal function deterioration, the use of ramipril/amlodipine should be discontinued and replaced by the individual components adequately adjusted.
Ramipril/amlodipine combination is not recommended during the first trimester of pregnancy and 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. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor 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 ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia.
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.
Ramipril/amlodipine combination is not recommended during lactation. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with ramipril/amlodipine should be made taking into account the benefit of breastfeeding to the child and the benefit of amlodipine therapy to the mother.
Because insufficient information is available regarding the use of ramipril during breastfeeding, ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
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. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breastfeeding to the child and the benefit of amlodipine therapy to the mother.
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.
Ramipril/amlodipine combination can have minor or moderate influence on the ability to drive and use machines. Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness, headache, fatigue) may impair the patient’s ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).
This can happen especially at the start of treatment, or when changing over from other preparations. Caution is recommended especially at the start of treatment.
The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.
The most commonly reported adverse reactions during treatment with amlodipine are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.
Adverse reactions frequency is defined 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).
The following adverse drug reactions have been reported during the treatment with ramipril and amlodipine independently:
| System organ class | Frequency | Ramipril | Amlodipine |
|---|---|---|---|
| Blood and lymphatic system disorders | Uncommon | Eosinophilia | |
| Rare | White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased | ||
| Very rare | Leukocytopenia, thrombocytopenia | ||
| Not known | Bone marrow failure, pancytopenia, haemolytic anaemia | ||
| Immune system disorders | Very rare | Allergic reactions | |
| Not known | Anaphylactic or anaphylactoid reactions, antinuclear antibody increased | ||
| Endocrine disorders | Not known | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | |
| Metabolism and nutrition disorders | Common | Blood potassium increased | |
| Uncommon | Anorexia, decreased appetite | ||
| Very rare | Hyperglycaemia | ||
| Not known | Blood sodium decreased | ||
| Psychiatric disorders | Uncommon | Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence | Depression, mood changes (including anxiety), insomnia |
| Rare | Confusional state | Confusion | |
| Not known | Disturbance in attention | ||
| Nervous system disorders | Common | Headache, dizziness | Somnolence, dizziness, headache (especially at the beginning of the treatment |
| Uncommon | Vertigo, paraesthesia, ageusia, dysgeusia | Tremor, dysgeusia, syncope, hypoesthesia, paraesthesia | |
| Rare | Tremor, balance disorder | ||
| Very rare | Hypertonia peripheral neuropathy | ||
| Not known | Cerebral ischemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia | Extrapyramidal disorder | |
| Eye disorders | Common | Visual disturbance (including diplopia) | |
| Uncommon | Visual disturbance including blurred vision | ||
| Rare | Conjunctivitis | ||
| Ear and labyrinth disorders | Uncommon | Tinnitus | |
| Rare | Hearing impaired, tinnitus | ||
| Cardiac disorders | Common | Palpitations | |
| Uncommon | Myocardial ischemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, Oedema peripheral | Arrhythmia, (including bradycardia, ventricular tachycardia and atrial fibrillation) | |
| Very rare | Myocardial infarction | ||
| Vascular disorders | Common | Hypotension, orthostatic blood pressure decreased, syncope | Flushing |
| Uncommon | Flushing | Hypotension | |
| Rare | Vascular stenosis, hypoperfusion, vasculitis | ||
| Very rare | Vasculitis | ||
| Not known | Raynaud’s phenomenon | ||
| Respiratory, thoracic and mediastinal disorders | Common | Non-productive tickling cough, bronchitis, sinusitis, dyspnoea | Dyspnoea |
| Uncommon | Bronchospasm including asthma aggravated, nasal congestion | Cough, rhinitis | |
| Gastrointestinal disorders | Common | Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting | Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea and constipation) |
| Uncommon | Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth | Vomiting, dry mouth | |
| Rare | Glossitis | ||
| Very rare | Pancreatitis, gastritis, gingival hyperplasia | ||
| Not known | Aphthous stomatitis | ||
| Hepatobiliary disorders | Uncommon Hepatic enzymes and/or bilirubin conjugated increased | ||
| Rare | Jaundice cholestatic, hepatocellular damage | ||
| Very rare | Hepatitis, jaundice, hepatic enzymes increased* | ||
| Not known | Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional) | ||
| Skin and subcutaneous tissue disorders | Common | Rash in particular maculo-papular | |
| Uncommon | Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis | Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria | |
| Rare | Exfoliative dermatitis, urticaria, onycholysis | ||
| Very rare | Photosensitivity reaction | Angioedema, erythema, multiforme, exfoliative dermatitis, Stevens- Johnson syndrome, Quincke oedema, photosensitivity | |
| Not known | Toxic Epidermal Necrolysis, Stevens- Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia | Toxic Epidermal Necrolysis (TEN) | |
| Musculoskeletal and connective tissue disorders | Common | Muscle spasms, myalgia | Ankle swelling, muscle cramps |
| Uncommon | Arthralgia | Arthralgia, myalgia, back pain | |
| Renal and urinary disorders | Uncommon | Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased | Micturition disorder, nocturia, increased urinary frequency |
| Reproductive system and breast disorders | Uncommon | Transient erectile impotence, libido decreased | Impotence, gynaecomastia |
| Not known | Gynaecomastia | ||
| General disorders and administration site conditions | Very common | Oedema | |
| Common | Chest pain, fatigue | Fatigue, asthenia | |
| Uncommon | Pyrexia | Chest pain, pain, malaise | |
| Rare | Asthenia | ||
| Investigations | Uncommon | Weight increased, weight decreased |
* most commonly with cholestasis
The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years old, during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:
Tachycardia, nasal congestion and rhinitis, “common” (ie, ≥1/100 to <1/10) in paediatric, and “uncommon” (i.e. ≥1/1,000 to <1/100) in adult population.
Conjunctivitis “common” (ie, ≥1/100 to <1/10) in paediatric and “rare” (i.e. ≥1/10,000 to <1/1,000) in adult population.
Tremor and urticaria “uncommon” (.ie. ≥1/1,000 to <1/100) in paediatric population and “rare” (i.e. ≥1/10,000 to <1/1,000) in adult population.
The overall safety profile for ramipril in paediatric patients does not differ significantly from the safety profile in adults.
Exceptional cases of extrapyramidal syndrome have been reported.
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