Amlodipine

Chemical formula: C₂₀H₂₅ClN₂O₅  Molecular mass: 408.876 g/mol  PubChem compound: 2162

Interactions

Amlodipine interacts in the following cases:

mTOR inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

Cardiac failure

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

CYP3A4 inducers

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Hepatic impairment

The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Grapefruit

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Strong or moderate CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

Antihypertensive

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

Cyclosporine

No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0%-40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.

Dantrolene

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Hypertensive crisis

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Pregnancy

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.

Nursing mothers

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 breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

Carcinogenesis, mutagenesis and fertility

Fertility

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.

Effects on ability to drive and use machines

Amlodipine can have minor 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. Caution is recommended especially at the start of treatment.

Adverse reactions


Summary of the safety profile

The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

Tabulated list of adverse reactions

The following adverse reactions have been observed and reported during treatment with amlodipine with the following frequencies: 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class Frequency Adverse reactions
Blood and lymphatic system disorders Very rare Leukocytopenia,
thrombocytopenia
Immune system disorders Very rare Allergic reactions
Metabolism and nutrition disorders Very rare Hyperglycaemia
Psychiatric disorders Uncommon Depression, mood changes (including anxiety), insomnia
Rare Confusion
Nervous system disorders Common Somnolence, dizziness, headache (especially at
the beginning of the treatment)
Uncommon Tremor, dysgeusia, syncope, hypoaesthesia,
paraesthesia
Very rare Hypertonia,
peripheral neuropathy
Not known Extrapyramidal disorder
Eye disorders Common Visual disturbance (including diplopia)
Ear and labyrinth disorders Uncommon Tinnitus
Cardiac disorders Common Palpitations
UncommonArrhythmia (including bradycardia, ventricular
tachycardia and atrial fibrillation)
Very rare Myocardial infarction
Vascular disorders Common Flushing
Uncommon Hypotension
Very rare Vasculitis
Respiratory, thoracic and mediastinal
disorders
Common Dyspnoea
Uncommon Cough, rhinitis
Gastrointestinal disorders Common Abdominal pain, nausea, dyspepsia, altered bowel
habits (including diarrhoea and constipation)
Uncommon Vomiting, dry mouth
Very rare Pancreatitis, gastritis, gingival hyperplasia
Hepatobiliary disorders Very rare Hepatitis, jaundice, hepatic enzyme increased*
Skin and subcutaneous tissue disorders Uncommon Alopecia, purpura, skin discolouration,
hyperhidrosis, pruritus, rash, exanthema, urticaria
Very rare Angioedema, erythema multiforme, exfoliative
dermatitis, Stevens-Johnson syndrome, Quincke
oedema, photosensitivity
Not known Toxic epidermal necrolysis
Musculoskeletal and connective tissue
disorders
Common Ankle swelling, muscle cramps
Uncommon Arthralgia, myalgia, back pain
Renal and urinary disorders Uncommon Micturition disorder, nocturia, increased urinary
frequency
Reproductive system and breast
disorders
Uncommon Impotence, gynaecomastia
General disorders and administration site
conditions
Very commonOedema
Common Fatigue, asthenia
Uncommon Chest pain, pain, malaise
Investigations Uncommon Weight increased, weight decreased

* mostly consistent with cholestasis

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