Linked to indapamide: Combinations that are not recommended: Lithium: Increased plasma lithium with signs of overdose, as with a salt-free diet (decreased urinary lithium excretion). However, if the use of diuretics is necessary, careful monitoring of plasma lithium and dose adjustment are required.
Combinations requiring precautions for use: Torsades de pointes-inducing medicines such as but not limited to: class Ia antiarrhythmic agents (e.g quinidine, hydroquinidine, disopyramide); class III antiarrhythmic agents (e.g amiodarone, sotalol, dofetilide, ibutilide, bretylium); some antipsychotics: phenothiazines (e.g chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (e.g amisulpride, sulpiride, sultopride, tiapride); butyrophenones (e.g droperidol, haloperidol); other antipsychotic (e.g pimozide); other substances (e.g bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine IV, methadone, astemizole, terfenadine).
Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalaemia is a risk factor).
Monitor for hypokalaemia and correct, if required, before introducing this combination. Clinical, plasma electrolytes and ECG monitoring.
Use substances which do not have the disadvantage of causing torsades de pointes in the presence of hypokalaemia.
N.S.A.I.Ds. (systemic route) including COX-2 selective inhibitors, high dose acetylsalicylic acid (≥ 3 g/day): Possible reduction in the antihypertensive effect of indapamide.
Risk of acute renal failure in dehydrated patients (decreased glomerular filtration). Hydrate the patient; monitor renal function at the start of treatment.
Angiotensin converting enzyme (A.C.E.) inhibitors: Risk of sudden hypotension and/or acute renal failure when treatment with an A.C.E. inhibitor is initiated in the presence of preexisting sodium depletion (particularly in patients with renal artery stenosis).
In hypertension, when prior diuretic treatment may have caused sodium depletion, it is necessary: either to stop the diuretic 3 days before starting treatment with the A.C.E. inhibitor, and restart a hypokalaemic diuretic if necessary; or give low initial doses of the A.C.E. inhibitor and increase the dose gradually.
In congestive heart failure, start with a very low dose of A.C.E. inhibitor, possibly after a reduction in the dose of the concomitant hypokalaemic diuretic.
In all cases, monitor renal function (plasma creatinine) during the first weeks of treatment with an A.C.E. inhibitor.
Other compounds causing hypokalaemia: amphotericin B (IV), gluco- and mineralo-corticoids (systemic route), tetracosactide, stimulant laxatives: Increased risk of hypokalaemia (additive effect).
Monitoring of plasma potassium and correction if required. Must be particularly borne in mind in case of concomitant digitalis treatment. Use non-stimulant laxatives.
Digitalis preparations: Hypokalaemia and/or hypomagnesaemia predispose to the toxic effects of digitalis.
Monitoring of plasma potassium, magnesium and ECG and, if necessary, adjust the treatment.
Baclofen: Increased antihypertensive effect.
Hydrate the patient; monitor renal function at the start of treatment.
Allopurinol: Concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.
Combinations to be taken into consideration: Potassium-sparing diuretics (amiloride, spironolactone, triamterene): Whilst rational combinations are useful in some patients, hypokalaemia or hyperkalaemia (particularly in patients with renal failure or diabetes) may still occur. Plasma potassium and ECG should be monitored and, if necessary, treatment reviewed.
Metformin: Increased risk of metformin induced lactic acidosis due to the possibility of functional renal failure associated with diuretics and more particularly with loop diuretics. Do not use metformin when plasma creatinine exceeds 15 mg/l (135 μmol/l) in men and 12 mg/l (110 μmol/l) in women.
Iodinated contrast media: In the presence of dehydration caused by diuretics, increased risk of acute renal failure, in particular when large doses of iodinated contrast media are used.
Rehydration before administration of the iodinated compound.
Imipramine-like antidepressants, neuroleptics: Antihypertensive effect and increased risk of orthostatic hypotension-(additive effect).
Calcium (salts): Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.
Ciclosporin, tacrolimus: Risk of increased plasma creatinine without any change in circulating ciclosporin levels, even in the absence of water/sodium depletion.
Corticosteroids, tetracosactide (systemic route): Decreased antihypertensive effect (water/sodium retention due to corticosteroids).
Linked to amlodipine: Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
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.
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. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co administered with clarithromycin.
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).
Effects of amlodipine on other medicinal products: The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co administered with amlodipine. 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.
Mechanistic Target of Rapamycin (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.
Ciclosporin: No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of ciclosporin were observed. Consideration should be given to monitoring ciclosporin levels in renal transplant patients on amlodipine, and ciclosporin dose reductions should be made as necessary.
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 to 20 mg daily in patients on amlodipine.