NATRIXAM Indapamide / Amlodipine Besilate 1.5mg / 10mg Modified-Release Tablet 1's

Indapamide + Amlodipine (Natrixam) is indicated as substitution therapy for treatment of essential hypertension in patients already controlled with indapamide and amlodipine given concurrently at the same dose level.

 

One tablet per day as single dose, preferably to be taken in the morning, to be swallowed whole with water and not chewed.
The fixed dose combination is not suitable for initiation therapy.
If a change of the posology is required, titration should be done with the individual components.
Pediatric population: The safety and efficacy of Indapamide + Amlodipine (Natrixam) in children and adolescents have not been established.
No data are available.
Patients with renal impairment: In severe renal impairment (creatinine clearance below 30 mL/min), treatment is contraindicated.
In patients with mild to moderate renal impairment, no dose adjustment is needed.
Older people: Older people can be treated with Indapamide + Amlodipine (Natrixam) according to renal function.
Patients with hepatic impairment: In severe hepatic impairment, treatment is contraindicated.
Dosage recommendations of amlodipine 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.
Method of administration: Oral administration.
Missed Dose: If a dose is forgotten, leave out that dose completely. Take the next dose at the right time. Do not take a double dose to make up for a forgotten dose.
Discontinuation of Treatment: As the treatment for high blood pressure is usually life-long, patient should discuss with the doctor before stopping this medicinal product.
If patient has any further questions on the use of this medicine, ask the doctor or pharmacist.

 

Overdosage

May be taken with or without food: Swallow whole w/ water, do not chew.

Hypersensitivity to the active substances, to other sulfonamides, to dihydropyridine derivatives or to any of the excipients; severe renal failure (creatinine clearance below 30 mL/min); hepatic encephalopathy or severe impairment of liver function; hypokalemia; lactation; severe hypotension; shock (including cardiogenic shock); obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis); hemodynamically unstable heart failure after acute myocardial infarction.

 

Warnings

Hypertensive crisis: The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Water and electrolyte balance: Plasma sodium: This must be measured before starting treatment, then at regular intervals subsequently. The fall in plasma sodium may be asymptomatic initially and regular monitoring is therefore essential, and should be even more frequent in the elderly and cirrhotic patients.
Any diuretic treatment may cause hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may be responsible of dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the incidence and degree of this effect are slight.
Plasma potassium: Potassium depletion with hypokalemia is the major risk of thiazide and related diuretics. The risk of onset of hypokalemia (<3.4 mmol/L) must be prevented in certain high risk populations, i.e. the elderly, malnourished and/or polymedicated, cirrhotic patients with edema and ascites, coronary artery disease and cardiac failure patients. In this situation, hypokalemia increases the cardiac toxicity of digitalis preparations and the risks of arrhythmias.
Individuals with a long QT interval are also at risk, whether the origin is congenital or iatrogenic. Hypokalemia, as well as bradycardia, is then a predisposing factor to the onset of severe arrhythmias, in particular, potentially fatal torsades de pointes.
More frequent monitoring of plasma potassium is required in all the situations indicated previously. The first measurement of plasma potassium should be obtained during the first week following the start of treatment.
Detection of hypokalemia requires its correction.
Plasma calcium: Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in plasma calcium. Frank hypercalcemia may be due to previously unrecognized hyperparathyroidism.
Treatment should be withdrawn before the investigation of parathyroid function.
Blood glucose: Due to the presence of indapamide, monitoring of blood glucose is important in diabetics, in particular in the presence of hypokalemia.
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 edema 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.
Renal function: Thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired (plasma creatinine below levels of the order of 25 mg/L, i.e. 220 μmol/L in an adult). In the elderly, this plasma creatinine must be adjusted in relation to age, weight and gender.
Hypovolemia, secondary to the loss of water and sodium induced by the diuretic at the start of treatment causes a reduction in glomerular filtration. This may lead to an increase in blood urea and plasma creatinine. This transitory functional renal insufficiency is of no consequence in individuals with normal renal function but may worsen preexisting renal insufficiency.
Amlodipine may be used in patients with renal failure at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable.
The effect of the combination Indapamide + Amlodipine (Natrixam) has not been tested in renal dysfunction. In renal impairment, Indapamide + Amlodipine (Natrixam) doses should respect those of the individual components taken individually.
Uric acid: Due to the presence of indapamide, tendency to gout attacks may be increased in hyperuricemic patients.
Hepatic function: The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose.
The effect of the combination Indapamide + Amlodipine (Natrixam) has not been tested in hepatic dysfunction. Taking into account the effect of indapamide and amlodipine, Indapamide + Amlodipine (Natrixam) is contraindicated in patients with severe hepatic impairment, and caution should be exercised in patients with mild to moderate hepatic impairment.
Excipients: Indapamide + Amlodipine (Natrixam) should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Driving and Using Machines: Indapamide + Amlodipine (Natrixam) has minor or moderate influence on the ability to drive and use machines: Indapamide does not affect vigilance but different reactions in relation with the decrease in blood pressure may occur in individual cases, especially at the start of the treatment or when another antihypertensive agent is added.
As a result the ability to drive vehicles or to operate machinery may be impaired.
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.
Use in the elderly: Older patients can be treated with Indapamide + Amlodipine (Natrixam) according to renal function.

 

Use In Pregnancy & Lactation

Summary of the safety profile: The most commonly reported adverse reactions with indapamide and amlodipine given separately are hypokalemia, somnolence, dizziness, headache, visual impairment, diplopia, palpitations, flushing, dyspnea, abdominal pain, nausea, dyspepsia, change of bowel habit, diarrhea, constipation, rash maculo-papular, ankle swelling, muscle spasms, edema, fatigue and asthenia.
Tabulated list of adverse reactions: The following adverse reactions have been observed and reported during treatment with indapamide and 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). (See Tables A and B.)

 

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: class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide); some antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol); others: bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine IV.
Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalemia is a risk factor).
Monitor for hypokalemia 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 hypokalemia.
N.S.A.I.Ds. (systemic route) including COX-2 selective inhibitors, high dose salicylic 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. 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 hypokalemic 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 hypokalemic diuretic.
In all cases, monitor renal function (plasma creatinine) during the first weeks of treatment with an A.C.E. inhibitor.
Other compounds causing hypokalemia: amphotericin B (IV), gluco- and mineralo-corticoids (systemic route), tetracosactide, stimulant laxatives: Increased risk of hypokalemia (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: Hypokalemia predisposing to the toxic effects of digitalis.
Monitoring of plasma potassium 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, hypokalemia or hyperkalemia (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 increased (additive effect).
Calcium (salts): Risk of hypercalcemia resulting from decreased urinary elimination of calcium.
Ciclosporine, tacrolimus: Risk of increased plasma creatinine without any change in circulating ciclosporine 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 hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, 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: There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
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 or 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.
Ciclosporine: No drug interaction studies have been conducted with ciclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of ciclosporine were observed. Consideration should be given to monitoring ciclosporine levels in renal transplant patients on amlodipine, and ciclosporine 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.

Storage

Action

Calcium Antagonists / Diuretics