CARDIDE SR 1.5 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Cardide SR 1.5 mg Prolonged-Release Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Prolonged-Release Tablet contains 1.5 mg indapamide.

Excipient(s) with known effect:

118.86 mg lactose monohydrate per tablet

For the full list of excipients, see section 6.1.

Prolonged-release tablet.

White, biconvex, round tablets debossed “1.5” on one side and plain on the other.

4.1 Therapeutic indications

Essential hypertension.

4.2 Posology and method of administration

Posology

Patients with renal impairment

In severe renal failure (creatinine clearance below 30 ml/min), treatment is contraindicated.

Thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired. (see sections 4.3 and 4.4)

Elderly

In the elderly, the plasma creatinine must be adjusted in relation to age, weight and gender. Elderly patients can be treated with Cardide SR when renal function is normal or only minimally impaired. (see section 4.4)

Patients with hepatic impairment

In severe hepatic impairment, treatment is contraindicated. (see sections 4.3 and 4.4)

Paediatric population

Cardide SR Prolonged-release tablets are not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Method of administration

For oral use.

One tablet per 24 hours, preferably in the morning, to be swallowed whole with water and not chewed.

At higher doses the antihypertensive action of indapamide is not enhanced but the saluretic effect is increased.

4.3 Contraindications

– Hypersensitivity to active substance, to other sulfonamides or to any of the excipients listed in section 6.1.

– Severe renal failure.

– Hepatic encephalopathy or severe impairment of liver function.

– Hypokalaemia.

4.4 Special warnings and precautions for use

Monitoring of blood glucose is important in diabetics, in particular in the presence of hypokalaemia.

Tendency to gout attacks may be increased in hyperuricaemic patients.

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 |imol/l in an adult). In the elderly, this plasma creatinine must be adjusted in relation to age, weight and gender.

Hypovolaemia, 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 pre-existing renal insufficiency.

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

The attention of athletes is drawn to the fact that this medicinal product contains a drug substance, which may give a positive reaction in doping tests.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations that are not recommended:

Increased plasma lithium with signs of overdosage, 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:

N.S.A.I.Ds. (systemic route) including COX-2 selective inhibitors, high dose acetylsalicylic acid (> 3 g/day):

Risk of sudden hypotension and/or acute renal failure when treatment with an A.C.E. is initiated in the presence of pre-existing 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.

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.

Increased antihypertensive effect.

Hydrate the patient; monitor renal function at the start of treatment.

Hypokalaemia predisposing to the toxic effects of digitalis.

Monitoring of plasma potassium and ECG and, if necessary, adjust the treatment.

Combinations to be taken into consideration:

Whilst rational combinations are useful in some patients, hypokalaemia (particularly in patients with renal failure or diabetes) or hyperkalaemia may still occur. Plasma potassium and ECG should be monitored and, if necessary, treatment reviewed.

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 |imol/l) in men and 12 mg/l (110 |imol/l) in women.

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.

Antihypertensive effect and increased risk of orthostatic hypotension increased (additive effect).

Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

Risk of increased plasma creatinine without any change in circulating ciclosporin levels, even in the absence of water/sodium depletion.

Decreased antihypertensive effect (water/sodium retention due to corticosteroids).

4.6 Fertility, pregnancy and lactation

Pregnancy:

As a general rule, the administration of diuretics should be avoided in pregnant women and should never be used to treat physiological oedema of pregnancy. Diuretics can cause foetoplacental ischaemia, with a risk of impaired foetal growth.

Breast-feeding:

Breast-feeding is inadvisable (indapamide is excreted in human milk).

4.7 Effects on ability to drive and use machines

Cardide SR has a minor or moderate influence on the ability to drive and use machines.

Cardide SR 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.

4.8 Undesirable effects

The majority of adverse reactions concerning clinical or laboratory parameters are dose-dependent. Thiazide-related diuretics, including Cardide SR, may cause the following undesirable effects ranked under the following frequency:

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).

Very rare: thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

Rare: vertigo, fatigue, headache, paresthesia.

Not known: choroidal effusion, acute myopia, acute angel-closure glaucoma.

Very rare: arrhythmia, hypotension.

Uncommon: vomiting.

Rare: nausea, constipation, dry mouth.

Very rare: pancreatitis.

Very rare: abnormal hepatic function.

Not known: possibility of onset of hepatic encephalopathy in case of hepatic insufficiency (see sections 4.3 and 4.4).

Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions.

Common: maculopapular rashes.

Uncommon: purpura.

Very rare: angioneurotic oedema and/or urticaria, toxic epidermic necrolysis, Steven Johnson syndrome.

Not known: possible worsening of pre-existing acute disseminated lupus erythematosus.

Cases of photosensitivity reactions have been reported (see section 4.4).

Renal and urinary disorders

Very rare: renal failure.

During clinical trials, hypokalaemia (plasma potassium <3.4 mmol/l) was seen in 10% of patients and <3.2 mmol/l in 4% of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.23 mmol/l.

Very Rare: hypercalcaemia.

Not known:

Potassium depletion with hypokalaemia, particularly serious in certain high risk populations (see section 4.4).

Hyponatraemia with hypovolaemia responsible for 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.

Increase in plasma uric acid and blood glucose during treatment blood glucose during treatment: appropriateness of these diuretics must be very carefully weighed in patients with gout or diabetes.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Cardide SR has been found free of toxicity at up to 40 mg, i.e. 27 times the therapeutic dose.

Signs of acute poisoning take the form above all of water/electrolyte disturbances (hyponatraemia, hypokalaemia). Clinically, possibility of nausea, vomiting, hypotension, cramps, vertigo, drowsiness, confusion, polyuria or oliguria possibly to the point of anuria (by hypovolaemia).

Initial measures involve the rapid elimination of the ingested substance(s) by gastric wash-out and/or administration of activated charcoal, followed by restoration of water/electrolyte balance to normal in a specialised centre.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sulfonamides, plain

ATC code: C03 BA11

Mechanism of action

Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, which acts by inhibiting the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.

Clinical efficacy and safety

Phase II and III studies using monotherapy have demonstrated an antihypertensive effect lasting 24 hours. This was present at doses where the diuretic effect was of mild intensity.

The antihypertensive activity of indapamide is related to an improvement in arterial compliance and a reduction in arteriolar and total peripheral resistance.

Indapamide reduces left ventricular hypertrophy.

Thiazide and related diuretics have a plateau therapeutic effect beyond a certain dose, while adverse effects continue to increase. The dose should not be increased if treatment is ineffective.

It has also been shown, in the short-, mid- and long-term in hypertensive patients, that indapamide:

. does not interfere with lipid metabolism: triglycerides, LDL-cholesterol and HDL-cholesterol;

. does not interfere with carbohydrate metabolism, even in diabetic hypertensive patients.

5.2 Pharmacokinetic properties

Indapamide is supplied in a prolonged release dosage based on a matrix system in which the drug substance is dispersed within a support which allows sustained release of indapamide.

Absorption:

The fraction of Indapamide released is rapidly and totally absorbed via the gastrointestinal digestive tract.

Eating slightly increases the rapidity of absorption but has no influence on the amount of the drug absorbed.

Peak serum level following a single dose occurs about 12 hours after ingestion; repeated administration reduces the variation in serum levels between 2 doses. Intraindividual variability exists.

Distribution:

Binding of indapamide to plasma proteins is 79%.

The plasma elimination half-life is 14 to 24 hours (mean 18 hours).

Steady state is achieved after 7 days.

Repeated administration does not lead to accumulation.

Elimination:

Elimination is essentially urinary (70% of the dose) and faecal (22%) in the form of inactive metabolites.

High risk individuals:

Pharmacokinetic parameters are unchanged in renal failure patients.

5.3 Preclinical safety data

The highest doses administered orally to different animal species (40 to 8000 times the therapeutic dose) have shown an exacerbation of the diuretic properties of indapamide. The major symptoms of poisoning during acute toxicity studies with indapamide administered intravenously or intraperitoneally were related to the pharmacological action of indapamide, i.e. bradypnoea and peripheral vasodilation.

Indapamide has been tested negative concerning mutagenic and carcinogenic properties.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate, spray-dried

Hypromellose, Methocel K4M Premium

Silica, colloidal anhydrous

Magnesium stearate

Tablet-coating (Opadry II white 33G28707):

Hypromellose 6cP (E464)

Titanium dioxide (E171)

Lactose monohydrate

Macrogol 3000

Triacetin

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

PVC/PVdC – Aluminium blisters. The pack sizes available are: 10, 14, 15, 20, 28, 30, 50, 60, 90, 98 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

TEVA UK Limited

Brampton Road

Hampden Park

East Sussex

BN22 9AG