Summary of medicine characteristics - LORVACS XL 1.5 MG PROLONGED-RELEASE TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Lorvacs XL 1.5 mg Prolonged-release Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 1.5 mg indapamide.
Excipient with known effect: 144.22 mg lactose monohydrate For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablet.
White to off-white, round shaped, biconvex, prolonged-release tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Essential hypertension.
4.2 Posology and method of administration
Posology
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.
Special population
Renal impairment (see sections 4.3 and 4.4):
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.
Hepatic impairment (see sections 4.3 and 4.4):
In severe hepatic impairment, treatment is contraindicated.
Elderly (see section 4.4):
In the elderly, the plasma creatinine must be adjusted in relation to age, weight and gender. Elderly patients can be treated with Lorvacs XL 1.5 mg when renal function is normal or only minimally impaired.
Paediatric population:
The safety and efficacy of Lorvacs XL 1.5 mg in children and adolescents have not been established. No data are available.
Method of administration
Oral use
4.3 Contraindications
Hypersensitivity to the active substance, 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
Special warnings
When liver function is impaired, thiazide-related diuretics may cause, particularly in case of electrolyte imbalance, hepatic encephalopathy which can progress to hepatic coma. Administration of the diuretic must be stopped immediately if this occurs.
Photosensitivity:
Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Excipients:
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Special precautions for use
– 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 (see sections 4.8 and 4.9). Any diuretic treatment may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia with hypovolaemia 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 hypokalaemia is the major risk of thiazide and related diuretics. Hypokalaemia may cause muscle disorders. Cases of Rhabdomyolysis have been reported, mainly in the context of severe hypokalaemia.The risk of onset of hypokalaemia (< 3.4 mmol/l) must be prevented in certain high risk populations, i.e. the elderly, malnourished and/or polymedicated, cirrhotic patients with oedema and ascites, coronary artery disease and cardiac failure patients. In this situation, hypokalaemia 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. Hypokalaemia, 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 above. The first measurement of plasma potassium should be obtained during the first week following the start of treatment.
Detection of hypokalaemia requires its correction. Hypokalaemia found in association with low serum magnesium concentration can be refractory to treatment unless serum magnesium is corrected.
Plasma calcium:
Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in plasma calcium. Frank hypercalcaemia may be due to previously unrecognised hyperparathyroidism.
Treatment should be withdrawn before the investigation of parathyroid function.
Plasma magnesium:
Thiazides and related diuretics including indapamide have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see section 4.5 and 4.8).
– Blood glucose:
Monitoring of blood glucose is important in diabetics, in particular in the presence of hypokalaemia.
– Uric acid:
Tendency to gout attacks may be increased in hyperuricaemic patients.
– Renal function and diuretics:
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 ^mol/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 preexisting renal insufficiency.
– Athletes:
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.
Choroidal effusion, acute myopia and secondary angle-closure glaucoma:
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.
Information on sodium content
This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Combinations that are not recommended:
N.S.A.I.D.s (systemic route) including COX-2 selective inhibitors, high dose salicylic acid (>3 g/day):
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.
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 nonstimulant laxatives.
Increased antihypertensive effect.
Hydrate the patient; monitor renal function at the start of treatment.
Hypokalaemia and/or hypomagnesaemia predispose to the toxic effects of digitalis.
Monitoring of plasma potassium, magnesium and ECG and, if necessary, adjust the treatment.
Combinations requiring special care:
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.
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:
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a foeto-placental ischaemia and growth retardation.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Indapamide during pregnancy.
Breast-feeding:
There is insufficient information on the excretion of indapamide/metabolites in human milk. Hypersensitivity to sulfonamide-derived medicines and hypokalaemia might occur. A risk to the newborns/infants cannot be excluded.
Indapamide is closely related to thiazide diuretics which have been associated, during breast-feeding, with decrease or even suppression of milk lactation.
Indapamide is not recommended during breast-feeding.
Fertility:
Reproductive toxicity studies showed no effect on fertility in female and male rats (see section 5.3). No effects on human fertility are anticipated.
4.7 Effects on 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.
4.8 Undesirable effects
Summary of safety profile
The most commonly reported adverse reactions are hypokalaemia, hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions and maculopapular rashes.
During phase II and III studies comparing indapamide 1.5mg and 2.5mg, plasma potassium analysis showed a dose-dependent effect of indapamide:
– Indapamide 1.5mg: 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.
– Indapamide 2.5 mg: Plasma potassium < 3.4 mmol/l was seen in 25% of patients and < 3.2 mmol/l in 10 % of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.41 mmol/l.
Tabulated summary of adverse reactions
The following undesirable effects have been observed with indapamide during treatment 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 (>1/100,000 to <1/10,000), not known (cannot be estimated from the available data).
| MedDRA System Organ Class | Undesirable Effects | Frequency |
| Blood and the lymphatic System Disorders | Agranulocytosis | Very rare |
| Aplastic anaemia | Very rare | |
| Haemolytic anaemia | Very rare | |
| Leucopenia | Very rare | |
| Thrombocytopenia | Very rare | |
| Metabolism and Nutrition Disorders | Hypokalaemia (see section 4.4) | Common |
| Hyponatraemia (see section 4.4) | Uncommon | |
| Hypochloraemia | Rare | |
| Hypomagnesaemia | Rare |
| Hypercalcaemia | Very rare | |
| Nervous System disorders | Vertigo | Rare |
| Fatigue | Rare | |
| Headache | Rare | |
| Paraesthesia | Rare | |
| Syncope | Not known | |
| Eye disorders | Myopia | Not known |
| Blurred vision | Not known | |
| Visual impairment | Not known | |
| Choroidal effusion | Not known | |
| Cardiac Disorders | Arrhythmia | Very rare |
| Torsade de pointes (potentially fatal) (see sections 4.4 and 4.5) | Not known | |
| Vascular Disorders | Hypotension | Very rare |
| Gastrointestinal Disorders | Vomiting | Uncommon |
| Nausea | Rare | |
| Constipation | Rare | |
| Dry mouth | Rare | |
| Pancreatitis | Very rare | |
| Hepatobiliary Disorders | Abnormal hepatic function | Very rare |
| Possibility of onset of hepatic encephalopathy in case of hepatic insufficiency (see sections 4.3 and 4.4) | Not known | |
| Hepatitis | Not known | |
| Skin and Subcutaneous Tissue Disorder | Hypersensitivity reactions | Common |
| Maculopapular rashes | Common | |
| Purpura | Uncommon | |
| Angioedema | Very rare | |
| Urticaria | Very rare | |
| Toxic epidermal necrolysis | Very rare | |
| Stevens-Johnson Syndrome | Very rare | |
| Possible worsening of pre-existing acute disseminated lupus erythematosus | Not known | |
| Photosensitivity reactions (see section 4.4) | Not known | |
| Renal and Urinary Disorders | Renal failure | Very rare |
| Reproductive system and breast disorders | Erectile dysfunction | Uncommon |
| Investigations | Electrocardiogram QT prolonged (see sections 4.4 and 4.5) | Not known |
| Blood glucose increased (see section 4.4) | Not known | |
| Blood uric acid increased (see section 4.4) | Not known | |
| Elevated liver enzyme levels | Not known |
Reporting of suspected adverse reactions
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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Sulfonamides, plain
ATC code: C03BA11
Mechanism of action
Indapamide is a sulphonamide 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.
Pharmacodynamic effects
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
Lorvacs XL 1.5 mg 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. Intra-individual 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.
Metabolism
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
5.3 Preclinical safety dataIndapamide has been tested negative concerning mutagenic and carcinogenic properties.
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.
Reproductive toxicity studies have not shown embryotoxicity and teratogenicity.
Fertility was not impaired either in male or in female rats.
6.1
Lactose monohydrate
Pregelatinised maize starch
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate
Macrogol 6000
Titanium dioxide (E171)
6.2
Not applicable.
6.3
2 years
6.4 Special precautions for storage
This product does not require any special storage conditions.
6.5 Nature and contents of container
10, 14, 15, 20, 30, 50, 60, 90, 100 tablets in blisters (PVC/aluminium).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements.
7 MARKETING AUTHORISATION HOLDER
Torrent Pharma (UK) Ltd.
3rd Floor, Nexus Building,
4 Gatwick Road,
Crawley,
West Sussex,
RH10 9BG,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 36687/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
Date of first authorisation: 22/12/2009
Date of latest renewal: