LISINOPRIL/HYDROCHLOROTHIAZIDE 10/12.5 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Lisinopril/Hy­drochlorothia­zide 10/12.5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg of lisinopril (as dihydrate) and 12.5 mg of hydrochlorothiazide

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Peach-coloured, round tablets (diameter 6 mm), marked LH on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of essential hypertension.

Lisinopril/hy­drochlorothia­zide fixed dose combination is indicated in patients whose blood pressure is not adequately controlled on lisinopril alone (or hydrochlorothiazide alone).

4.2 Posology and method of administration

Posology

The selection of a suitable antihypertensive dose of lisinopril and hydrochlorothiazide will depend upon the clinical evaluation of the patient.

The administration of the fixed combination lisinopril and hydrochlorothiazide is usually recommended after dose titration with the individual components.

When clinically appropriate a direct change from monotherapy to fixed combination may be considered.

10 mg/12.5 mg tablets may be administered in patients whose blood pressure is not adequately controlled by 10 mg lisinopril alone (see section 4.4).

20 mg/12.5 mg tablets and 20 mg /25 mg tablets may be administered in patients whose blood pressure is not adequately controlled by 20 mg lisinopril alone (see section 4.4).

A maximum daily dose of 40 mg lisinopril/25 mg hydrochlorothiazide should not be exceeded.

As with all other medicinal products taken once daily, the tablets should be taken approximately at the same time every day.

Renal impairment

The combination lisinopril /hydrochlorot­hiazide is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min.). In patients with creatinine clearance between 30 and 80 ml/min it may be used only after titration of the individual components.

The recommended initial dose of lisinopril as mono-therapy for these patients is 5–10 mg (see section 4.4).

Diuretic treated patients

Symptomatic hypotension may occur following the initial dose; this is more likely in patients who are volume and/or salt depleted because of diuretic therapy. Diuretics should be discontinued for 2–3 days before starting lisinopril/hy­drochlorothia­zide combination. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose. Renal function and serum potassium should be monitored. The subsequent dose of lisinopril should be adjusted according to blood pressure response. If required, diuretic therapy may be resumed (see section 4.4 and section 4.5).

Paediatric population

Safety and efficacy of the combination of lisinopril and hydrochlorothiazide in children have not been established. Therefore, use in children is not recommended.

Elderly

Clinical studies on the combination of lisinopril and hydrochlorothiazide have not shown that age is associated with any changes in efficacy or tolerability. However, in the elderly patients the renal function is more likely to be impaired and dose-adjustment should be made when appropriate. In the elderly patients the dose should be adjusted carefully (titration of the individual components) See the above section on „Renal impairment“.

Method of administration

Oral use

4.3 Contraindications

– Hypersensitivity to the active substances, any other angiotensin converting enzyme (ACE) inhibitor or other sulphonamide-derived drugs or to any of the excipients listed in section 6.1

– History of angioedema with previous ACE inhibitor therapy.

– Hereditary or idiopathic angioedema.

– Second and third trimesters of pregnancy (see sections 4.4 and 4.6)

– Severe renal impairment (creatinine clearance < 30 ml/min)

– Anuria

– Severe hepatic impairment

– The concomitant use of lisinopril/hy­drochlorothia­zide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m2) (see sections 4.5 and 5.1).

– Concomitant use with sacubitril/val­sartan therapy.

Lisinopril/Hy­drochlorothia­zide must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see also sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

Symptomatic hypotension

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients, but is more likely to occur if the patient has been volume depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see sections 4.5 and 4.8). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients.

In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be monitored under close medical supervision.

Particular consideration applies to patients with ischaemic heart or cerebrovascular disease, because an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If hypotension occurs the patient should be placed in the supine position and, if necessary should receive an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution.

A transient hypotensive response is not a contraindication for further doses. Following restoration of effective blood volume and pressure, reinstitution of therapy at reduced dose may be possible; or either of the components may be

used appropriately alone.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of lisinopril/hy­drochlorothia­zide may be necessary.

As with other ACE-inhibitors lisinopril should be given with caution to patients with aortic stenosis or hypertrophic cardiomyopathy.

Renal impairment

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (corresponds to moderate or severe renal insufficiency).

Lisinopril/hy­drochlorothia­zide should not be administered to patients with renal insufficiency (creatinine clearance less than or equal to 80 ml/min) until titration of the individual components has shown the need for the doses present in the combination tablet.

In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.

In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, renal function should be monitored during the first few weeks of lisinopril/hy­drochlorothia­zide therapy.

Some hypertensive patients with no apparent pre-existing renal disease have developed usually minor and transient increases in blood urea and serum creatinine when lisinopril has been given concomitantly with a diuretic. If this occurs during therapy with lisinopril/hy­drochlorothia­zide, the combination should be discontinued. Reinstitution of the therapy at reduced dose may be possible, or either of the two components may be used appropriately a­lone.

The diuretic therapy should be discontinued for 2–3 days prior to initiation with lisinopril/hy­drochlorothia­zide. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose.

Renal transplantation

The medicinal product should not be used, since there is no experience with lisinopril in patients with recent kidney transplantation.

Anaphylactoid reactions in haemodialytic patients

The use of lisinopril/hy­drochlorothia­zide is not indicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported in patients, undergoing certain haemodialysis procedures (e.g. with the high-flux membranes AN 69 and during low-density lipoproteins (LDL) apheresis with dextran sulphate) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive medicinal product.

Anaphylactoid reactions related to low-density lipoproteins (LDL) apheresis

In rare occasions, patients treated with ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have shown life-threatening anaphylactic reactions. These symptoms could be avoided by temporary discontinuation of the treatment with ACE inhibitors before each apheresis.

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see section 4.3). Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving lisinopril/hy­drochlorothia­zide who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril/hy­drochlorothia­zide and receive appropriate medical follow-up.

Surgery/anaesthesia

In patients undergoing major surgery or during anaesthesia with medicinal products that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be required. In diabetic patients treated with oral antidiabetic medicinal products or insulin, glycaemic levels should be closely monitored during the first month of treatment with an ACE inhibitor. Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. However, lisinopril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothi­azide.

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothi­azide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and does not require treatment. Thiazides have been shown to increase the urinary excretions of magnesium, which may result in hypomagnesaemia.

Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyro­idism.

Thiazides should be discontinued before carrying out tests for parathyroid function.

Hyperkalaemia

ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function, diabetes mellitus, and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics (e.g. spironolactone, triamterene, or amiloride), or other medicinal products associated with increases in serum potassium (e.g. heparin, trimethoprim or co-trimoxazole also known as trimethoprim/sul­famethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers), hyperkalaemia can occur. If concomitant use of the abovementioned medicinal products is deemed appropriate, they should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be regularly monitored (see section 4.5).

In diabetic patients treated with oral antidiabetic medicinal products or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5).

Hypersensitivi­ty/angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported uncommonly in patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This may occur at any time during therapy. In such cases, lisinopril should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. In such cases emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).

Concomitant use of ACE inhibitors with sacubitril/val­sartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/val­sartan must not be initiated earlier than 36 hours after the last dose of Lisinopril/Hy­drochlorthiazi­de. Treatment with Lisinopril/Hy­drochlorthiazi­de must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

The risk of angioedema may also be increased in patients concomitantly

treated with ACE inhibitors and tissue plasminogen activator (see section 4.5).

In patients receiving thiazides, hypersensitivity reactions may occur with and without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Desensitisation

Patients receiving ACE-inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE-inhibitors were temporarily withheld but they reappeared upon inadvertent rechallenge.

Neutropaenia/A­granulocytosis

Neutropaenia/a­granulocytosis, thrombocytopenia and anaemia have been reported for patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors neutropaenia occurs rarely. Neutropaenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Lisinopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If lisinopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.

Race

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients. As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients than in non-black patients, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor induced cough should be considered as part of the differential diagnosis of cough.

Lithium

The combination of ACE inhibitors and lithium is generally not recommended (see section 4.5).

Anti-doping test

The hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

Pregnancy

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Sulphonamide or sulphonamide derivative medicinal products can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, acute 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 medicinal product initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide 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 sulphonamide or penicillin allergy.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction Medicinal products increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/val­sartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4).

Concomitant use of ACE inhibitors with NEP inhibitors (e.g. racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), vildagliptin or tissue plasminogen activator may lead to an increased risk for angioedema (see section 4.4).

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Diuretic medicinal products and ACE inhibitors reduce the renal clearance of lithium and pose a high risk of lithium toxicity. The combination of lisinopril and hydrochlorothiazide with lithium is therefore not recommended and careful monitoring of serum lithium levels should be performed if the combination proves necessary (see section 4.4).

Potassium supplements, potassium -sparing diuretics or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels

The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with lisinopril/hy­drochlorothia­zide. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes, particularly in patients with impaired renal function or diabetes mellitus, may lead to significant increases in serum potassium. Care should also be taken when lisinopril is co-administered with other medicinal products that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sul­famethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of lisinopril/hy­drochlorothia­zide with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Torsades de pointes-inducing medicinal products

Because of the risk of hypokalaemia the concomitant administration of hydrochlorothiazide and medicinal products that induce torsades de pointes, e.g. some antiarrhythmics, some antipsychotics and other medicinal products known to induce torsades de pointes, should be used with caution.

Tricyclic antidepressants/ antipsychotics /anaesthetics/bar­biturates/alco­hol

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further lowering of blood pressure (see section 4.4). Hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics with thiazides.

Non steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid Chronic administration of NSAIDs (including selective cyclooxygenase-2 inhibitors) may reduce the antihypertensive effect of an ACE inhibitor. NSAIDs and ACE inhibitors may exert an additive effect on the deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.

Gold

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

Sympathomimetics

Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors.

Pressor amines

Hydrochlorothiazide may decrease arterial responsiveness to pressor amines (e.g. noradrenaline), but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ACEinhibitors, angiotensin II receptor blockers or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting medicinal product (see sections 4.3, 4.4 and 5.1).

Other antihypertensive medicinal products

Concomitant use of these medicinal products may increase the hypotensive effect of lisinopril/hy­drochlorothia­zide. Concomitant use of glyceryl trinitrate and other nitrates or other vasodilators may further reduce blood pressure.

Antidiabetics:

Epidemiological studies indicate that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic medicinal products) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combination treatment and in patients with renal impairment. Treatment with a thiazide diuretic may impair glucose tolerance. Other antidiabetic drugs including insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Other kaliuretic diuretics, amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulant laxatives

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

Calcium salts/vitamin D

Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics. If calcium supplements or vitamin D must be prescribed, serum calcium levels should be monitored and the dose adjusted accordingly.

Cardiac glycosides

There is increased risk of digitalis toxicity associated with thiazide induced hypokalaemia (e.g. increased ventricular irritability).

Colestyramine and colestipol

These may delay or reduce absorption of hydrochlorothi­azide. Therefore, sulphonamide diuretics should be taken at least 1 hour before or 4–6 hours after intake of these medicinal products.

Non-depolarizing muscle relaxants (e.g. tubocurarine chloride)

The effect of these medicinal products may be potentiated by hydrochlorothi­azide.

Sotalol

Thiazide induced hypokalaemia can increase the risk of sotalol induced arrhythmias.

Diazoxide

The hyperglycaemic effect of diazoxide may be enhanced by thiazides.

Amantadine

Thiazides may increase the risk of adverse events caused by amantadine.

Allopurinol

Concomitant administration of ACE inhibitors and allopurinol increases the risk of renal damage and can lead to an increased risk of leukopenia.

Ciclosporin

Concomitant administration of ACE inhibitors and ciclosporin increases the risk of hyperkalaemia. Monitoring of serum potassium is recommended.

Concomitant administration of ACE inhibitors and ciclosporin increases the risk of renal damage. Concomitant administration of thiazides and ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

Heparin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

Lovastatin

Concomitant administration of ACE inhibitors and lovastatin increases the risk of hyperkalaemia.

Cytostatics, immunosuppressives, procainamide

Concomitant administration of ACE inhibitors can lead to increased risk of leukopenia (see section 4.4).

Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

4.6 Fertility, pregnancy and lactation

Pregnancy:

ACE-inhibitors:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothi­azide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breast-feeding

ACE inhibitors

Because no information is available regarding the use of lisinopril/hy­drochlorothia­zide              during              b­reastfeeding,

lisinopril/hy­drochlorothia­zide is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of lisinopril/hy­drochlorothia­zide during breast-feeding is not recommended. If lisinopril/hy­drochlorothia­zide is used during breast-feeding, doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

As with other antihypertensives, lisinopril/hy­drochlorothia­zide combination products may have a mild to moderate effect on the ability to drive and use machines.

Especially at the start of the treatment or when the dose is modified, and also when used in combination with alcohol, but these effects depend on the individual's sus­ceptibility. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with lisinopril and/or hydrochlorothiazide 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)

The most commonly reported adverse drug reactions are cough, dizziness, hypotension, and headache which may occur in 1 to 10% of treated patients. In clinical studies, adverse reactions have usually been mild and transient, and in most instances have not required interruption of therapy.

Lisinopril

Blood and lymphatic system disorders:

Endocrine Disorders

Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinopril/hy­drochlorothia­zide combination who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril/hy­drochlorothia­zide combination and receive appropriate medical follow up.

* * A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, a positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.

Hydrochlorothiazide (frequencies not known)

*Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

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 (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

Limited data are available for overdose in humans. Symptoms associated with overdose of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

The recommended treatment of overdose is intravenous infusion of normal sodium chloride solution. If hypotension occurs, the patient should be placed in the supine position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. If ingestion is recent, take measures aimed at eliminating lisinopril (e.g. emesis, gastric lavage, administration of absorbents and sodium sulphate). Lisinopril may be removed from the general circulation by haemodialysis (see section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.

Additional symptoms of hydrochlorothiazide overdose are increased diuresis, depression of consciousness (incl. coma), convulsions, paresis, cardiac arrhythmias and renal failure.

Bradycardia or extensive vagal reactions should be treated by administering atropine.

If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors and diuretics, ATC code: C09BA03

Lisinopril/hy­drochlorothia­zide consists of a combination of lisinopril, an inhibitor of angiotensin converting enzyme, and hydrochlorothi­azide, a thiazide diuretic. Both components have complimentary modes of action, and exert an additive antihypertensive effect.

Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting enzyme (ACE), that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion in adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II in plasma resulting in decreased vasopressor activity and reduced aldosterone secretion. The latter may result in an increase in serum potassium concentration.

While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is shown also to have an antihypertensive effect in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Bradykinin is a potential vasodepressive peptide, and to which extent the increased level plays a role in the therapeutic effects of lisinopril has not been elucidated yet.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

Lisinopril: Approximately 25% with interpatient variability (6–60%) at all doses tested (5–80 mg). The absorption of lisinopril is not influenced by food. Maximal serum concentration is reached after 6–8 hours. Effect on blood pressure is observed after 1–2 hours. The effect is maximal after 6 hours and lasts for at least 24 hours.

Hydrochlorothi­azide: Diuretic effect is seen within 2 hours. Maximal effect is reached after 4 hours. Clinically adequate diuretic effect lasts for 6–12 hours.

Distribution

Protein binding: Lisinopril is not bound to plasma proteins other than ACE. Reduced volume of distribution in elderly can give a higher plasma concentration than in younger patients.

Biotransforma­tion/eliminati­on

Both of the active substances are eliminated unchanged via the kidneys. Approximately 60% of hydrochlorothiazide that is administrated orally is eliminated within 24 hours.

Half-life: Lisinopril: On multiple dosing 12 hours. Hydrochlorothi­azide: 5 1/2 – 15 hours.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In animal tests angiotensin converting enzyme inhibitors induce adverse reactions on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin-angiotensin system and partly due to the ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol.

Calcium hydrogen phosphate dihydrate

Pregelatinized maize starch.

Croscarmellose sodium.

Magnesium stearate.

Yellow iron oxide (E 172) Red iron oxide (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25oC.

6.5 Nature and contents of container

PVC/PVDC/aluminium blisters. PP-container with a LDPE-stopper and desiccant

Pack sizes:

Blisters:

10, 28, 30, 50, 98,100,50×1 (perforated unit dose blisters) and 100×1 (perforated unit dose blisters) tablets.

PP-container:

100 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 04416/0517

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

02/04/2008