LISINOPRIL +HCT 10/12.5 MG TABLETS - summary of medicine characteristics

Lisinopril + HCT 10 mg/12.5 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains: Lisinopril dihydrate 10.9 mg equivalent to lisinopril 10 mg and hydrochlorothiazide 12.5 mg.

Excipient with known effect: Each film-coated tablet contains 26.4 mg of mannitol.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Pink, round, biconvex, one-sided score notch with a diameter of 6.9–7.3mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of essential hypertension. Lisinopril + HCT 10mg/12.5 mg tablets fixed dose combination (10 mg lisinopril and 12.5 mg hydrochlorothi­azide) is indicated in patients whose blood pressure is not adequately controlled on lisinopril alone (or hydrochlorothiazide alone) (see sections 4.3, 4.4, 4.5 and 5.1).

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.

Lisinopril + HCT 10mg/12.5 mg tablets should be taken once daily.

The administration of the fixed combination lisinopril and hydrochlorothi­azide is

usually recommended after dosage 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.

20 mg/12.5 mg tablets may be administered in patients whose blood pressure is not adequately controlled by 20 mg lisinopril alone.

A maximum daily dose of 40 mg lisinopril/25 mg hydrochlorothiazide should not be exceeded. (see sections 4.3, 4.4, 4.5 and 5.1).

Prior diuretic treatment

Symptomatic hypotension may occur following the initial dose; this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. Diuretics should be discontinued for 2–3 days before starting Lisinopril + HCT 10 mg/12.5 mg tablets. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose. These patients should be carefully monitored for objective and subjective symptoms of hypotension after the first dose of Lisinopril + HCT 10 mg/12.5 mg tablets (see section 4.4, hypotension and electrolyte/fluid imbalance).

Renal impairments

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).

Elderly

Clinical studies on the combination of lisinopril and hydrochlorothiazide have not shown that age is associated with any changes in efficacy or tolerability. See the above section on “Renal impairment”.

Paediatric population

The safety and efficacy of Lisinopril + HCT 10 mg/12.5 mg tablets in children has not been established.

Method of administration Oral use.

4.3 Contraindications

– Hypersensitivity to active substances or to any of the excipients listed in section 6.1.

– Hypersensitivity to any other angiotensin converting enzyme (ACE) inhibitor.

– Hypersensitivity to any sulphonamide-derived medicinal product.

– Lisinopril + HCT is contraindicated in patients with anuria.

– Lisinopril + HCT is contraindicated in patients with a history of angioedema

relating to previous treatment with an ACE inhibitor.

– Hereditary or idiopathic angioedema.

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

– Severe hepatic impairment.

– Concomitant use of Lisinopril + HCT with sacubitril/val­sartan therapy. Lisinopril + HCT must not be initiated earlier than 36 hours after the last dose of sacubitril/val­sartan (see sections 4.4 and 4.5).

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

– Concomitant administration with aliskiren-containing medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

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 (HCT) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCT could act as a possible mechanism for NMSC.

Patients taking HCT 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 HCT may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

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 renindependent hypertension (see sections 4.5 and 4.8).

Regular monitoring 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 should be given when therapy is administered to patients with ischaemic heart or cerebrovascular disease because an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular event/ accident.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of physiological/ normal saline. A transient hypotensive response is not a contraindication for further doses. Following restoration of effective blood volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used alone, as appropriate.

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 lisinoprilhydrochlo­rothiazide may be necessary.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors Lisinopril + HCT 10 mg/12.5 mg tablets should be given with caution to patients with, mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

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.

Renal function impairment

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

Lisinopril + HCT 10 mg/12.5 mg tablets 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 some 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 ACE 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. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or lisinopril may be required.

Prior diuretic therapy

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

Lisinopril + HCT should not be used, since there is no experience with patients recently transplanted with a kidney.

Anaphylactoid reactions in haemodialytic patients

The use of Lisinopril + HCT is not indicated in patients requiring dialysis for renal failure. Anaphylactic reactions have been reported in patients, undergoing certain haemodialysis procedures (e.g. with the high-flux dialysis 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 medication.

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 reactions/ symptoms could be avoided by temporarily discontinuation of treatment with ACE inhibitor therapy prior to 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 hepatic necrosis and (sometimes) death. The mechanism of the syndrome is not understood. Patients receiving lisinopril-hydrochlorothiazide who develop jaundice or marked elevations of hepatic enzymes should discontinue the lisinopril-hydrochlorothiazide and receive appropriate medical follow-up.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that cause 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

ACE inhibitor and thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may increase in be required. In diabetic patients treated with oral antidiabetic drugs or insulin, glycaemia 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 some 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.

Thiazide therapy may decrease urinary calcium excretion and may cause an 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 hyperkalemia 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), other drugs associated with increase in serum potassium (e.g. heparin, trimethoprim or co-trimoxazole also known as trimethoprim/sul­famethoxazole) and especially aldosterone antagonists or angiotensin-receptor blockers, hyperkalemia can occur. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, serum potassium and renal function should be monitored (see section 4.5).

Diabetic patients

In diabetic patients treated with oral antidiabetic agents 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 extremities, face, lips, tongue, glottis and/ or larynx has been reported uncommonly in patients treated with ACE 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 appropriate 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 + HCT. Treatment with Lisinopril + HCT 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.

In patients receiving thiazides, hypersensitivity reactions may occur with or 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.

Neutropenia/a­granulocytosis

Neutropenia/a­granulocytosis, thrombocytopenia and anaemia have been reported for patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors neutropenia occurs rarely. Neutropenia 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.

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.

Race

ACE 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.

Lithium

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

Anti-doping test

The hydrochlorothiazide contained in this medication 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).

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.

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothi­azide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis

of ARDS is suspected, Lisinopril + HCT should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

This medicine 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

Antihypertensive agents

When combined with other antihypertensive agents, additive falls in blood pressure may occur. Concomitant use of glyceryl trinitrate and other nitrates or other vasodilators may further reduce the blood pressure.

The combination of lisinopril with aliskiren-containing medicines should be avoided (see sections 4.3 and 4.4).

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of angiotensin II receptor blockers, ACE inhibitors, or direct renin inhibitors (such as 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 agent (see sections 4.3, 4.4 and 5.1).

Medicines increasing the risk of angioedema

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

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increase in the risk of angioedema (see section 4.4).

Concomitant treatment of ACE inhibitors with tissue plasminogen activators may increase the risk of angioedema.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Diuretic agents 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-sparing diuretics, potassium supplements 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. Use of 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 a significant increase in serum potassium.

Care should also be taken when lisinopril is co-administered with other agents 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 + HCT with the above-mentioned drugs is not recommended. If concomitant use of lisinopril/hy­drochlorothia­zide is indicated, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Torsades de pointes-inducing drugs

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

Tricyclic antidepressan­ts/antipsycho­tics/anesthetics

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).

Non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid Chronic administration of NSAID (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid >3 g/day and non-selective NSAIDs) may reduce the antihypertensive and diuretic effect of ACE inhibitors and thiazide diuretics. NSAID and ACE inhibitors may exert an additive effect on the increase in serum potassium and may result in a 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 effects of ACE inhibitors.

Thiazides may decrease arterial responsiveness to noradrenaline, but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Anti-diabetics

Treatment with a thiazide diuretic may impair glucose tolerance. This phenomenon may be more likely to occur during the first weeks of combination treatment, and in patients with renal impairment.

Other antidiabetic drugs including insulin requirements in diabetic patients may be increased, decreased, or unchanged.

The hyperglycaemic effect of diazoxide may be enhanced by thiazides.

Corticosteroids, amphotericin B (parenteral), carbenoxolone, corticotropin (ACTH) or stimulant laxatives

The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by drugs associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, salicylic acid derivatives).

Hypokalaemia may develop during concomitant use of steroids or adrenocorticotropic hormone (ACTH).

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or Vitamin D must be prescribed, serum calcium levels should be monitored and the dose adjusted accordingly.

Cardiac glycosides

Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability).

Colestyramine and colestipol

The absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine. Therefore, sulphonamide diuretics should be taken at least 1 hour before or 4–6 hours after intake of these agents.

Non-depolarizing muscle relaxants

Thiazides may increase the responsiveness to non-depolarising skeletal muscle relaxants (e.g. tubocurarine).

Trimethoprim

Concomitant administration of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalaemia.

Sotalol

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

Allopurinol

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

Ciclosporin

Concomitant administration of ACE inhibitors and ciclosporin increases the risk of renal damage and hyperkalaemia.

Monitoring of serum potassium is recommended.

Concomitant treatment with 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.

Procainamide, cytostatic or immunosuppressive agents

Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects (see section 4.4).

Amantadine

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

Alcohol, Barbiturates or Anaesthetics

Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics.

Ability to drive and use machines

Lisinopril/hy­drochlorothia­zide combination products may have a mild to moderate effect on the ability to drive and use machines (see section 4.7).

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 inhibitors 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 inhibitors 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 + HCT during breast-feeding, Lisinopril + HCT 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 + HCT during breast feeding is not recommended. If Lisinopril + HCT 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 ADRs are cough, dizziness, hypotension, and headache which may occur in 1 to 10% of treated patients. In clinical studies, side effects have usually been mild and transient, and in most instances have not required interruption of therapy.

Lisinopril

Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinoprilhydrochlo­rothiazide 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:

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCT 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Limited data are available for overdose in humans.

Symptoms associated with overdosage of ACE inhibitors may include: hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

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

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

Management

The recommended treatment of overdose is intravenous infusion of normal saline 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.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitor and diuretic, ATC code: C09B A03.

This medicine is a fixed dose combination product containing lisinopril, an inhibitor of angiotensin converting enzyme (ACE) and hydrochlorothi­azide, a thiazide diuretic. Both components have complementary modes of action and exert an additive antihypertensive effect.

Lisinopril

Mechanism of action

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 by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion.

The latter decrease may result in an increase in serum potassium concentration.

Pharmacodynamic effects

While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated.

Clinical efficacy and safety

Renin-angiotensin system (RAS)-acting agents

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 endorgan 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.

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Hydrochlorothiazide

Mechanism of action

Hydrochlorothiazide is a diuretic and an antihypertensive agent. It affects the distal renal tubular mechanism of electrolyte reabsorption and increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. The mechanism of the antihypertensive effect of the thiazides is unknown.

Pharmacodynamic effects

Thiazides do not usually affect normal blood pressure.

Non-melanoma skin cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between HCT and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCT use (>50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCT: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7–2.6) increasing to OR 3.9 (3.0–4.9) for high use (~25,000 mg) and OR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

5.2 Pharmacokinetic properties

Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.

Lisinopril

Absorption

Following oral administration of lisinopril, peak serum concentrations occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with interpatient variability (6–60%) at all doses tested (5–80 mg) The absolute bioavailability is reduced approximately 16% in patients with heart failure.

Lisinopril absorption is not affected by the presence of food.

Distribution

Lisinopril does not bound to bind to other serum proteins other than circulating ACE. Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

Elimination

Lisinopril does not undergo metabolism and absorbed drug is excreted unchanged entirely in the urine.

On multiple dosing lisinopril has an effective half-life of accumulation of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 ml/min. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose.

Hepatic impairment

Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about 30% as determined by urinary recovery) but an increase in exposure (approximately 50%) compared to healthy subjects due to decreased clearance.

Renal impairment

Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 ml/min.

With a creatinine clearance of 30–80ml/min, mean AUC was increased by 13% only, while a 4–5-fold increase in mean AUC was observed with creatinine clearance of 5–30ml/min.

Lisinopril can be removed by dialysis. During 4 hours of haemodialysis, plasma lisinopril concentrations decreased on average by 60%, with a dialysis clearance between 40 and 55 ml/min.

Heart Failure

Patients with heart failure have a greater exposure of lisinopril when compared to healthy subjects (an increase in AUC on average of 125%), but based on the urinary recovery of lisinopril, there is reduced absorption of approximately 16% compared to healthy subjects.

Elderly

Elderly patients have higher blood levels and higher values for the area under the plasma concentration time curve (increased approximately 60%) than younger patients.

Hydrochlorothiazide

When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

At least 61% of the dose is eliminated unchanged within 24 hours. After oral hydrochlorothi­azide, diuresis begins within 2 hours, peaks in about 4 hours and lasts 6 to 12 hours.

Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

5.3 Preclinical safety data

Lisinopril and hydrochlorothiazide are both drugs on which extensive clinical experience has been obtained, both separately and in combination. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

calcium hydrogenphosphate dihydrate

croscarmellose sodium

mannitol

maize starch

magnesium stearate

ferric oxide red (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The tablets are packed in polyvinylchloride /aluminium blisters and inserted into a carton.

Package sizes: 14, 28, 30, 50, 56, 98, 100, 400.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

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

7 MARKETING AUTHORISATION HOLDER

Crescent Pharma Limited,

Key House, Sarum Hill,

Basingstoke, RG21 8SR,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0597