4.1. Therapeutic indications

Zestoretic is indicated in the management of mild to moderate hypertension in patients who have been stabilised on the individual components given in the same proportions.

4.2. Posology and method of administration

Primary Hypertension

The usual dosage is one tablet, administered once daily. As with all other medication taken once daily, Zestoretic should be taken at approximately the same time each day.

In general, if the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks at this dose level, the dose can be increased to two tablets administered once daily.

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 (i.e. moderate or severe renal insufficiency).

Zestoretic is not to be used as initial therapy in any patient with renal insufficiency.

In patients with creatinine clearance of >30 and <80 ml/min, Zestoretic may be used, but only after titration of the individual components. The recommended dose of lisinopril, when used alone, in mild renal insufficiency, is 5 to 10 mg.

Prior Diuretic Therapy

Symptomatic hypotension may occur following the initial dose of Zestoretic; this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. The diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with Zestoretic. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose.

Elderly

No adjustment of dosage is required in the elderly.

In clinical studies the efficacy and tolerability of lisinopril and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.

Lisinopril, within a daily dosage range of 20 to 80 mg, was equally effective in the elderly (65 years or over) and non-elderly hypersensitive patients, monotherapy with lisinopril was as effective in reducing diastolic blood pressure as monotherapy with either hydrochlorothiazide or atenolol. In clinical studies, age did not affect the tolerability of lisinopril.

Paediatric population

The safety and efficacy in children have not been established.

4.3. Contraindications

Hypersensitivity to the 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 drugs.

History of angioedema associated with previous ACE inhibitor therapy.

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

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 Zestoretic with aliskiren-containing products is contraindicated in patients with diabetes mellitus or 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 (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 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 renin-dependant 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 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 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.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, lisinopril 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 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 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

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/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 agent.

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 sulfate 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 agents 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

ACE inhibitor and thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. In diabetic patients treated with oral antidiabetic agents 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 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 hypochloremic 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. 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 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 face, extremities, 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 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.

ACE 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 Zestoretic. Treatment with Zestoretic 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.

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.

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 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 anti-hypertensive 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, Zestoretic should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

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 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 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 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 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. 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 Zestoretic 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 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 anti-psychotics and other drugs known to induce torsades de pointes, should be used with caution.

Tricyclic antidepressants/ antipsychotics /anaesthetics

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

Antidiabetics

Treatment with a thiazide diuretic may impair glucose tolerance. This phenomenon appeared to 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.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, 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).

Hypokalemia 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

Hypokalemia 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-depolarising 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 arrhythmia.

Allopurinol

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

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.

Cytostatics, immunosuppressives, procainamide

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 contra-indicated 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 anti-hypertensive 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.

ACE inhibitor therapy exposure 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 also section 5.3 'Preclinical safety data'). 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 also 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 primary 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 breast-feeding, 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 influence 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 affects 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:

Blood and lymphatic system disorders:

Rare

Decreases in haemoglobin, decreases in haematocrit.

Very rare

Bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease.

Immune system disorders

Not known

Anaphylactic/anaphylactoid reaction

Endocrine disorders

Rare

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:

Very rare

Hypoglycaemia.

Psychiatric disorders and nervous system disorders

Common

Dizziness, headache, syncope.

Uncommon

Paraesthesia, vertigo, taste disturbance, sleep disturbances, mood alterations, depressive symptoms.

Rare

Mental confusion, Olfactory disturbance.

Not known

Hallucinations.

Cardiac and vascular disorders

Common

Orthostatic effects (including orthostatic hypotension).

Uncommon

Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see section 4.4), palpitations, tachycardia, Raynaud's syndrome.

Not known

Flushing.

Respiratory, thoracic and mediastinal disorders

Common

Cough (see section 4.4).

Uncommon

Rhinitis.

Very rare

Bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders

Common

Diarrhoea, vomiting.

Uncommon

Nausea, abdominal pain and indigestion.

Rare

Dry mouth.

Very rare

Pancreatitis, intestinal angioedema.

Hepatobiliary disorders

Uncommon

Elevated liver enzymes and bilirubin.

Very rare

Hepatitis - either hepatocellular or cholestatic, jaundice and hepatic failure (see section 4.4).*

Skin and subcutaneous tissue disorders

Uncommon

Rash, pruritus.

Rare

Hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4), urticaria, alopecia, psoriasis.

Very rare

Diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma.**

Renal and urinary disorders

Common

Renal dysfunction.

Rare

Uraemia, acute renal failure.

Very rare

Oliguria/anuria.

Reproductive system and breast disorders

Uncommon

Impotence.

Rare

Gynaecomastia.

General disorders and administration site conditions

Uncommon

Asthenia, fatigue.

Investigations

Uncommon

Increases in blood urea, increases in serum creatinine, hyperkalaemia.

Rare

Hyponatraemia.

* 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:

Infections and infestations

Not Known

Sialadenitis.

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Not Known

Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma).

Blood and lymphatic system disorders

Not Known

Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression.

Metabolism and nutrition disorders

Not Known

Anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypokalaemia, hypochloremic alkalosis and hypomagnesaemia), increases in cholesterol and triglycerides, gout.

Psychiatric disorders

Not Known

Restlessness, depression, sleep disturbance.

Nervous system disorders

Not Known

Loss of appetite, paraesthesia, light-headedness.

Eye disorders

Not Known

Xanthopsia, transient blurred vision, acute myopia and acute angle-closure glaucoma.

Choroidal effusion.

Ear and labyrinth disorders

Not Known

Vertigo.

Cardiac disorders

Not Known

Postural hypotension.

Vascular disorders

Not Known

Necrotising angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

Very Rare

Acute respiratory distress syndrome (ARDS) (see section 4.4.).

Not Known

Respiratory distress (including pneumonitis and pulmonary oedema).

Gastrointestinal disorders

Not Known

Gastric irritation, diarrhoea, constipation, pancreatitis.

Hepatobiliary disorders

Not Known

Jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders

Not Known

Photosensitivity reactions, rash, systemic lupus erythematosus, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal, connective tissue and bone disorders

Not Known

Muscle spasm, muscle weakness.

Renal and urinary disorders

Not Known

Renal dysfunction, interstitial nephritits.

General disorders

Not Known

Fever, weakness.

Description of selected adverse reactions

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 website: 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.