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1. Lisinopril/Hydrochlorothiazide 20/12.5mg Tablets
2. Lisinopril/Hydrochlorothiazide 20/12.5mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lisinopril/Hydrochlorothiazide 20/12.5mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains lisinopril dihydrate equivalent to 20 mg anhydrous lisinopril and hydrochlorothiazide 12.5 mg

For the full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Tablets

Appearance:

White, round tablets (diameter 8 mm) with break line, LH embossed 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

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 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 (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 medication taken once daily, the tablets should be taken approximately at the same time every day.

Dosage in 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 dosage 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).

Use in children

Safety and efficacy of the combination of lisinopril and hydrochlorothiazide in children have not been established.

Use in 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 elderly patients the renal function is more likely to be impaired and adjustment of the dose should be made when appropriate. In elderly patients the dose should be adjusted carefully (titration of the individual components). See the above section on “Renal impairment".

4.3 Contraindications

• Hypersensitivity to lisinopril,to any of the excipients listed in section 6.1 or any other angiotensin converting enzyme (ACE) inhibitor

•    Hypersensitivity to hydrochlorothiazide or other sulphonamide-derived drugs

•    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

•    Concomitant use of ACE inhibitors - including lisinopril_hydrochlorothiazide -or of angiotensin receptor antagonists (ARBs) with aliskiren in patients with Type 2 diabetes and in patients with renal impairment (GFR < 60 ml/min/1,73m²) (see section 4.5)

4.4 Special warnings and precautions for use

Symptomatic hypotension

Symptomatic hypertension 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 rennin-dependant hypertension (see section 4.5 and 4.8). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients.

In patients with 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 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 blood pressure, reinstitution of therapy at reduced dosage may be possible; or either of the two components of the product may be used appropriately alone.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy As with other vasodilators, lisinopril /hydrochlorothiazide 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.

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 to 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 also is present, there is an increased risk of severe hypotension and renal insufficiency. In these patients the treatment should be started under close medical supervision with a low dose 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 treatment with the 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.

The use of ACEIs - including lisinopril_hydrochlorothiazide - or of ARBs with aliskiren should be avoided in patients with severe renal impairment (GFR < 30 ml/min) (see section 4.5, subsection dual blockade of the RAS).

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 diseases

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

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. Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. 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.

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 is carrying out tests for parathyroid function. Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including lisinopril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the abovementioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (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 anti-histamines 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).

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

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 (see section 4.8).

Race

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black 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 a separate diagnosis.

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).

Dual Blockade of the Renin-Angiotensin System (RAS)

Caution is required while co-administering ACEIs, including lisinopril_hydrochlorothiazide, with other agents blocking the RAS such as ARBs or aliskiren (see section 4.5, subsection dual blockade of the RAS).

Acute myopia and secondary angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in 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 drug 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 sulfonamide or penicillin allergy.

4.5 Interaction with other medicinal products and other forms of interaction

Dual blockade of the Renin-Angiotensin System with ACEIs, ARBs or aliskiren The concomitant use of ACEIs, including lisinopril, with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalemia, and changes in renal

function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on lisinopril_hydrochlorothiazide and other agents that affect the RAS (see section 4.4).

The concomitant use of ACEIs, including lisinopril_hydrochlorothiazide, or of ARBs with aliskiren, is contraindicated in patients with severe renal impairment (GFR < 30 ml/min) (see section 4.3).

The concomitant use of ACEIs, including lisinopril_hydrochlorothiazide, or of ARBs with aliskiren is contraindicated in patients with Type 2 diabetes (see section 4.3).

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

The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. The use of potassium supplements, potassium -sparing agents or potassium-containing salt substitutes, particularly in patients with impaired renal function or diabetes mellitus, may lead to a significant increase in serum potassium. If concomitant use of lisinopril/hydrochlorothiazide and any of these agents is required, 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 antiarrhythmias, 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 acetvlsalicvlic 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

Sympatomimetics can reduce the antihypertensive effect of ACE inhibitors.

Other antihypertensive agents

Concomitant use of these agents 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 medicines (insulin, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with an increased risk of hypoglycaemia.

This phenomenon appeared to be more likely to occur during the first weeks of treatment, and in patients with renal impairment.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulant laxatives

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

Calcium salts

Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.

Cardiac glycosides

There is increased risk of digitalis toxicity associated with thiazide induced hypokalaemia.

Cholestyramine and cholestipol

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 agents.

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

The effect of these agents may be potentiated by hydrochlorothiazide.

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.

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 leucopenia (see section 4.4).

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:

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.

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 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.

Lactation

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 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 the lymphatic system (	isorders:
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
Metabolism and nutrition disorders:
Very rare	Hypoglycaemia
Nervous system disorders and psychiatric disorders
Common	Dizziness, headache, syncope
Uncommon	Paraestesia, vertigo, taste disturbance, sleep disturbances, mood alterations
Rare	Mental confusion
Frequency unknown	Depressive symptoms
Cardiac disorders 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

Unknown

Flushing

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, instestinal angioedema
Hepatobiliary disorders
Uncommon	Elevated liver enzymes and bilirubin
Very rare	Hepatitis - either hepatocellular or cholestatic, jaundice, 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 c	isorders
Uncommon	Impotence
Rare	Gynaecomastia
Endocrine Disorders
Rare	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

General disorders and administration site conditions

Uncommon	Asthenia, fatigue
Investigations

Uncommon	Increases in blood urea, increases in serum
	creatinine, hyperkalaemia
Rare	Hyponatriaemia

* 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 unknown)

Infections and infestations	Sialadenitis
Blood and lymphatic system disorders	Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression
Metabolism and nutrition disorders	Anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypokalaemia, hypochloremic alkalosis and hypomagnesaemia), increases in cholesterol and triglycerides, gout
Psychiatric disorders	Restlessness, depression, sleep disturbance
Nervous system disorders	Loss of appetite, paraestesia, lightheadedness
Eye disorders	Xanthopsia, transient blurred vision
Ear and labyrinth disorders	Vertigo
Cardiac disorders	Postural hypotension
Vascular disorders	Necrotising angiitis (vasculitis, cutaneous vasculitis).
Respiratory, thoracic and mediastinal disorders	Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders	Gastric irritation, diarrhoea, constipation, pancreatitis.
Hepatobiliary disorders	Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders	Photosensitivity reactions, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis
Musculo-skeletal, connective tissue and bone disorders	Muscle spasm, muscle weakness
Renal and urinary disorders	Renal dysfunction, interstitial nephritits
General disorders	Fever, weakness

4.9 Overdose

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.

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.

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.

5 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.

Hydrochlorothiazide is a diuretic and an antihypertensive agent. It affects the distal renal tubular effect in the kidneys to reabsorb electrolytes and to increase the excretion of sodium and chloride in approximately equivalent amounts. The loss of sodium may be followed by a loss of potassium and sodium hydrogen carbonate. The antihypertensive mode of action of thiazides is unknown. Thiazides do not usually affect normal blood pressure.

When combined with other antihypertensives, an additive fall in blood pressure may occur.

Lisinopril may attenuate potassium loss induced by hydrochlorothiazide.

5.2    Pharmacokinetic properties

The combination tablet is bioequivalent with separate administration of each of the active substances.

Absorption: 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.

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

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.

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 effects on the late fetal development, resulting in fetal death and congenital effects, in particular affecting the skull. Fetotoxicity, 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 fetal renin-angiotensin system and partly due to the iscahemia resulting from maternal hypotension and decreases in fetal-placental blood flow and oxygen/nutrients delivery to the fetus.

6.1 List of excipients

Mannitol.

Calcium hydrogen phosphate dihydrate.

Pregelatinized maize starch.

Croscarmellose sodium.

Magnesium stearate.

6.2.    Incompatibilities

Not applicable

6.3.    Shelf-Life

36 months

6.4.    Special Precautions for Storage

Do not store above 30°C.

6.5.    Nature and Content of Container

PVC/PVdC/aluminium blisters of 10, 28, 30, 50, 56, 60, 98, 100, 50x1(perforated unit dose blisters), 100x1 (perforated unit dose blisters) and 500x1 (perforated unit dose blisters) tablets.

PP containers of 100 tablets.

Not all pack sizes will be marketed.

6.6 Special precautions for disposal and other handling

No special requirements

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 04416/0518

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/04/2008

10 DATE OF REVISION OF THE TEXT

16/04/2014