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1. Lisoretic 20mg/12.5mg Tablets
2. Lisoretic 20mg/12.5mg Tablets

1. NAME OF THE MEDICINAL PRODUCT

Lisoretic 20 mg/12.5 mg Tablets

Lisinopril & Hydrochlorothiazide 20mg/12.5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Lisinopril 20mg as dihydrate and Hydrochlorothiazide 12.5mg For the full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Tablets

White to off white, circular, biconvex uncoated tablets.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lisinopril/hydrochlorothiazide 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 (see sections 4.3, 4.4, 4.5 and 5.1).

4.2    Posology and method of administration

Posology

Essential Hypertension:

The usual dosage is one tablet, administered once daily. As with all other medication taken once daily, lisinopril/hydrochlorothiazide 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.

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 older people 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:

Safety and effectiveness in children have not been established.

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). Lisinopril/hydrochlorothiazide Tablets are not to be used as initial therapy in any patient with renal insufficiency. In patients with creatinine clearance of >30 and <80 ml/min, Lisinopril/hydrochlorothiazide 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 (see sections 4.3, 4.4, 4.5 and 5.1).

Prior Diuretic Therapy:

Symptomatic hypotension may occur following the initial dose of lisinopril/ hydrochlorothiazide; 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 lisinopril/hydrochlorothiazide. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose.

Method of administration

Swallow the tablet with a drink of water

4.3 Contraindications

•    Hypersensitivity to lisinopril or 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 associated with previous ACE inhibitor therapy

•    Hereditary or idiopathic angioedema

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

•    Anuria, aortic stenosis or hyperkalaemia

•    Severe hepatic impairment

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

•    The concomitant use of Lisinopril and hydrochlorothiazide with aliskiren-containing products

is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60

2

ml/min/1.73 m ) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Symptomatic Hypotension

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients, but is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see section 4.5 and section 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 considerations 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 to 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.

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 < 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 angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, renal function should be monitored during the first 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 especially when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting 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 of therapy 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. 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 patients. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient.

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

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

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

Patients receiving co-administration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

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.

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 different class of antihypertensive agent.

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

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 have reappeared upon inadvertent rechallenge.

Hepatic disease

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 developed jaundice or marked elevations of hepatic enzymes should discontinue Lisinopril/hydrochlorothiazide and receive appropriate medical follow-up.

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

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

As with other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients than in non-blacks, 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 nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

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/Diabetic Patients

ACE inhibitor and thiazide therapy may impair glucose intolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic levels should be closely monitored during the first month of treatment with an ACE inhibitor (see section 4.5). 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

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 above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Lithium

The combination of lithium and ACE inhibitors 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-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.

4.5 Interaction with other medicinal products and other forms of interaction Dual blockade of the renin-angiotensin-aldosterone system

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 higher frequency of adverse events such as hypotension, hyperkalaemia, and decreased renal function (including acute renal failure) compared to use of a single RAAS acting agent (see sections 4.3, 4.4. and 5.1).

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 diuretics 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)

If lisinopril is given with a potassium-losing diuretic, such as the thiazide diuretic present in lisinopril/hydrochlorothiazide, diuretic-induced hypokalaemia may be ameliorated.

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

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Diuretics agents and ACE inhibitors reduce the renal clearance of lithium and may increase the risk of lithium toxicity. Use of Lisinopril/hydrochlorothiazide with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

Non-steroidal anti-inflammatory/anti-rheumatic drugs (NSAIDs) including acetylsalicylic acid

Chronic administration of NSAIDs (including selective COX-2 inhibitors, acetylsalicylic acid>3g/day and non-selective NSAIDs) may reduce the antihypertensive and diuretic effect of ACE inhibitor and thiazide diuretics. NSAIDs and ACE inhibitors 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.

Antihypertensive Agents

When combined with other antihypertensive agents, additive falls in blood pressure may occur. Concomitant use of these agents may increase the hypotensive effects of Lisinopril/hydrochlorothiazide. Concomitant use of glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.

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

Tricyclic antidepressants / Antipsychotics / Anaesthetics

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see section 4.4)

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Antidiabetics

Epidemiological studies indicate that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Long term controlled clinical trials with lisinopril have not confirmed these findings and do not preclude the use of lisinopril in diabetic patients. It is advised, however that these patients be monitored. (See below for information regarding antidiabetic drugs and thiazide diuretics).

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.

Colestyramine and colestipol

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

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).

Alcohol

Alcohol may enhance the hypotensive effect of any antihypertensive.

Antacids

Cause a decrease in the bioavailability of ACE inhibitors.

Pressor amines (e.g. epinephrine (adrenaline))

Concomitant administration can lead to a reduced response to pressor amines, but insufficient to exclude their use.

Barbiturates or narcotics

Potentiation of orthostatic hypotension may occur.

Mammalian Target of Rapamycin (mTOR) inhibitors

Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see section 4.4, Special warnings and precautions for use).

Other agents

Indometacin may diminish the antihypertensive effect of concomitantly administered Lisinopril/ Hydrochlorothiazide. The antihypertensive effect of Lisinopril/ Hydrochlorothiazide may be potentiated when given concomitantly with other agents likely to cause postural hypotension.

Other concomitant therapy

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

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 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4)

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative 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). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, an ultrasound check of renal function and the skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

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

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

Breast-feeding ACE inhibitors:

Because no information is available regarding the use of Lisinopril hydrochlorothiazide during breastfeeding, lisinopril/hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide^

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of lisinopril & hydrochlorothiazide combination during breast feeding is not recommended. If lisinopril & hydrochlorothiazide combination 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

Lisinopril/ Hydrochlorothiazide is usually well tolerated. In clinical studies, side effects have usually been mild and transient, and in most instances have not required interruption of therapy. The side effects that have been observed have been limited to those reported previously with lisinopril or hydrochlorothiazide.

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 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
Endocrine disorders
Rare	Syndrome of Inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders:
Very rare:	Hypoglycaemia
Nervous system disorders and Psychiatric disorders:
Common:	dizziness, headache, syncope
Uncommon:	paraesthesia, vertigo, taste disturbance, sleep disturbances, mood alterations, depressive symptoms
Rare	Olfactory disturbance, mental confusion
Frequency Unknown	Hallucinations
Cardiac and Vascular disorders:
Common	Orthostatic effects (including orthostatic hypotension)

* Very

rarely,

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ed that

in

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s the

undesi

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develo

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hepatit is has progre ssed to hepati c

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):

System Organ Class	Adverse Event
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, electrolyte imbalance (including hyponatraemia, hypochloremic alkalosis, hypomagnesaemia and hypokalaemia), increases in cholesterol and triglycerides, gout, hyperuricaemia, loss of appetite
Psychiatric disorders	Restlessness, depression, sleep disturbance.
Nervous system disorders	Paraesthesia, light-headedness.
Eye disorders	Xanthopsia, transient blurred vision acute myopia and acute angle-closure glaucoma
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, constipation, diarrhoea, pancreatitis
Skin and subcutaneous tissue disorders	photosensitivity reactions, rash, systemic lupus erythematosuscutaneous lupus erythematous-like reactions, urticaria, reactivation of cutaneous lupus-erythematosus, anaphylactic reactions, toxic epidermal necrolysis, purpura
Renal and urinary disorders	renal dysfunction, interstitial nephritis
General disorders	Fever, weakness
Hepatobiliary disorders	Jaundice (intrahepatic cholestatic jaundice)
Musculoskeletal, connective tissue and bone disorders	Muscle spasm, muscle weakness.

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.

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: Angiotensin converting enzyme inhibitor and thiazide diuretic, ATC-code C09B A03.

Lisinopril/hydrochlorothiazide Tablets are 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

Whilst 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 safety and efficacy 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 end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

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

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.

5.2 Pharmacokinetic properties

Concomitant multiple doses of lisinopril and hydrochlorothiazide have little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to concomitant administration of the separate entities. The pharmacokinetics of the individual components are described in the following sections:

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 inter-patient variability of 6-60% over the dose range studied (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 appear to be bound to serum proteins other than to circulating angiotensin converting enzyme (ACE).

Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.

Elimination

Lisinopril does not undergo metabolism and is excreted entirely unchanged into 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.

T able 1 Pharmacokinetic parameters of lisinopril to different groups of renal patients after administration of a multiple 5 mg dose

Renal Function Measured by creatinine clearance	n	Cmax (ng/ml)	Tmax (hr)	AUC (0-24 hrs) (ng/hr/ml)	11/2 (hr)
>80 ml/min	6	40.3	6	492+/-172	6.0+/- 1.1
30-80 ml/min	6	36.6	8	555+/-364	11.8+/- 1.9
5-30 ml/min	6	106.7	8	2228+/-938	19.5+/- 5.2

In mild to moderate renal impairment (creatinine clearance 30-80 ml/min) mean AUC was increased by 13% only, while a 4.5-fold increase in mean AUC was observed in severe renal impairment (creatinine clearance 5-30 ml/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%) compared with younger subjects.

Hydrochlorothiazide:

When plasma levels of hydrochlorothiazide 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.

For lisinopril, preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects in the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal renin-angiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Calcium hydrogen phosphate dihydrate

Mannitol

Maize starch

Pregelatinised starch

Magnesium stearate

6.2. Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4.    Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5.    Nature and contents of container

Aluminium/PVDC coated PVC blister strips containing 14 tablets. Blister strips packaged into outer container to give total of 28 tablets.

6.6.    Instruction for use and handling (, and disposal)

No special requirements.

7.    MARKETING AUTHORISATION HOLDER

Bristol Laboratories Ltd Unit 3, Canalside Northbridge Road Berkhamsted HP4 1EG

8.    MARKETING AUTHORISATION NUMBER

PL 17907/0074

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/10/2005

10 DATE OF REVISION OF THE TEXT

14/06/2016