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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Tablet contains:

Lisinopril dihydrate equivalent to anhydrous Lisinopril 20mg and

Hydrochlorothiazide 12.5mg

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

Yellow, hexagonal tablets, plain on both sides

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets 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

Route of administration: Oral

Essential Hypertension

The usual dosage is one tablet, administered once daily. As with all other medication taken once daily, Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets 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.

Use 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 was equally effective in elderly (65 years or older) and nonelderly hypertensive patients. In elderly hypertensive 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.

Use in children

Safety and effectiveness in children have not been established.

Dosage in Renal Insufficiency

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

Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablet is not to be used as initial therapy in any patient with renal insufficiency.

In patients with creatinine clearance of >30 and <80ml/min, Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets may be used, but only after titration of the individual components.

Prior Diuretic Therapy

Symptomatic hypotension may occur following the initial dose of Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets; 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 and Hydrochlorothiazide 20mg/12.5mg Tablets. If this is not possible, treatment should be started with lisinopril alone, in a 2.5 mg dose.

4.3 Contraindications Lisinopril

Hypersensitivity to lisinopril, or any other angiotensin converting enzyme (ACE) inhibitor

History of angioedema associated with previous ACE inhibitor therapy Hereditary or idiopathic angioedema

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

History of hypersensitivity to hydrochlorothiazide or other sulphonamide-derived drugs

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

Severe hepatic impairment

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

Lactation (see section 4.6)

Lisinopril/Hydrochlorothaizide combination

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is contraindicated in patients with anuria or aortic stenosis or hyperkalaemia.

The use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets during pregnancy is not recommended. When pregnancy is detected Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets should be discontinued as soon as possible, unless it is considered life-saving for the mother.

The concomitant use of Lisinopril and Hydrochlorothiazide Tablets with

aliskiren-containing products is contraindicated in patients with diabetes

2

mellitus or renal impairment (GFR < 60 ml/min/1.73 m ) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

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.

Lisinopril

Symptomatic Hypotension

Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive patients receiving lisinopril, hypotension 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). In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom 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, which can be given usually without difficulty once the blood pressure has increased after volume expansion.

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 may be necessary.

Hypotension In Acute Myocardial Infarction

Treatment with lisinopril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are patients with systolic blood pressure of 100mm Hg or lower or those in cardiogenic shock. During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120mm Hg or lower. Maintenance doses should be reduced to 5mg or temporarily to 2.5mg if systolic blood pressure is 100mm Hg or lower. If hypotension persists (systolic blood pressure less than 90mm Hg for more than 1 hour) then lisinopril should be withdrawn.

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

In cases of renal impairment (creatinine clearance <80ml/min), the initial lisinopril dosage should be adjusted according to the patient’s creatinine clearance and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine is part of normal medical practice for these patients.

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 with a 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, they should be discontinued and renal function should be monitored during the first few weeks of lisinopril therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially 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.

In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177micromol/l and/or proteinuria exceeding 500mg/24h. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 265micromol/l or a doubling from the pre-treatment value) then the physician should consider withdrawal of lisinopril.

Hypersensitivity/Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely 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).

Anaphylactoid reactions in Haemodialysis Patients

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. AN 69) 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

Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to 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 readministration of the medicinal product.

Hepatic failure

Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving lisinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril and receive appropriate medical follow-up.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in 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 non-productive, 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.

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).

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).

Lithium

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

Pregnancy and lactation

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).

Use of lisinopril is not recommended during breast-feeding.

Hydrochlorothiazide Renal impairment

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

In patients with renal disease, thiazides may precipitate azotaemia. Cumulative effects of the drug may develop in patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by rising nonprotein nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy (see section 4.3).

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).

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

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, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting.

Hypokalaemia may develop with the use of thiazide diuretics. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Anti-doping test

Hydrochlorothiazide contained in this medication could produce a positive analytical result in an anti-doping test.

Other

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Lisinopril/Hydrochlorothiazide combination

Renal impairment

Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets should not be administered to patients with renal insufficiency (creatinine clearance <80ml/min) until titration of the individual components has shown the need for the doses present in the combination tablet.

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

be a contributory factor to the above, renal function should be monitored during the first few weeks of therapy.

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

Pregnancy

Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is not recommended during the first trimester of pregnancy (see section 4.6). If treatment is discontinued due to pregnancy, the prescriber should decide whether treatment of hypertension should be continued.

Risk of hypokalaemia

The combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular monitoring of kalaemia should be performed.

Combination with lithium

Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is not recommended in association with lithium due to the potentiation of lithium toxicity (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

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).

Lisinopril

Diuretics

When a diuretic is added to the therapy of a patient receiving lisinopril the antihypertensive effect is usually additive.

Patients already on diuretics and especially those, in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when lisinopril is added. The possibility of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to initiation of treatment with lisinopril (see section 4.4).

Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes

Although in clinical trials, serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes. The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.

If lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of lisinopril 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 drugs (NSAIDs) including acetylsalicylic acid > 3g/day

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. 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.

Other antihypertensive agents

Concomitant use of these agents may increase the hypotensive effects of lisinopril. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.

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 have suggested 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.

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates.

Hydrochlorothiazide

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

Enhanced possibility of digitalis toxicity associated with thiazide induced hypokalaemia.

Cholestyramine resin and colestipol

May delay or decrease absorption of hydrochlorothiazide. Sulphonamide diuretics should be taken at least one hour before or four to six hours after these medications.

Non-depolarising muscle relaxants (eg. tubocurarine chloride)

Effects of these agents may be potentiated by hydrochlorothiazide.

Drugs associated with torsades de pointes

Because of the risk of hypokalaemia, caution should be used when hydrochlorothiazide is coadministered with drugs associated with torsades de pointes, e.g. some anti-arrhythmics, some antipsychotics and other drugs known to induce torsades de pointes.

Clinical Chemistry

Hydrochlorothiazide may cause diagnostic interference of the bentiromide test. Thiazides may decrease serum PBI (Protein Bound Iodine) levels without signs of thyroid disturbance.

Lisinopril/Hydrochlorothiazide combination

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. 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.

Non-steroidal anti-inflammatory medicinal products

It has been described that non-steroidal anti-inflammatory medicinal products (NSAIDs) and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are, in principle, reversible. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as the elderly or dehydrated. Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. The administration of NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.

Serum potassium

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, may lead to a significant increase in serum potassium. If concomitant use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets and any of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

4.6 Fertility, pregnancy and lactation

Lisinopril

Pregnancy

ACE Inhibitors:

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

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

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

Lactation

ACE Inhibitors:

Because no information is available regarding the use of Lisinopril Hydrochlorothiazide tablets during breastfeeding, Lisinopril Hydrochlorothiazide tablets 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

Pregnancy

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

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 tablets during breast feeding is not recommended. If Lisinopril Hydrochlorothiazide tablets is used during breast feeding, doses should be kept as low as possible.

Lisinopril/Hydrochlorothiazide combination Pregnancy

The use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets during pregnancy is not recommended. When pregnancy is detected Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets should be discontinued as soon as possible, unless it is considered life-saving for the mother.

If Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is used during pregnancy, the patient should be apprised of the potential hazard to the foetus. In those rare cases where use during pregnancy is deemed essential, serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is detected, Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets should be discontinued unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the foetus has sustained irreversible injury.

Infants whose mothers have taken Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets should be closely observed for hypotension, oliguria and hyperkalaemia. Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion. There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.

Lactation

It is not known whether lisinopril is secreted in human milk; however, thiazides do appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets, taking into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

When operating machinery or driving vehicles, it should be taken into account that dizziness, hypotension and tiredness may occur as adverse events of the combination.

4.8 Undesirable effects

Lisinopril

The following undesirable effects have been observed and reported during treatment with lisinopril and other ACE inhibitors 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)

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

Metabolism and nutrition disorders: very rare:    hypoglycaemia

Nervous system and psychiatric disorders: common:    dizziness, headache

uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep disturbances

rare:    mental confusion

Cardiac and vascular disorders:

common:    orthostatic effects (including hypotension)

uncommon:    myocardial infarction    or cerebrovascular    accident, possibly

secondary to excessive hypotension in high risk patients (see section 4.4), palpitations, tachycardia Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders: common:    cough

uncommon:    rhinitis

very rare:    bronchospasm, sinusitis.    allergic alveolitis/eosinophilic

pneumonia

Gastrointestinal disorders:

Skin and subcutaneous tissue disorders:

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

diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome erythema multiforme

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.

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:    fatigue, asthenia

Investigations:

uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia rare:    increases in serum bilirubin, hyponatraemia

Hydrochlorothaizide

Infections and infestations: sialadenitis

Blood and lymphatic system disorders:

leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression

Metabolism and nutrition disorders:

anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides

Psychiatric disorders:

restlessness, depression, sleep disturbances Nervous system disorders: loss of appetite, paraesthesia, light-headedness Eye disorders:

xanthopsia, transient blurred vision

Ear and labyrinth disorders: vertigo

Cardiac disorders:

postural hypotension, cardiac arrhythmias 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

Hepato-biliary 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

Musculoskeletal, connective tissue and bone disorders: muscle spasm

Renal and urinary disorders: renal dysfunction, interstitial nephritis General disorders fever, weakness

Lisinopril/Hydrochlorothiazide combination

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.

One of the most common clinical side effects was dizziness, which generally responded to dosage reduction and seldom required discontinuation of therapy.

Other side effects were headache, dry cough, fatigue and hypotension including orthostatic hypotension.

Less common were diarrhoea, nausea, vomiting, dry mouth, rash, gout, palpitations, chest discomfort, muscle cramps and weakness, paraesthesia, asthenia and impotence.

Pancreatitis has been reported rarely with lisinopril and with hydrochlorothiazide and, therefore, is a potential side effect of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets.

Hypersensitivity/Angioneurotic Oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely (see section 4.4). In very rare cases, intestinal angioedema has been reported.

A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia and leucocytosis, rash, photosensitivity, or other dermatological manifestations.

Laboratory Test Findings

Laboratory side effects have rarely been of clinical importance. Occasional hyperglycaemia, hyperuricaemia and hyper- or hypokalaemia have been noted. Usually minor and transient increases in blood urea nitrogen and serum creatinine have been seen in patients without evidence of pre-existing renal impairment. If such increases persist, they are usually reversible upon discontinuation of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets. Bone marrow depression, manifest as anaemia and/or thrombocytopenia and/or leucopenia has been reported. Agranulocytosis has been rarely reported. Small decreases in haemoglobin and haematocrit have been reported frequently in hypertensive patients treated with Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets but were rarely of clinical importance unless another cause of anaemia co-existed. Rarely, elevations of liver enzymes and/or serum bilirubin have occurred, but a causal relationship

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

4.9 Overdose Lisinopril

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 shock position. If available, treatment with angiotensin II 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.

Hydrochlorothiazide

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias. The degree

Lisinopril/Hydrochlorothiazide combination

No specific information is available on the treatment of overdosage with Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets. Treatment is symptomatic and supportive.

Therapy with Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets should be discontinued and the patient should be kept under very close supervision. Therapeutic measures depend on the nature and severity of the symptoms. Measures to prevent absorption and methods to speed elimination should be employed.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors and Diuretics ATC code: C09BA03

Lisinopril

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.

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.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide 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 and, to a lesser extent, the excretion of potassium and magnesium. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not usually affect normal blood pressure.

When combined with other antihypertensive agents, additive falls in blood pressure may occur.

Above a certain dose, thiazide diuretics reach a plateau in terms of therapeutic effect whereas adverse reactions continue to multiply. When treatment is ineffective, increasing the dose beyond recommended doses serves no useful purpose and often gives rise to adverse reactions.

Lisinopril/Hydrochlorothiazide combination

Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is a fixed dose combination product containing lisinopril, an inhibitor of angiotensin converting enzyme (ACE) and hydrochlorothiazide, a thiazide diuretic. Both components have complementary modes of action and exert an additive antihypertensive effect.

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.

5.2 Pharmacokinetic properties Lisinopril

Lisinopril is an orally active non-sulphydryl-containing ACE inhibitor.

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 50ml/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 30ml/min. In mild to moderate renal impairment (creatinine clearance 30-80ml/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 5-30ml/min).

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

Older 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

Oral absorption of hydrochlorothiazide is relatively rapid. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the dose is eliminated unchanged within 24 hours. After oral hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts 6 to 12 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

Lisinopril/Hydrochlorothiazide combination

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

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

Animal studies performed during organogenesis with hydrochlorothiazide have not shown any teratogenic effect. Preclinical data reveal no other specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicology, genotoxicity and carcinogenicity. Lisinopril/Hydrochlorothiazide combination

Lisinopril and hydrochlorothiazide are well established in medical use. Preclinical data is broadly consistent with clinical experience. For reproduction toxicity, see section 4.6.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Mannitol (E 421)

Calcium Hydrogen Phosphate Dihydrate

Maize Starch

Pregelatinised starch

Magnesium stearate

Yellow Iron Oxide

6.2    Incompatibilities

Not Applicable

2 years.

6.4 Special precautions for storage

Store below 30°C. Store in the original carton in order to protect from light.

6.5    Nature and contents of container

PVC/PVDC/Al blisters in a carton.

Packs of 1, 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100, 500 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

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

7    MARKETING AUTHORISATION HOLDER

Lupin (Europe) Limited Victoria Court Bexton Road Knutsford WA16 0PF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 35507/0055

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/11/2009

14/11/2014