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2. Lizam 20mg/10mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lizam 20 mg/10 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg lisinopril (as dihydrate) and 10 mg amlodipine (as besylate).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White or off-white, round, biconvex tablets. Engraving on one side: “CF3”, other side without engraving. Diameter approx. 11 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of essential hypertension in adults.

Lizam tablet is indicated as substitution therapy of adult patients with blood pressure adequately controlled with lisinopril and amlodipine given concurrently at the same dose level.

4.2 Posology and method of administration

The recommended dose is one tablet daily. The maximum daily dose is one tablet. Since food does not affect the absorption of the preparation, Lizam may be taken irrespective of meals, i.e. before, during or after meals.

In general, fixed dose combination preparations are not suitable for initial therapy.

Lizam is indicated only for patients in whom the optimal maintenance dose of lisinopril and amlodipine has been titrated to 20 mg and 10 mg, respectively.

If dose adjustment becomes necessary, dose titration with the individual components can be considered.

Patients with renal impairment

To find the optimal starting dose and maintenance dose of patients with renal impairment, the patients should be individually titrated using the free combination of lisinopril and amlodipine.

The monitoring of renal function, serum potassium and sodium levels should be continued during therapy with Lizam. In the case of renal function deterioration Lizam should be withdrawn and replaced by the therapy with individual components adequately adjusted. Amlodipine is not dialyzable

Patients with hepatic impairment

Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range (see sections 4.4 and 5.2). To find the optimal starting dose and maintenance dose of patients with hepatic impairment, the patients should be individually titrated using the free combination of lisinopril and amlodipine.

The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Paediatric population (<18 years)

The safety and efficacy of Lizam in children aged below 18 years have not been established.

Elderly (> 65 years)

Elderly patients should be treated with caution.

In clinical studies, there was no age-related change in the efficacy or safety profile of amlodipine or lisinopril. To find the optimal maintenance dose of elderly patients they should be individually titrated using the free combination of lisinopril and amlodipine.

4.3 Contraindications

Related to lisinopril:

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

-    History of angioedema associated with previous ACE inhibitor therapy

-    Hereditary or idiopathic angioedema

-    2^nd and 3^rd trimesters of pregnancy (see sections 4.4 and 4.6)

-    The concomitant use of Lizam with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

Related to amlodipine:

-    Hypersensitivity to amlodipine or to any other dihydropyridine derivative

-    Severe hypotension

-    Shock (including cardiogenic shock)

-    Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis)

-    Haemodynamically unstable heart failure after acute myocardial infarction

Related to Lizam:

All of the above detailed contraindications related to the individual monocomponents are also relating to the fixed combination Lizam.

-    Hypersensitivity to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

All of the warnings with regard to the individual monocomponents detailed below are also relating to the fixed combination Lizam.

Related to 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 100 mmHg 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 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily 2.5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg 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 <80 ml/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. 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 initiatedjn patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/l and/or proteinuria exceeding 500 mg/24 hour. If renal dysfunction develops during treatment with lisinopril (serum creatinine concentration exceeding 265 micromol/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 ACE inhibitors, including lisinopril. This may occur at any time during therapy. In such cases, lisinopril should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the 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 re-administration 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.

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 section 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.

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 level 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

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Use of lisinopril is not recommended during breast-feeding.

Related to amlodipine:

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Patients with cardiac failure

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group (see section 5.1).

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Use in _patients with impaired hepatic _ function

The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function and dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Use in elderly patients

In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

Use in renal failure

Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. Amlodipine is not dialyzable.

4.5    Interaction with other medicinal products and other forms of interaction

Interactions linked to lisinopril

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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).

Diuretics

When a diuretic is added to the therapy of a patient receiving Lizam 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 minimised by discontinuing the diuretic prior to initiation of treatment with lisinopril (see section 4.4 and section 4.2).

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 >3 g/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.

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.

Other antihypertensive agents

Concomitant use of these agents may increase the hypotensive effect 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 effect of ACE inhibitors.

Antidiabetics

Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (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.

Interactions linked to amlodipine

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors:

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers:

There is no data available on the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John's wort [Hypericum perforatum]) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion):

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine.

Simvastatin:

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

4.6 Fertility, pregnancy and lactation

Pregnancy

No experience is available with the use of Lizam in pregnant women from adequately controlled clinical studies. However, the use of both active substances during pregnancy is either not recommended or contraindicated (for substance-specific details, see below).

When pregnancy is diagnosed, treatment with Lizam should be stopped immediately and, if appropriate, alternative therapy should be started (see section 4.4).

Lizam should not be initiated during pregnancy. Unless continued Lizam therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments with an established safety profile for use in pregnancy.

Linked to lisinopril:

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 section 5.3). Should exposure to ACE inhibitor have occurred from the second or third 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).

Linked to amlodipine:

The safety of amlodipine in human pregnancy has not been established.

In animal studies, reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Breast-feeding

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

Fertility

No experience is available with the effect of lisinopril and amlodipine on fertility from adequately controlled clinical studies.

Linked to amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Linked, to lisinopril:

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.

Linked to amlodipine:

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

According to the above Lizam may influence the ability to drive and operate machines (particularly during the initial period of treatment).

4.8 Undesirable effects

During a controlled clinical study (n=195), the incidence of adverse reactions was not higher in subjects receiving both active substances concomitantly than in patients on monotherapy. Adverse reactions were consistent with those reported previously with amlodipine and/or lisinopril. Adverse reactions were usually mild, transient and rarely warranted the discontinuation of treatment. The most common adverse reactions with the combination were headache (8%), cough (5%), and dizziness (3%).

Frequencies are defined as follows: 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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following adverse drug reactions (ADRs) have been reported during the treatment with lisinopril and amlodipine independently:

System Organ Class	Frequency	ADRs with lisinopril	ADRs with amlodipine
Blood and lymphatic system disorders	Very rare	Bone marrow depression, Agranulocytosis (see section 4.4), Leucopenia, Neutropenia, Thrombocytopenia, Haemolytic anaemia, Anaemia, Lymphadenopathy	Thrombocytopenia, Leucopenia
Immune system disorders	Very rare	Autoimmune disorder	Allergic reaction
Endocrine disorders	Rare	Inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders	Very rare	Hypoglycaemia	Hyperglycaemia
Psychiatric disorders	Uncommon Rare Not known	Mood changes, Sleep disturbances Mental confusion Depression	Insomnia, Mood changes (including anxiety), Depression Confusion
Nervous system disorders	Common	Dizziness, Headache	Somnolence, Dizziness,

System Organ Class	Frequency	ADRs with lisinopril	ADRs with amlodipine
			Headache, (especially at the beginning of the treatment)
	Uncommon	Vertigo, Paraesthesia,	Syncope, Tremor, Dysgeusia,
		Dysgeusia	Hypoaesthesia, Paraesthesia
	Very rare		Hypertonia, Peripheral neuropathy
	Not known	Syncope
Eye disorders	Uncommon		Visual disturbances (including diplopia)
Ear and labyrinth disorders	Uncommon		Tinnitus
Cardiac disorders	Common		Palpitations
	Uncommon	Myocardial infarction possibly secondary to excessive hypotension in high risk patients (see section 4.4), Tachycardia, Palpitations
	Very rare		Myocardial infarction, Arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation)
Vascular disorders	Common	Orthostatic hypotension	Flushing
	Uncommon	Cerebrovascular accident possibly secondary to excessive hypotension in high risk patients (see section 4.4), Raynaud’s phenomenon	Hypotension
	Very rare		Vasculitis
Respiratory, thoracic and	Common	Cough
mediastinal disorders	Uncommon	Rhinitis	Dyspnoea, Rhinitis
	Very rare	Bronchospasm, Alveolitis allergic/Eosinophilic pneumonia, Sinusitis	Cough
Gastrointestinal disorders	Common	Diarrhoea, Vomiting	Abdominal pain, Nausea
	Uncommon	Abdominal pain, Nausea,	Vomiting, Dyspepsia,
		Indigestion	Alteredbowel habit (diarrhoea and constipation), Dry mouth
	Rare	Dry mouth
	Very rare	Pancreatitis, Intestinal	Pancreatitis, Gastritis,
		angioedema	Gingival hyperplasia
Hepatobiliary disorders	Very rare	Hepatic failure, Hepatitis, Cholestatic jaundice, (see section 4.4)	Hepatitis, Jaundice
Skin and subcutaneous	Uncommon	Rash, Pruritus	Alopecia, Rash, Exanthema,
tissue disorders	Rare	Psoriasis, Urticaria, Alopecia, Hypersensitivity / angioedema	Purpura, Skin discolouration, Hyperhidrosis, Pruritus

System Organ Class	Frequency	ADRs with lisinopril	ADRs with amlodipine
	Very rare	of the face, extremities, lips, tongue, glottis and/or larynx (see section 4.4) Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, Erythema multiforme, Pemphigus, Hyperhidrosis, Cutaneous pseudolymphoma*	Erythema multiforme, Angioedema, Urticaria, Exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, Photosensitivity
Musculoskeletal and connective tissue disorders	Common Uncommon		Ankle swelling Arthralgia, Myalgia, Muscle cramps, Back pain
Renal and urinary disorders	Common Uncommon Rare Very rare	Renal dysfunction Acute renal failure, Uraemia Oliguria/Anuria	Micturition disorder, Nocturia, Increased urinary frequency
Reproductive system and breast disorders	Uncommon Rare	Impotence Gynaecomastia	Impotence, Gynaecomastia
General disorders and administration site conditions	Common Uncommon	Fatigue, Asthenia	Oedema, Fatigue Chest pain, Pain, Malaise, Asthenia
Investigations	Uncommon Rare Very rare	Blood urea increased, Serum creatinine increased, Hyperkalaemia, Hepatic enzymes increased Haemoglobin decreased, Haematocrit decreased Serum bilirubin increased, Hyponatraemia	Weight increase, Weight decrease Hepatic enzymes increased**

* 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.

** Mostly consistent with cholestasis.

Exceptional cases of extrapyramidal syndrome have been also reported with the use of amlodipine.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Linked to lisinopril 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 shock 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 4.4 special warning and precautions for use). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.

Linked to amlodipine overdose:

In humans experience with intentional overdose is limited.

Symptoms:

Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment:

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Overdose with Lizam can result in excessive peripheral vasodilatation with marked hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Symptomatic treatment (placing the patient in a supine position, monitoring -and when necessary, support - of cardiac and respiratory function, blood pressure, fluid and electrolyte balance, and creatinine concentrations) is recommended. In case of serious hypotension, the lower extremities should be elevated, and when intravenous administration of fluid does not elicit sufficient response, supportive treatment added-on with administration of peripheral vasopressor agents may be necessary, unless contraindicated. If available, treatment with angiotensin II infusion may also be considered. Intravenous administration of calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Bradycardia should be corrected by administering atropine. Pacemaker therapy should be considered in treatment-resistant bradycardia. Since absorption of amlodipine is slow, gastric lavage (or emesis, and administration of adsorbents and sodium sulphate) may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Lisinopril can be removed from the systemic circulation by haemodialysis. The use of high-flux polyacrylonitrile membranes should be avoided during dialysis.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers, ATC code: C09BB03

Lizam is a fixed dose combination containing the active substances lisinopril and amlodipine.

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.

The effect of lisinopril on mortality and morbidity in heart failure has been studied by comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or 5 mg once daily). In a study of 3164 patients, with a median follow up period of 46 months for surviving patients, high dose lisinopril produced a 12% risk reduction in the combined endpoint of all-cause mortality and all-cause hospitalisation (p = 0.002) and an 8% risk reduction in all-cause mortality and cardiovascular hospitalisation (p = 0.036) compared with low dose. Risk reductions for all-cause mortality (8%; p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a post-hoc analysis, the number of hospitalisations for heart failure was reduced by 24% (p=0.002) in patients treated with high-dose lisinopril compared with low dose. Symptomatic benefits were similar in patients treated with high and low doses of lisinopril.

The results of the study showed that the overall adverse event profiles for patients treated with high or low dose lisinopril were similar in both nature and number. Predictable events resulting from ACE inhibition, such as hypotension or altered renal function, were manageable and rarely led to treatment withdrawal. Cough was less frequent in patients treated with high dose lisinopril compared with low dose.

In the GISSI-3 trial, which used a 2x2 factorial design to compare the effects of lisinopril and glyceryl trinitrate given alone or in combination for 6 weeks versus control in 19,394 patients who were administered the treatment within 24 hours of an acute myocardial infarction, lisinopril produced a statistically significant risk reduction in mortality of 11% versus control (2p=0.03). The risk reduction with glyceryl trinitrate was not significant but the combination of lisinopril and glyceryl trinitrate produced a significant risk reduction in mortality of 17% versus control (2p=0.02). In the sub-groups of elderly (age >70 years) and females, pre-defined as patients at high risk of mortality, significant benefit was observed for a combined endpoint of mortality and cardiac function. The combined endpoint for all patients, as well as the high-risk sub-groups, at 6 months also showed significant benefit for those treated with lisinopril or lisinopril plus glyceryl trinitrate for 6 weeks, indicating a prevention effect for lisinopril. As would be expected from any vasodilator treatment, increased incidences of hypotension and renal dysfunction were associated with lisinopril treatment but these were not associated with a proportional increase in mortality.

In a double-blind, randomised, multicentre trial which compared lisinopril with a calcium channel blocker in 335 hypertensive Type 2 diabetes mellitus subjects with incipient nephropathy characterised by microalbuminuria, lisinopril 10 mg to 20 mg administered once daily for 12 months, reduced systolic/diastolic blood pressure by 13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the calcium channel blocker, which produced a similar reduction in blood pressure, those treated with lisinopril showed a significantly greater reduction in urinary albumin excretion rate, providing evidence that the ACE inhibitory action of lisinopril reduced microalbuminuria by a direct mechanism on renal tissues in addition to its blood pressure lowering effect.

Lisinopril treatment does not affect glycaemic control as shown by a lack of significant effect on levels of glycated haemoglobin (HbA1c).

In a clinical study involving 115 paediatric patients with hypertension, aged 6-16 years, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or 20 mg of lisinopril once a day, and patients who weighed 50 kg or more received either 1.25 mg,

5 mg or 40 mg of lisinopril once a day. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with a consistent antihypertensive efficacy demonstrated at doses greater than 1.25 mg.

This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and race.

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.

Amlodipine

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle.

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma bronchiale, diabetes mellitus, and gout.

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) A randomized, double-blind, morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/d ay (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD (coronary heart disease) risk factor, including: previous myocardial infarction or stroke (> 6 months prior to enrolment) or documentation of other atherosclerotic CVD (cardiovascular disease)

(overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dl (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI [0.90-1.07] p=0.65. However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.96 95% CI [0.89-1.02] p=0.20.

In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5 mg dose and 5.0 mg dose of amlodipine with placebo, showed that both doses reduced systolic blood pressure significantly more than placebo. The difference between the two doses was not statistically significant.

The long-term effects of amlodipine on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

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 interpatient 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 and protein binding

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 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.

Pharmacokinetic features in special populations

Hepatic impairment

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

Renal impairment

Impaired renal function decreases the elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically relevant only when the glomerular filtration rate is below 30 ml/min. In mild to moderate renal impairment (creatinine clearance 30 to 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 between 5 and 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 a reduced absorption of approximately 16% compared to healthy subjects.

Paediatrics

The pharmacokinetic profile of lisinopril was studied in 29 paediatric hypertensive patients, aged between 6 and 16 years, with a GFR above 30 ml/min/1.73m². After doses of 0.1 to 0.2 mg/kg, steady-state peak plasma concentrations of lisinopril occurred within 6 hours, and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults.

AUC and Cmax values in children in this study were consistent with those observed in adults.

Elderly

Older patients have higher blood levels and higher values for the area under the plasma concentration-time curve (increased approximately 60-per-cent) compared with younger subjects.

Amlodipine

Absorption

After oral administration amlodipine is well absorbed, producing peak plasma concentrations between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The bioavailability of amlodipine is not affected by food intake.

Distribution and plasma protein binding

The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Biotransformation and elimination

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Pharmacokinetic features in special populations Use in hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Elderly

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients.

Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

A population PK study has been conducted in 74 hypertensive children aged from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 l/h, respectively in males and 16.4 and 21.3 l/h, respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

Fixed dose combination

No pharmacokinetic interactions have been described between the active substances of Lizam. Pharmacokinetic parameters (AUC, C_max, t_max, half-life) were not different from those observed after administration of the individual components separately.

The gastrointestinal absorption of Lizam is not influenced by food.

5.3 Preclinical safety data

Non-clinical studies have not been conducted with the combination lisinopril-amlodipine.

Results related to lisinopril

Non-clinical data reveal no special hazard for humans based on conventional studies of general pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

ACE inhibitors, as a class, have been shown to induce adverse effects on 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.

Results related to amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of carcinogenicity. The highest dose (for mice similar to, and for rats twice* the maximum recommended clinical dose of 10 mg/day on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome level.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg/day on a mg/m² basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

* Based on patient weight of 50 kg.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, microcrystalline Sodium starch glycolate (type A)

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25 °C.

Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

28, 30, 50, 56, 60, 90, 98 or 100 tablets in white, PVC/PE/PVDC/Aluminium blister and in a carton.

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 of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Gedeon Richter Plc.

H-1103 Budapest Gyomroi ut 19-21.

Hungary

8    MARKETING AUTHORISATION NUMBER(S)

PL 04854/0117

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/01/2013

10    DATE OF REVISION OF THE TEXT

23/05/2015