4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Zesger Plus 20 mg/12.5 mg tablets fixed dose combination (lisinopril (as dehydratedihydrate) 20 mg and hydrochlorothiazide 12.5 mg) is indicated in patients whose blood pressure is not adequately controlled on lisinopril alone (or hydrochlorothiazide alone).

4.2 Posology and method of administration
Method of Administrationadministration
For oral use.

4.4 Special warnings and precautions for use

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, co-trimoxazole also known as trimethoprim/sulfamethoxazole). If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Symptomatic hypotension

If hypotension occurs, the patient should be placed in the supine position and, and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication for future doses. Following restoration of effective blood volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril. This effect is anticipated and is nornot usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of lisinopril-/hydrochlorothiazide may be necessary.

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

Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Lisinopril

mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angioedema (see section 4.4).

Co-trimoxazole (trimethoprim/sulfamethoxazole)
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).

Tissue plasminogen activators (TPA’stPA’s)
Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.

Hydrochlorothiazide

Colestyramine and colestipol
These may delay or reduce the absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least one hour before or four to six hours after intake of these agents

4.6 Fertility, pregnancy and lactation

Breast-feeding

ACE-inhibitors:

4.8 Undesirable effects

Lisinopril

Gastrointestinal disorders
Common: diarrhoea, vomiting
Uncommon: nausea, indigestion, pancreatitis, abdominal pain, dry mouth.
Rare: dry mouth
Very rare: pancreatitis, intestinal angioedema

Hydrochlorothiazide (frequencies not known):

Metabolism and nutrition disorders: anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypokalaemia, hypochloremic alkalosis and hypomagnesaemia), increases in cholesterol and triglycerides and , gout

Hepato-biliary disorders: jaundice (intrahepatic cholestatic jaundice)

10. DATE OF REVISION OF THE TEXT

December 2015FebruaryMarch 2017

4.2 Posology and method of administration

Posology

The selection of a suitable antihypertensive dose of lisinopril

 

and /hydrochlorothiazide will depend upon the clinical evaluation of the patient.

 

The usual dose is

 

 

Zesger Plus 20 mg/12.5 mg one tablet should be taken administered once daily.

 

The administration of

 

the a fixed combination lisinopril and / hydrochlorothiazide is usually recommended after dosage titration with the individual components.

 

When clinically appropriate a direct change from monotherapy to fixed combination may be considered.

 

Lisinopril/hydrochlorothiazide 20 mg/12.5 mg tablets may be administrated in patients whose blood pressure is not adequately controlled by 20 mg lisinopril alone.

 

In general, if the desired therapeutic effect cannot be achieved in a period of 2 to 4 weeks at lisinopril/hydrochlorothiazide 20 mg/12.5 mg, the dose can be increased to two tablets administered once daily.

A maximum daily dose of 40 mg lisinopril/ 25 mg hydrochlorothiazide should not be exceeded.

As with other medicines that are taken once daily, Zesger Plus 20 mg/12.5 mg tablets should be taken at about the same time each day.

Renal impairment

 

The combination

 

of lisinopril/hydrochlorothiazide is contraindicated in patients with severe renal impairment.

 

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

Lisinopril/hydrochlorothiazide is not to be used as initial therapy in any patient with renal insufficiency.

Lisinopril/hydrochlorothiazide

 

 

Zesger Plus 20 mg/12.5 mg tablets may be used in patients with creatinine clearance >30 and <80 ml/min, but only after titration of the individual components.

 

The recommended initial dose of lisinopril as monotherapy for these patients is 5-10 mg.

Previous diuretic treatment

Symptomatic hypotension may occur after the initial dose of

 

lisinopril/hydrochlorothiazideZesger Plus 20 mg/12.5 mg tablets; this occurs more often in patients that are volume and/or salt depleted as a result of previous treatment with diuretics.

 

The diuretic should be discontinued 2 to 3 days before the start of treatment with

 

lisinopril/hydrochlorothiazide Zesger Plus 20 mg/12.5 mg tablets. If this is not possible, treatment should be started at a dose of 2.5 mg lisinopril alone.

 

Elderly

Clinical studies on the combination of lisinopril/hydrochlorothiazide have not shown that age is associated with any changes in efficacy or tolerability (see [Renal Impairment]).

Paediatric population

The safety and efficacy of

 

lisinopril/hydrochlorothiazide Zesger Plus 20 mg/12.5 mg tablets in children has not been established.

 

Older people

Clinical studies on the combination of lisinopril and hydrochlorothiazide have not shown that age is

associated with any changes in efficacy or tolerability. (see [Renal Impaiment])

Method of administration

For oral use.

As with other medicines that are taken once daily, Zesger Plus 20 mg/12.5 mg tablets should be taken at about the same time each day.

4.3 Contraindications



 

 

Renal artery stenosis.

 



 

 

Hypersensitivity to lisinopril the active substances or to any of the excipients (listed in section 6.1)

 



 

Hypersensitivity or to any other angiotensin converting enzyme (ACE) inhibitors

 



 

Hypersensitivity to hydrochlorothiazide or any other sulphfonamide-derived drugs

 



 

History of angioedema with previous ACE inhibitor therapy

 



 

Hereditary or idiopathic angioedema

 



 

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

 



 

Severe hepatic impairment

 



 

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

 



 

The concomitant use of Lisinopril and Hydrochlorothiazide 20 mg/12.5 mg tablets with aliskirencontaining

 

products is contraindicated in patients with diabetes mellitus or renal impairment

(GFR < 60 ml/min/1.73 m

 

2) (see sections 4.5 and 5.1).

 



 

Anuria

 

4.4 Special warnings and precautions for use

Renal transplantation

Lisinopril/hydrochlorothiazide

 

 

Sshould not be used, since there is no experience with patients recently transplanted with a kidney.

 

Anaphylactoid reactions in haemodialytic patients

The use of lisinopril

 

-/hydrochlorothiazide is not indicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported in patients, undergoing certain haemodialysis procedures (e.g. with the high-flux membranes AN 69 and during low-density lipoproteins (LDL) apheresis with dextran sulphfate) 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 related to low-density lipoproteins (LDL) apheresis In rare occasions, patients treated with ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sul

 

phfate have shown life-threatening anaphylactoid reactions. These symptoms can be avoided by temporary discontinuation of the treatment with ACE inhibitors before each apheresis.

 

Hypokalaemia

Although hypokalaemia may develop through the use of thiazide diuretics, concomitant use of lisinopril may decrease diuretic-induced hypokalaemia. Regular checks of serum potassium should take place.

The possibility of hypokalaemia is strongest in patients with cirrhosis of the liver, in patients experiencing rapid diuresis, in patients having an inadequate oral intake of electrolytes and in patients concomitantly treated with corticosteroids or ACTH (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 ACE-inhibitors and lithium is generally not recommended (see section 4.5). Metabolic and endocrine effects

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycaemi

 

ca levels control should be closely monitored during the first month of treatment with an ACE inhibitor. Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

 

Cholesterol and triglycerides

Increases of cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Uricaemia

Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. However, lisinopril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide.

Symptomatic hypotension

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients, but is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has severe renin-dependent hypertension (see sections 4.5 and 4.8). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be monitored under close medical supervision. Particular consideration applies to patients with ischaemic heart or cerebrovascular disease, because an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If hypotension occurs, the patient should be placed in the supine position and,

 

and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication for future doses. Following restoration of effective blood volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone.

 

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril. This effect is anticipated and is

 

nor not usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of lisinopril-/hydrochlorothiazide may be necessary.

 

As with other vasodilators, caution must be exercised when administering lisinopril / hydrochlorothiazide to patients suffering from aortic stenosis or hypertrophic cardiomyopathy.

Although hypokalaemia may develop through the use of thiazide diuretics, concomitant use of lisinopril may decrease diuretic-induced hypokalaemia. Regular checks of serum potassium should take place. The possibility of hypokalaemia is strongest in patients with cirrhosis of the liver, in patients experiencing rapid diuresis, in patients having an inadequate oral intake of electrolytes and in patients concomitantly treated with corticosteroids or ACTH (see [Interactions with other medicinal products]).

In hot weather hyponatraemia may occur in oedematous patients. The chloride deficiency is generally mild and does not need treatment.

Thiazides may reduce calcium excretion via urine excretion and cause a slight intermittent increase in serum calcium levels even in the absence of known disorders in calcium metabolism. Distinct hypercalcaemia may be a hint of hidden hyperparathyroidism. Thiazides should be discontinued before parathyroid function tests are performed. Thiazides have been shown to increase the renal magnesium excretion, which may result in hypomagnesemia.

Renal

 

function impairment

 

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance

 

values of less than 30 ml/min or below (corresponds to moderate or severe renal

 

insufficiency).

Zesger Plus 20 mg/12.5 mg tablets

 

 

Lisinopril/hydrochlorothiazide should not be administered to patients with renal insufficiency (creatinine clearance less than or equal to 80 ml/minute) until titration of the individual components has shown the need for the doses present in the combination tablet.

 

In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.

 

Some hypertensive patients with no apparent pre-existing renal disease have developed usually minor and transient increases in blood urea levels and serum creatinine levels when lisinopril was 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 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 Zesger Pluslisinopril/hydrochlorothiazide therapy.

 

In patients with renal diseases, thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects of the medication may occur. If a progressive renal insufficiency develops, characterized by an increase in non-protein nitrogen, careful evaluation of the therapy is necessary, and stopping the diuretics therapy should be considered (see section 4.4).

Prior diuretic therapy

The diuretic therapy should be discontinued for 2-3 days prior to initiation with lisinopril/hydrochlorothiazide. If this is not possible, treatment should be started with lisinopril alone, in a

 

2.5 mg dose (see section 4.2).

 

Hepatic

 

disease impairment

 

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see section 4.3). Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving

 

Zesger Plus lisinopril/hydrochlorothiazide who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril/hydrochlorothiazide Zesger Plus and receive appropriate medical follow-up.

 

4.5 Interaction with other medicinal products and other forms of interaction

 

 

 

 

The following interactions between

 

lisinopril/hydrochlorothiazideZesger Plus 20 mg/12.5 mg tablets, other ACE-inhibitors or products containing hydrochlorothiazide have been reported.

 

 

 

 

 

Lisinopril

 

 

 

 

Diuretics

When a diuretic is added to the therapy of a patient receiving

 

Llisinopril 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

 

Llisinopril is added. The possibility of symptomatic hypotension with Llisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with Llisinopril (see sections 4.2 and 4.4).

 

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

Chronic administration of NSAIDs (including selective cyclooxygenase-2 inhibitors

 

, acetylsalicylic acid > 3g/day and non-selective NSAIDs) may reduce the antihypertensive and diuretic effect of an ACE inhibitors and thiazide diuretics.

 

NSAIDs and ACE inhibitors

 

may exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.

 

Other antihypertensives

Concomitant use of these agents may increase the hypotensive effects of

 

lisinopril/hydrochlorothiazideZesger Plus. Concomitant use of glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce the blood pressure.

 

Haemodialysis

Lisinopril/hydrochlorothiazide

 

 

Zesger Plus is not indicated in patients requiring dialysis as a high incidence of anaphylactoid reactions have been reported in patients dialysed with high flux membranes and treated concomitantly with an ACE inhibitor. This combination should be avoided (see section 4.4).

 

Procainamide, cytostatics or immunosuppressives

Concomitant administration with ACE inhibitors can lead to an increased risk of leucopenia (see section 4.4).

 

Tissue plasminogen activators (TPA’s)

 

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

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

Although in clinical trials with ACE inhibitors serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients.

 

 

The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. The use of potassium supplements, potassiumsparing agents or potassium containing salt substitutes, particularly in patients with impaired renal function or diabetes mellitus, may lead to a significant increase in serum potassium.

 

If concomitant use of lisinopril

 

/-hydrochlorothiazide and any of these agents is required, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4). Although in clinical trials with ACE inhibitors serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients.

 

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

Lactation

 

 

Breast-feeing

 

ACE-inhibitors:

Because no information is available regarding the use of

 

Zesger Plus Tablets lisinopril/hydrochlorothiazide during breastfeeding, Zesger Plus Tablets is are not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

 

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of

 

lisinopril/hydrochlorothiazide Zesger Plus Tablets during breast- feeding is not recommended. If Zesger Plus Tablets is are used during breast- feeding, doses should be kept as low as possible.

 

4.7 Effects on ability to drive and use machines

As with other antihypertensives,

 

lisinopril/hydrochlorothiazide Lisinopril-Hydrochlorothiazide combination products may have a mild to moderate effect on the ability to drive and use machines. Eespecially, at the start of the treatment or when the dose is modified, and also when used in combination with alcohol, but these effects depend on the individual’s susceptibility.

 

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

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with

 

lisinopril and/or hydrochlorothiazide Zesger Plus 20 mg/12.5 mg tablets with the following frequencies: vVery common

 

(

 

>≥1/10), cCommon (>≥1/100: to <1/10), uUncommon (>≥1/1,000, to <1/100), rRare (>≥1/10,000; to <1/1,000), vVery rare (<1/10,000), nNot known (cannot be estimated from the available data) including isolated reports.

 

Psychiatric disorders

Uncommon: sleep disturbance, mood alterations, depressive symptoms
Rare: mental confusion
Not known: hallucinations

Nervous system

 

and psychiatric disorders

 

Common: dizziness, which generally responded to dosage reduction and seldom required discontinuation of therapy; headache,

 

fatigue, syncope
Uncommon: paraesthesia, asthenia, vertigo, taste disturbances, sleep disturbance, mood alterations
Rare: olfactory disturbancemental confusion
Not known: depressive symptoms

 

Cardiac

 

and vascular disorders:

 

Common: orthostatic effects (including orthostatic hypotension)
u

 

 

Uncommon: Myocardial infarction or cerebrovascular accident, possible secondary to excessive hypotension in high risk patients (see section 4.4), palpitation, chest pain, muscle spasms and muscle weakness, tachycardia, Raynaud’s syndrome
Not known: flushing

 

Vascular disorders

Uncommon: myocardial infarction or cerebrovascular accident, possible secondary to excessive hypotension in high risk patients (see section 4.4), Raynaud’s syndrome
Not known: flushing

 

 

Respiratory, thoracic and mediastinal disorders

 

Common: dry and persistent cough (see section 4.4), which disappears after discontinuation of therapy
Uncommon: rhinitis
Very rare: bronchospasm, sinusitis, allergic, alveolitis/eosinophilic pneumonia

Gastrointestinal disorders

Common: diarrhoea, vomiting
Uncommon: nausea, indigestion,

 

pancreatitis, abdominal pain,Rare: dry mouth
Very rare: pancreatitis, intestinal angioedema

 

Musculoskeletal and connective tissue disorders

Uncommon: muscle spasms and muscle weakness

General disorders and administration site conditions

Uncommon: asthenia, fatigue

 

, chest pain

 

Others

Rare: a complex of symptoms, consisting of one or more of the following: fever, vasculitis, myalgia, artralgia or arthritis, positive ANA test; increased ESR, eosinophilia, leukocytosis, rash, photosensitivity or other dermatologic manifestations.

Findings in laboratory tests

Changes in laboratory values have rarely been of clinical significance. Hyperglycaemia, hyperuricaemia and hyperkalaemia or hypokalaemia are seen occasionally. Mild and temporary increases in blood nitrogen urea and serum creatinine are usually seen in patients without pre-existing kidney failure. If such increases are persistent, they generally disappear when treatment is discontinued.

Bone marrow depression, manifested as anaemia and/or thrombocytopenia and/or leucopenia, has been reported. Agranulocytosis is reported rarely, although a causal connection has not been established. A small fall in haemoglobin and haematocrit is often reported in hypertensive patients treated with

 

Zesger Plus 20 mg/12.5 mg tabletslisinopril/hydrochlorothiazide, but it was rarely of clinical significance unless another cause of anaemia existed simultaneously.

 

An increase in liver enzymes and/or serum bilirubin is rarely seen, but a causal connection with

 

lisinopril/hydrochlorothiazideZesger Plus 20 mg/12.5 mg tablets has not been established. Haemolytic anaemia has been rarely reported.

 

Undesirable effects reported of the individual components:

 

 

 

 

 

 

 

Metabolism and nutrition disorders: anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypokalaemia, hypochloremic alkalosis and hypomagnesaemia), increases in cholesterol and triglycerides

 

, and gout

 

Psychiatric disorders: restlessness, depression, sleep disturbance

Nervous system disorders: loss of appetite, paraesthesia, light-headedness

Eye disorders: xanthopsia, transient blurred vision

 

, acute myopia and acute angle-closure glaucoma

 

 

 

 

 

Ear and labyrinth disorders: vertigo

Cardiac disorders: Postural hypotension, cardiac arrhythmias

Vascular disorders: necrotising angiitis (vasculitis, cutaneous vasculitis)

Respiratory, thoracic and mediastinal disorders: respiratory distress (including pneumonitis and pulmona

 

tory oedema)

 

Gastrointestinal disorders: gastric irritation, diarrhoea, constipation, pancreatitis

Hepato-biliary disorders: jaundice (intrahepatic chol

 

estatic jaundice)

 

Skin and subcutaneous

 

tissue disorders: photosensivity reactions, rash, systemic lupus erythematosus, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis

 

Musculoskeletal

 

, and connective tissue and bone disorders: muscle spasm, muscle weakness

 

 

 

 

General disorders

 

and administration site conditions: fever, weakness

 

 

 

 

Lisinopril and other ACE inhibitors:

 

 

 

 

Blood and the lymphatic system disorders:

Rare: decreases in haemoglobin, decreases in haematocrit.
Very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia, lymphadenopathy, autoimmune disease

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 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:

Common: diarrhoea, vomiting
Uncommon: nausea, abdominal pain and indigestion
Rare: dry mouth
Very rare: pancreatitis, intestinal angioedema, hepatitis- either hepatocellular or cholestatic, jaundice and hepatic failure (see 4.4)

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus
Rare: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see 4.4), urticaria, alopecia, psoriasis
Very rare: 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, 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.

 

 

 

 

Symptoms

 

 

 

 

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.

 

 

 

Hydrochlorothiazide: the most common signs and symptoms are those that are due to electrolyte reduction (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration due to significant diuresis.

Additional symptoms hydrochlorothiazide overdose are increased diuresis, depression of consciousness (incl. coma), convulsions, paresis, cardiac arrhythmias and renal failure. Bradycardia or extensive vagal reactions should be treated by administering atropine. If digitalis has also been administered hypokalaemia may accentuate cardiac arrhythmias.

 

 

Management

 

 

 

 

 

No specific information is available on the treatment of overdose of lisinopril/hydrochlorothiazide. Treatment is symptomatic and supportive. Treatment with Lisinopril and Hydrochlorothiazide 20 mg/12.5 mg tablets should be discontinued and the patient should be monitored very closely. Therapeutic measures depend on the nature and the severity of the symptoms. Measures should be instituted to prevent absorption and to promote elimination. The recommended measures include inducing vomiting and/or gastric lavage if the drug was ingested recently, while dehydration, disturbances of the electrolyte balance and hypotension should be treated in the usual manner.

 

 

 

 

The recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the supine position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may

 

also be considered. If ingestion is recent, take measures aimed at eliminating Llisinopril (e.g. emesis, gastric lavage, administration of absorbents and sodium sulphfate).

 

Hydrochlorothiazide: the most common signs and symptoms are those that are due to electrolyte reduction (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration due to significant diuresis.

Additional symptoms hydrochlorothiazide overdose are increased diuresis, depression of consciousness (incl. coma), convulsions, paresis, cardiac arrhythmias and renal failure. Bradycardia or extensive vagal reactions should be treated by administering atropine. If digitalis has also been administered hypokalaemia may accentuate cardiac arrhythmias.

 

 

 

 

 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

 

 

 

 

Pharmacotherapeutic group: ACE inhibitor

 

s (ACE: angiotensin converting enzyme) and thiazide diuretics, lisinopril and diuretics, ATC- code: C09B A03

 

 

 

 

 

Mechanism of action

 

 

 

 

 

Both components,

 

Llisinopril, the ACE inhibitor and Hhydrochlorothiazide, a diuretic, have complementary modes of action and exert an additive antihypertensive effect.

 

 

 

 

 

Lisinopril

 

 

 

 

 

Mechanism of action

Lisinopril is a peptidyl dipeptidase inhibitor and inhibits angiotensin converting enzyme (ACE).

 

 

ACE catalyses the conversion of angiotension I to angiotension II, which has a strong vasoconstrictor effect and stimulates aldosterone secretion. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion. The latter decrease may result in an increase in serum potassium concentration.

 

Pharmacodynamic effects

 

 

 

 

 

The antihypertensive effect of

 

Llisinopril is mainly due to the suppression of the renin angiotensinaldosterone system with reduction of plasma concentration of angiotension II (resulting in decreased vasopressor activity) and aldosterone. Lisinopril exerts an antihypertensive effect even in patients with lowrenin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. It remains unclear whether increased levels of bradykinin (a potent vasodilator) plays a role in the therapeutic effect of lisinopril.

 

 

 

 

 

Hydrochlorothiazide is a thiazide diuretic and an antihypertensive that increase the plasma-renin activity. Hydrochlorothiazide suppresses the renal reabsorption of electrolytes in the renal distal tubule and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonates and water. The excretion of calcium may be reduced.

 

 

Concomitant administration of lisinopril and hydrochlorothiazide gives a greater reduction in blood pressure than monotherapy. Lisinopril normally attenuates the potassium loss associated with hydrochlorothiazide.

 

The effects of the fixed dose combination of lisinopril

 

and /hydrochlorothiazide on mortality and cardiovascular morbidity are currently unknown.

 

 

 

 

 

Clinical safety and efficacy

 

 

 

 

 

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

 

 

 

 

Hydrochlorothiazide

 

 

 

 

 

Mechanism of action

Hydrochlorothiazide is a thiazide diuretic and an antihypertensive that increase the plasma-renin activity. Hydrochlorothiazide suppresses the renal reabsorption of electrolytes in the renal distal tubule and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonates and water. The excretion of calcium may be reduced.

Pharmacodynamic effect

Thiazides do not usually affect normal blood pressure.

 

 

 

 

 

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from

such medicinal product and other handling of the product

 

 

 

 

No special requirements

 

for disposal.

 

 

 

 

 

10. DATE OF REVISION OF THE TEXT

 

 

 

 

June

 

 

November 2015

 

 

 

 

 

4.3 Contraindications

REMOVED:
Concomitant administration with aliskirencontaining medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR<60ml/min/1.73m2 (see section 4.5)
REPLACED WITH:
The concomitant use of Lisinopril and Hydrochlorothiazide 20 mg/12.5 mg tablets with aliskiren containing
products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

ADDED:
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or
aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

4.5 Interaction with other medicinal products and other forms of interaction

Other antihypertensives
ADDED:
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).
Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes

REMOVED:
Dual blockade of the renin-angiotensin-aldosterone system
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of 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). Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with increased risks of hypotension,
syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on lisinopril and other agents that affect the RAAS. Do not co-administer aliskiren with lisinopril in patients with diabetes. Avoid use of aliskiren with lisinopril in patients with renal impairment (GFR < 60 ml/min/1.73m2) (see section 4.3).

4.8 Undesirable effects

Reporting of suspected adverse reactions
CONTACT DETAILS UPDATE:
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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971 FREE; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5.1 Pharmacodynamic properties

ADDED:
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.

10. DATE OF REVISION OF THE TEXT

CHANGED TO:
June 2015



(internal ref: DK/H/0616/IB/032 PR 433263)

Extensive list of changes in line with the CSP updates.

4.3 Contra-indications$0$0$0$0$0- Second or and third trimesters of pregnancy (see Ssections 4.4 and 4.6)$0$0- Lactation (see Section 4.6))$0$0$0$0$0$0$0$0$0$04.6 Use during pregnancy and lactation$0$0$0$0$0Pregnancy$0$0$0$0$0ACE-inhibitors:$0$0The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy (see section 4.3 and 4.4).$0$0$0$0$0Epidemiological evidence regarding the risk to  of teratogenicicty 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. $0$0$0$0$0$0$0When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy ACE inhibitor therapy exposure during the second and third trimesters is known to induce human foetotoxicity. (decreased renal function, olidohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also section 5.3 ‘Preclinical safety data’).$0$0Should 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 also sections 4.3 and 4.4).$0$0$0$0$0Hydrochlorothiazide:$0$0There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.$0$0$0$0$0Hydrochlorothiazide 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.$0$0$0$0$0Hydrochlorothiazide 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.$0$0$0$0$0Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.$0$0$0$0$0Prolonged use of hydrochlorothiazide during the third trimester may cause fetoplacental ischemia and risk of growth retardation. Following exposure near to term rare cases of neonatal hypoglycaemia and thrombocytopenia have been observed .$0$0Hydrochlorothiazide may reduce plasma volume as well as uteroplacental blood flow.$0$0$0$0$0$0$0Lactation$0$0$0$0$0ACE-inhibitors:$0$0Because no information is available regarding the use of Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets during breastfeeding, Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.$0$0$0$0$0Hydrochlorothiazide:$0$0Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets during breast feeding is not recommended. If Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is used during breast feeding, doses should be kept as low as possible.$0$0Lisinopril/Hydrochlorothiazide is contraindicated during lactation. Both lisinopril and hydrochlorothiazide are excreted into human milk.$0$0$0$0$0The use of thiazide by breast feeding mothers has been associated with decreased or even suppressed milk secretion. Hypersensivity to sulphonamide-derived drugs, hypokalemia and nuclear icterus have also been observed.$0$0Because of the potential for serious adverse effects in breast-fed infants, a decision should be made to either discontinue breastfeeding or discontinue lisinopril/hydrochlorothiazide therapy. The importance of this therapy to the mother should be taken in account.$0$0$0$0$0$0$04.7 Effects on ability to drive and use machines$0$0$0$0$0As with other antihypertensives, the ability to drive and use machines may be reduced, e.g. at the start of the treatment or when the dose is modified, and also when used in combination with alcohol, but these effects depend on the individual’s susceptibility.$0$0$0$0$0$0$0$0$010. DATE OF REVISION OF THE TEXT$0$0$0$0$0March 2013$0$0$0$0$0$0$0$0$0$0$0$0$0$0$0$0$0$0$0$0(Ref: IB/027 PhVWP updates)$0

4.3 Contra-indications

 Second or and third trimesters of pregnancy (see Ssections 4.4 and 4.6)
 Lactation (see Section 4.6))

4.6 Use during pregnancy and lactation

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapyACE inhibitor therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, olidohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

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

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

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

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

Lactation

ACE-inhibitors:
Because no information is available regarding the use of Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets during breastfeeding, Lisinopril and Hydrochlorothiazide 20mg/12.5mg Tablets is not recommended and alternative treatments with better established safety profiles during breastfeeding
are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets during breast feeding is not recommended. If Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is used during breast feeding, doses should be kept as low as possible.
Lisinopril/Hydrochlorothiazide is contraindicated during lactation. Both lisinopril and hydrochlorothiazide are excreted into human milk.

In Section 4.4, a paraghraph is added for to indicate the special warnings for Pregnancy
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

In Section 4.5, a paragraph is added to indicate the interaction with Alcohol
Alcohol
The ability to drive and use machines may be reduced when used in combination with alcohol.

Under Secion 4.6. The following changes were made:
Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy (see section 4.3 and 4.4).

Epidemiological evidence regarding the risk to  teratogenicicty 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, olidohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also section 5.3 ‘Preclinical safety data’).

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 also section 4.3 and 4.4).
Prolonged use of hydrochlorothiazide during the third trimester may cause fetoplacental ischemia and risk of growth retardation. Following exposure near to term rare cases of neonatal hypoglycaemia and thrombocytopenia have been observed .

Hydrochlorothiazide may reduce plasma volume as well as uteroplacental blood flow.

Section 9: Date of first authorisation added.