4.1. Therapeutic indications

Innozide is indicated for the treatment of mild to moderate hypertension in patients who have been stabilised on the individual components given in the same proportions.

(See sections 4.3, 4.4, 4.5 and 5.1).

4.2. Posology and method of administration

Posology

The dosage of Innozide should be determined primarily by the experience with the enalapril maleate component.

Adults

Essential hypertension

The usual dosage is one tablet, taken once daily. If necessary, the dosage may be increased to two tablets, taken once daily.

Prior diuretic therapy: symptomatic hypotension may occur following the initial dose of Innozide; this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. The diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with Innozide.

Dosage in renal insufficiency

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

In patients with creatinine clearance of >30 mL/min and <80 mL/min, Innozide should be used only after titration of the individual components.

Use in the elderly

In clinical studies the efficacy and tolerability of enalapril maleate and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.

Paediatric population

Safety and effectiveness in children have not been established.

Method of administration

Oral use.

4.3. Contraindications

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

• Severe renal impairment (creatinine clearance ≤30 mL/min).

• Anuria.

• History of angioneurotic oedema associated with previous ACE-inhibitor therapy.

• Hereditary or idiopathic angioedema.

• Hypersensitivity to sulfonamide-derived drugs.

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

• Severe hepatic impairment.

• Stenosis of the renal arteries

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

• Combination with sacubitril/valsartan due to the increased risk of angioedema. Do not administer Innozide within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

Enalapril Maleate - Hydrochlorothiazide

Hypotension and Electrolyte Fluid Imbalance

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving Innozide, symptomatic hypotension is more likely to occur if the patient has been volume depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhoea or vomiting (see sections 4.5 and 4.8). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients. Special attention should be paid to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. In hypertensive 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 these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of Innozide and/or diuretic is adjusted. Similar considerations may 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 contra-indication 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 Innozide. This effect is anticipated, and usually is not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose and/or discontinuation of the diuretic and/or Innozide may be necessary.

Renal Function Impairment

Renal failure has been reported in association with enalapril and has been mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible.

Innozide should not be administered to patients with renal insufficiency (creatinine clearance <80 mL/min. and >30 mL/min) until titration of enalapril has shown the need for the dose present in this formulation (see section 4.2).

Some hypertensive patients with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic (see Special warnings and precautions for use, Enalapril Maleate, Renal Function Impairment; Hydrochlorothiazide, Renal Function Impairment in section 4.4). If this occurs, therapy with Innozide should be discontinued. This situation should raise the possibility of underlying renal artery stenosis (see Special warnings and precautions for use, Enalapril Maleate, Renovascular Hypertension in section 4.4).

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.

Hyperkalaemia

The combination of enalapril and a low-dose diuretic cannot exclude the possibility of a hyperkalaemia to occur (see Special warnings and precautions for use, Enalapril Maleate, Hyperkalaemia in section 4.4).

Lithium

The combination of lithium with enalapril and diuretic agents is generally not recommended (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.

Paediatric population

Safety and efficacy in children has not been established.

Enalapril Maleate

Aortic Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators, ACE inhibitors should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

Renal Function Impairment

Renal failure has been reported in association with enalapril and has been mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. If recognized promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible (see section 4.2 and Special warnings and precautions for use, Enalapril Maleate-Hydrochlorothiazide, Renal Function Impairment; Hydrochlorothiazide, Renal Function Impairment in section 4.4).

Renovascular Hypertension

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function.

Haemodialysis Patients

The use of enalapril is not indicated in patients requiring dialysis for renal failure. 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 a different class of antihypertensive agent.

Kidney Transplantation

There is no experience regarding the administration of enalapril in patients with a recent kidney transplantation. Treatment with enalapril is therefore not recommended.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up (see Special warnings and precautions for use, Hydrochlorothiazide, Hepatic Disease in section 4.4).

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. Enalapril 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 enalapril 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.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, inter-current events in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g., heparin, trimethoprim-containing products such as cotrimoxazole). The use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase serum potassium, particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of enalapril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see Special warnings and precautions for use, Enalapril Maleate-Hydrochlorothiazide, Hyperkalaemia; Hydrochlorothiazide, Metabolic and Endocrine Effects in section 4.4 and section 4.5).

Hypoglycaemia

Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use (see Special warnings and precautions for use, Hydrochlorothiazide, Metabolic and Endocrine Effects in section 4.4 and section 4.5).

Hypersensitivity/Angioneurotic Oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate. This may occur at any time during treatment. In such cases, Innozide should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with 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. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway, should be administered promptly.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to Whites. However, in general it appears that Blacks have an increased risk for 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 ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

The combination of enalapril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of enalapril therapy. If treatment with sacubitril/valsartan is stopped, enalapril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Anaphylactoid Reactions during Hymenoptera Desensitisation

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

Anaphylactoid Reactions during LDL-Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactic reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

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

Enalapril blocks angiotensin II formation and therefore impairs the ability of patients undergoing major surgery or anaesthesia with agents that produce hypotension to compensate via the renin-angiotensin system. Hypotension which occurs due to this mechanism can be corrected by volume expansion (see section 4.5).

Pregnancy

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

Ethnic Differences

As with other angiotensin converting enzyme inhibitors, enalapril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Hydrochlorothiazide

Renal Function Impairment

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 mL/min or below (i.e., moderate or severe renal insufficiency) (see section 4.2 and Special warnings and precautions for use, Enalapril Maleate-Hydrochlorothiazide, Renal Function Impairment; Enalapril Maleate, Renal Function Impairment in section 4.4).

Innozide should not be administered to patients with renal insufficiency (creatinine clearance ≤80 mL/min) until titration of the individual components has shown the need for the doses present in the combination tablet.

Hepatic Disease

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see Special warnings and precautions for use, Enalapril Maleate, Hepatic Failure in section 4.4).

Metabolic and Endocrine Effects

Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see Special warnings and precautions for use, Enalapril Maleate, Diabetic Patients in section 4.4). Thiazides may decrease serum sodium, magnesium and potassium levels.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, at the 12.5 mg dose of hydrochlorothiazide contained in Innozide, minimal or no effect was reported. In addition, in clinical studies with 6 mg of hydrochlorothiazide no clinically significant effect on glucose, cholesterol, triglycerides, sodium, magnesium or potassium was reported.

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

Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. This effect on hyperuricemia appears to be dose-related. In addition enalapril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides (including hydrochlorothiazide) can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are xerostomia, thirst, weakness, lethargy, somnolence, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastro-intestinal disturbances such as nausea and vomiting.

Although hypokalaemia may develop during use of thiazide diuretics, concurrent therapy with enalapril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients with inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

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

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

Eye disorders

Choroidal effusion, acute myopia and secondary angle-closure glaucoma:

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Innozide should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Anti-doping test

Hydrochlorothiazide contained in this product can produce a positive analytic result in an anti-doping test.

Hypersensitivity

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy and bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC (see section 4.8).

4.5. Interaction with other medicinal products and other forms of interaction

Enalapril Maleate-Hydrochlorothiazide

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

Clinical trial data have 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).

Other Antihypertensive Agents

Concomitant use of these agents may increase the hypotensive effects of enalapril and hydrochlorothiazide. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

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 further increase lithium levels and enhance the risk of lithium toxicity with ACE inhibitors.

Use of Innozide 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 selective cyclooxygenase-2 (COX-2) inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors or diuretics may be attenuated by NSAIDs including selective COX-2 inhibitors.

The coadministration of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or 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 patients who are volume-depleted, including those on diuretic therapy). Therefore, the combination should be administered with caution in patients with compromised renal function.

Enalapril Maleate

Potassium-sparing Diuretics, Potassium Supplements, or other drugs that may increase serum potassium

ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium (e.g., heparin, trimethoprim-containing products such as cotrimoxazole) may lead to significant increases in serum potassium. If concomitant use of enalapril and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).

Diuretics (thiazide or loop diuretics)

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril (see sections 4.2 and 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic or by increasing volume or salt intake.

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).

Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.

Medicines increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors (see section 4.5).

Alcohol

Alcohol enhances the hypotensive 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 (see sections 4.4 and 4.8).

Acetyl Salicylic Acid, Thrombolytics and β-blockers

Enalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and β-blockers.

Hydrochlorothiazide

Non-depolarising Muscle Relaxants

Thiazides may increase the responsiveness to tubocurarine.

Alcohol, Barbiturates, or Opioid Analgesics

Potentiation of orthostatic hypotension may occur.

Antidiabetic Drugs (Oral Agents and Insulin)

Dosage adjustment of the antidiabetic drug may be required (see sections 4.4 and 4.8).

Cholestyramine and Colestipol Resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastro-intestinal tract by up to 85 and 43 percent, respectively.

Increasing the QT Interval (e.g., quinidine, procainamide, amiodarone, sotalol)

Increased risk of torsades de pointes.

Digitalis Glycosides

Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalaemia.

Kaliuretic Diuretics (e.g., Furosemide), Carbenoxolone, or Laxative Abuse

Hydrochlorothiazide may increase the loss of potassium and/or magnesium.

Pressor Amines (e.g., Noradrenaline)

The effect of pressor amines may be decreased (see section 4.5).

Cytostatics (e.g., Cyclophosphamide, Methotrexate)

Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

ACE inhibitors:

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

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative 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.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development.

Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

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

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

Breast feeding

Enalapril:

Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of Innozide in breast-feeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of Innozide in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect.

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 Innozide during breast-feeding is not recommended. If Innozide is used during breast-feeding, doses should be kept as low as possible.

4.7. Effects on ability to drive and use machines

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur (see section 4.8).

4.8. Undesirable effects

Innozide is usually well-tolerated. In clinical studies, side effects have usually been mild and transient, and in most instances have not required interruption of therapy.

The most common side effects reported during clinical study with Innozide were headache and cough.

The following undesirable side effects have been reported for Innozide, enalapril alone or hydrochlorothiazide alone either during clinical studies or after the drug was marketed.

Table 1. Undesirable effects of Innozide

System organ class

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)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)

Blood and lymphatic system disorders

Anaemia (including aplastic and haemolytic)

Neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases

Endocrine disorders

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders

Hypokalaemia, increase of cholesterol, increase of triglycerides, hyperuricaemia

Hypoglycaemia (see section 4.4), hypomagnesaemia, gout**

Increase in blood glucose

Hypercalcaemia (see section 4.4)

Nervous system and psychiatric disorders

Headache, depression, syncope, taste alteration

Confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, decreased libido**

Dream abnormality, sleep disorders, paresis (due to hypokalaemia)

Eye disorders

Blurred vision

Choroidal effusion

Ear and labyrinth disorders

Tinnitus

Cardiac and vascular disorders

Dizziness

Hypotension, orthostatic hypotension, rhythm disturbances, angina pectoris, tachycardia

Flushing, palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high risk patients (see section 4.4)

Raynaud's phenomenon

Respiratory, thoracic, and mediastinal disorders

Cough

Dyspnoea

Rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma

Pulmonary infiltrates, respiratory disorders (including pneumonitis and pulmonary oedema), rhinitis, allergic alveolitis/eosinophilic pneumonia

Acute respiratory distress syndrome (ARDS) (see section 4.4)

Gastrointestinal disorders

Nausea

Diarrhoea, abdominal pain

Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence**

Stomatitis/aphthous ulcerations, glossitis

Intestinal angioedema

Hepatobiliary disorders

Hepatic failure, hepatic necrosis (may be fatal), hepatitis – either hepatocellular or cholestatic, jaundice, cholecystitis (in particular in patients with pre-existing cholelithiasis)

Skin and subcutaneous tissue disorders

Rash (exanthema)

hypersensitivity/ angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4)

Diaphoresis, pruritus, urticaria, alopecia

Erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigus

A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.

Musculoskeletal, connective tissue, and bone disorders

Muscle cramps†

Arthralgia**

Renal and urinary disorders

Renal dysfunction, renal failure, proteinuria

Oliguria, interstitial nephritis

Reproductive system and breast disorders

Impotence

Gynecomastia

General disorders and administration site conditions

Asthenia

Chest pain, fatigue

Malaise, fever

Investigations

Hyperkalaemia, increases in serum creatinine

Increases in blood urea, hyponatraemia

Elevations of liver enzymes, elevations of serum bilirubin

* Incidence rates were comparable to those in the placebo and active control groups in the clinical trials.

** Only seen with doses of hydrochlorothiazide 12.5 mg and 25 mg

† The frequency of muscle cramps as common pertains to doses of hydrochlorothiazide 12.5 mg and 25 mg, whereas, the frequency of the event is uncommon as it pertains to 6 mg doses of hydrochlorothiazide.

Description of Selected Adverse Reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed (see sections 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No specific information is available on the treatment of overdosage with Innozide. Treatment is symptomatic and supportive. Therapy with Innozide should be discontinued and the patient observed closely. Suggested measures include induction of emesis, administration of activated charcoal, and administration of a laxative if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Enalapril Maleate

The most prominent features of overdosage reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Symptoms associated with overdosage of ACE inhibitors may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril maleate, respectively.

The recommended treatment of overdosage 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 enalapril maleate (e.g., emesis, gastric lavage, administration of absorbents, and sodium sulfate). Enalaprilat may be removed from the general circulation by haemodialysis (see section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Hydrochlorothiazide

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