ACE inhibitors / thiazide diuretics (thiazides).

Enalapril, hydrochlorothiazide

Each tablet of 'Innozide' contains 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide.

'Innozide' is supplied as round, fluted, yellow tablets with 'MSD 718' on one side and scored on the other

'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.

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 23 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 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 use

Safety and effectiveness in children have not been established.

Route of administration: Oral.

Not recommended.

'Innozide' is contraindicated in patients with anuria.

'Innozide' is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioneurotic oedema relating to previous treatment with an angiotensinconverting enzyme (ACE) inhibitor and in patients with hereditary or idiopathic angioedema.

'Innozide' is contraindicated in patients who are hypersensitive to other sulphonamidederived drugs.

'Innozide' is contraindicated in patients with stenosis of the renal arteries.

'Innozide' is contraindicated in the second and third trimester of pregnancy.

Enalapril maleate - Hydrochorothiazide

Symptomatic Hypotension

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, dialysis, diarrhoea or vomiting. Regular determination of serum electrolytes should be performed at appropriate intervals in such patients. 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 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.

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. Dosage reduction of enalapril and/or discontinuation of the diuretic may be required. This situation should raise the possibility of underlying renal artery stenosis.

Lithium

The combination of lithium and enalapril is generally not recommended

Lactose

'Innozide' contains lactose and therefore should not be used by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 'Innozide' contains less than 200 mg of lactose per tablet.

Paediatric use

Safety and efficacy in children has not been established.

Enalapril maleate

Aortic or mitral valve 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.

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

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 'Innozide' in patients with a recent kidney transplantation. Treatment with 'Innozide' 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.

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 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). 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. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of 'Innozide' and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Hypoglycemia

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.

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 'Innozide'. 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 edema or tongue edema. 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 non-blacks.

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

Anaphylactoid reactions during hymenoptera desensitization

Rarely, patients receiving ACE inhibitors during desensitization 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 anaphylactoid 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/anesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks 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.

Pregnancy and lactation

Ace inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitors 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.

Use of enalapril is not recommended during breast feeding.

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.

Hydrochorothiazide

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). 

'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.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. Thaizides 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 contained in 'Innozide', minimal or no effect was reported.

Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism.

Thiazides should be discontinued before carrying out tests for parathyroid function.

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

Although no data exist for 'Innozide' from controlled clinical trials, as for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides (including hydrochlorothiazide) can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are 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.

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 hypomagnesia.

Anti-doping test

Hydrochorothiazide 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.

Enalapril maleate- hydrochlorothiazide

Other antihypertensive agents

Concomitant use of these agents may increase the hypotensive effects of enalapril. Concomitant use with nitroglycerine 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

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor or may decrease the diuretic, natriuretic and antihypertensive effects of diuretics.

NSAIDs (including COX-2 inhibitors) 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 patients who are volume-depleted including those on diuretic therapy).

Enalapril maleate

Potassium sparing diuretics or potassium supplements

ACE inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of serum potassium.

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. The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake or by initiating therapy with a low dose of enalapril.

Tricyclic antidepressants/antipsychotics/anesthetics/narcotics

Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.

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.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

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.

Acetyl salicylic acid, thrombolytics and βblockers

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

Hydrochorothiazide

Nondepolarising 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)

The use of antidiabetic drugs and thiazide diuretics may require dosage adjustment of the antidiabetic drug.

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. 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: may result in intensified electrolyte depletion, particularly hypokalaemia with thiazide diuretics.

Pressor amines (e.g. adrenaline): possible decreased response to pressor amines but not sufficient to preclude their use.

Cytostatics (e.g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

Undesirable effects reported for enalapril alone or hydrochlorothiazide alone either during clinical studies or after the drug was marketed include:

[Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).]

Blood and the lymphatic system disorders:

uncommon: anaemia (including aplastic and hemolytic)

rare: neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine disorders:

not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders:

common: hypokalaemia, increase of cholesterol, increase of triglycerides, hyperuricaemia

uncommon: hypoglycaemia, gout

rare: increase in blood glucose

very rare: hypercalcaemia

Psychiatric disorders:

uncommon: decreased libido

Nervous system disorders:

common: headache, depression, syncope, taste alteration

uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo

rare: dream abnormality, sleep disorders

Eye disorders:

very common: blurred vision

Ear and labyrinth disorders:

uncommon: tinnitus

Cardiac and Vascular disorders:

very common: dizziness

common: hypotension (including orthostatic hypotension), rhythm disturbances, angina pectoris, tachycardia

uncommon: orthostatic hypotension, palpitations, myocardial infarction or cerebrovascular accident^*, possibly secondary to excessive hypotension in high risk patients

rare: Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders:

very common: cough

common: dyspnoea

uncommon: rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma

rare: pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary oedema), rhinitis, allergic alveolitis/eosinophilic pneumonia

Gastrointestinal disorders:

very common: nausea,

common: diarrhea, abdominal pain

uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence

rare: stomatitis/aphthous ulcerations, glossitis

very rare: intestinal angioedema

Hepatobilliary disorders:

rare: hepatic failure, hepatitis – either hepatocellular or cholestatic, hepatitis including necrosis, cholestatsis (including jaundice)

Skin and subcutaneous tissue disorders:

common: rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported

uncommon: diaphoresis, pruritus, urticaria, alopecia

rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, pemphigus, erythroderma

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 leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.

Renal and urinary disorders:

uncommon: renal dysfunction, renal failure, proteinuria

rare: oliguria, intestinal nephritis

Reproductive system and breast disorders:

uncommon: impotence

rare: gynecomastia

General disorders and administration site conditions:

very common: asthenia

common: chest pain, fatigue

uncommon: muscle cramps, flushing, , malaise, fever

Investigations:

common: increases in serum creatinine

uncommon: increases in blood urea, hyponatraemia

rare: elevations of liver enzymes, elevations of serum bilirubin

MSD

(POM)

26 June 2009