Treatment of hypertensive patients who have insufficiently responded to treatment with enalapril or a diuretic as a single therapy.

 

Posology

 

Hypertension

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

 

Prior Diuretic Therapy

Symptomatic hypotension may occur following the initial dose of CO-RENITEC; this is more likely in patients who are volume- or salt-depleted as a result of prior diuretic therapy. Therefore, diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with CO-RENITEC (see section 4.4).

                                                      

Dosage in Renal Insufficiency

Since the initial dose of enalapril in mild renal impairment (creatinine clearance greater than 30 ml/min to less than 80 ml/min) is 5-10 mg, CO-RENITEC is not recommended as initial therapy in these patients (see section 4.4).

CO-RENITEC should not be administered to these patients until after titration of the individual components.

CO-RENITEC is contraindicated in patients who have a creatinine clearance less than or equal to 30 ml/min.

 

Paediatric population

CO-RENITEC is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

 

Method of administration

 

Oral use.

• Hypersensitivity to the active substance or to any of the excipients 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 sections 4.4 and 4.6). • Severe hepatic impairment. • The concomitant use of CO-RENITEC 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).

Enalapril Maleate-Hydrochlorothiazide

Hypotension and Electrolyte Fluid Imbalance

Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving CO-RENITEC, 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 ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident

 

If hypotension occurs, the patient should be placed in the supine position and, if necessary, should  receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.

 

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with CO-RENITEC. 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 CO-RENITEC may be necessary

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 CO-RENITEC 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.

 

Renal Function Impairment

CO-RENITEC should not be administered to patients with renal insufficiency (creatinine clearance < 80 ml/min and > 30 ml/min) until titration with the individual components 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 section 4.4). If this occurs, therapy with CO-RENITEC should be discontinued. This situation should raise the possibility of underlying renal artery stenosis (see section 4.4).

 

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

 

Dual blockade of the reinin-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 section 4.4).

 

Lithium

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

 

Lactose

CO-RENITEC contains less than 200 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

 

Enalapril Maleate

 

Aortic Stenosis/Hypertrophic Cardiomyopathy

As with all vasodilators, ACE inhibitors should be given with caution to patients with left ventricular valvular 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 recognised promptly and treated appropriately, renal failure when associated with therapy with enalapril is usually reversible (see sections 4.2 and 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.

 

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.

 

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.

 

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 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, intercurrent 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). 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 CO-RENITEC and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see sections 4.4 and 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 sections 4.4 and 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, CO-RENITEC 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 non-blacks. However, in general it appears that black people have an increased risk for angioedema.

 

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

 

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

 

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 sulphate 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 nonproductive, 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 sections 4.2 and 4.4).

 

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 section 4.4).

 

Metabolic and Endocrine Effects

Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see section 4.4).

 

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy; however, at the 12.5 mg dose of hydrochlorothiazide, minimal or no effect was reported.

 

Thiazide therapy has been associated with the development of hyperuricaemia and/or gout in certain patients. In addition, enalapril may increase urinary uric acid and thus 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 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 gastrointestinal 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 usually not require treatment.

 

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

 

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

 

Hypersensitivity

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

 

 

Anti-doping test:

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

2.1            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 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 CO-RENITEC 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 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 co-administration 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 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 (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).

 

Sympathomimetics

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

 

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).

 

Alcohol

Alcohol enhances the hypotensive effect of ACE inhibitors (see section 4.5).

 

Acetyl salicylic acid, Thrombolytics and b-blockers

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

 

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.

 

Mammalian Target of Rapamycin (mTOR) Inhibitors

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

 

Hydrochlorothiazide

 

Nondepolarizing Muscle Relaxants

Thiazides may increase the responsiveness to tubocurarine.

 

Alcohol, Barbiturates, or Opioid Analgesics

Potentiation of orthostatic hypotension may occur (see section 4.5).

 

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 gastrointestinal 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.

 

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 trimesters of pregnancy (see sections 4.3 and 4.4).

 

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

 

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

 

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). 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 CO-RENITEC 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 CO-RENITEC 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 CO-RENITEC

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

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

CO-RENITEC 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 CO-RENITEC were headache and cough.

 

The following undesirable side effects have been reported with CO-RENITEC, enalapril alone or hydrochlorothiazide alone, either during clinical studies or after the drug was marketed:

 

Table 1. Undesirable effects of CO-RENITEC

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)
Blood and lymphatic system disorders			Anaemia (including aplastic and haemolytic)	Neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombo- cytopenia, agranulo- cytosis, bone marrow depression, leukopenia, pancytopenia, lymphadeno- pathy, autoimmune diseases

 

 

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)
Endocrine disorders						Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		Hypo- kalaemia, increase of cholesterol, increase of triglycerides, hyper- uricaemia	Hypo- glycaemia (see section 4.4), hypo- magnesaemia, gout**, electrolyte imbalance (including hypo- natraemia)	Increase in blood glucose	Hyper- calcaemia (see section 4.4)
Nervous system and psychiatric disorders		Headache, depression, syncope, taste alteration	Confusion, somnolence, insomnia, nervousness, paresthesia, vertigo, decreased libido**	Dream abnormality, sleep disorders, paresis (due to hypokalaemia)
Ear and labyrinth disorders			Tinnitus
Cardiac and vascular disorders	Dizziness	Hypotension, orthostatic hypotension, rhythm disturbances, angina pectoris, tachycardia	Flushing, palpitations, myocardial infarction or cerebro- vascular accident*, possibly secondary to excessive hypotension in high risk patients (see section 4.4)	Raynaud’s phenomenon
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)
Respiratory, thoracic, and mediastinal disorders	Cough	Dyspnoea	Rhinorrhoea, sore throat and hoarseness, bronchospasm/ asthma	Pulmonary infiltrates, respiratory distress (including pneumonitis and pulmonary oedema), rhinitis, allergic alveolitis/ eosinophilic pneumonia
Gastrointestinal disorders	Nausea	Diarrhoea, abdominal pain	Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, peptic ulcer, flatulence**	Stomatitis/ aphthous ulcerations, glossitis	Intestinal angio- oedema
Hepatobiliary disorders				Hepatic failure, hepatic necrosis (may be fatal), hepatitis – either hepatocellular or cholestatic, jaundice cholecystitis (in particular in patients with pre-existing cholelithiasis)
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)
Skin and subcutaneous tissue disorders		Rash (exanthema) Hyper- sensitivity/ angio- neurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4)	Diaphoresis, pruritus, urticaria, alopecia, photo- sensitivity	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, or other dermatologic manifestations may occur.
Musculoskeletal, connective tissue, and bone disorders		Muscle cramps***	arthralgia**
Renal and urinary disorders			Renal dysfunction, renal failure, proteinuria, glycosuria	Oliguria, interstitial nephritis
Reproductive system and breast disorders			Impotence	Gynaecomastia
General disorders and administration site conditions	Asthenia	Chest pain, fatigue	Malaise, fever
Investigations		Hyper- kalaemia, 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.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 National Pharmacovigilance and Drug Safety Centre (NPC).

 

 

•       Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)

o Fax: +966-11-205-7662

o Call NPC at +966-11-20382222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

o E-mail: npc.drug@sfda.gov.sa

o Website: www.sfda.gov.sa/npc

 

•       Other GCC States:

Please contact the relevant competent authority.

No specific information is available on the treatment of overdosage with CO-RENITEC. Treatment is symptomatic and supportive. Therapy with CO-RENITEC should be discontinued and the patient observed closely. Suggested measures include induction of emesis, administration of activated charcoal, 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 sulphate). 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.

Pharmacotherapeutic group: enalapril and diuretics, ATC code: C09B A02.

 

CO-RENITEC (enalapril maleate and hydrochlorothiazide) is a formulation of an angiotensin converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide) which is effective in the treatment of hypertension. Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolysed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion. Hydrochlorothiazide is a diuretic and antihypertensive agent which increases plasma renin activity. The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide usually does not affect normal blood pressure.

 

CO-RENITEC provides antihypertensive and diuretic activities. Enalapril maleate and hydrochlorothiazide have been used singly and concomitantly for the treatment of hypertension. The effect on blood pressure reduction is significantly greater than that seen with enalapril given alone. In addition, the antihypertensive effect of CO-RENITEC was sustained for at least 24 hours.

 

ACE is identical to kininase II. Thus enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril remains to be elucidated.

 

Mechanism of action

While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension.

 

Pharmacodynamic effects

Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.

 

Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril maleate has not been associated with rapid increase in blood pressure.

 

Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration. The duration of effect is dose-related. However, at recommended doses, antihypertensive and hemodynamic effects have been shown to be maintained for at least 24 hours.

 

In hemodynamic studies with enalapril in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.

 

Antihypertensive treatment with enalapril leads to a significant regression of left ventricular hypertrophy with preservation of left ventricular systolic performance.

 

The effect of the fixed dose combination of enalapril and hydrochlorothiazide on morbidity and mortality has not been studied.

 

Dual Blockade

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), 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.

 

Absorption

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril maleate is approximately 60 %. The absorption of oral enalapril is not influenced by the presence of food in the gastrointestinal tract.

 

Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril. The principal components in urine are enalaprilat, accounting for about 40 % of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady state serum concentrations of enalaprilat were reached after four days of treatment. The extent of absorption and hydrolysis of enalapril are similar for the various doses in the recommended therapeutic range.

 

Distribution

Over the range of concentrations which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60 %.

 

Biotransformation

Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney.

 

Elimination

Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40 % of the dose, and intact enalapril (about 20 %). Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61 % of the oral dose is eliminated unchanged within 24 hours.

 

Renal impairment

The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 ml/min), AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (see section 4.2.). Enalaprilat may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min.

 

Lactation

After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7 μg/L (range 0.54 to 5.9 μg/L) at 4 to 6 hours after the dose. The average

peak enalaprilat level was 1.7 μg/L (range 1.2 to 2.3 μg/L); peaks occurred at various

times over the 24-hour period. Using the peak milk level data, the estimated maximum

intake of an exclusively breast-fed infant would be about 0.16 % of the maternal weight-adjusted dosage. A woman who had been taking oral enalapril 10 mg daily for 11 months

had peak enalapril milk levels of 2 μg/L 4 hours after a dose and peak enalaprilat levels of 0.75 μg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44 μg/L and 0.63 μg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2 μg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10mg in two mothers; enalapril levels were not determined.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that enalapril has no effects on fertility and reproductive performance in rats, and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is secreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the fetus) when given in the second or third trimester.

 

Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

Sodium bicarbonate lactose hydrous corn starch

yellow ferric oxide (E172) pregelatinised starch magnesium stearate (E572).

Sodium bicarbonate lactose hydrous corn starch

yellow ferric oxide (E172) pregelatinised starch magnesium stearate (E572).

 

Not applicable.

3 Years

Store below 30 °C. store in the original package.

Box with three blisters of 10 tablets each and box with two blisters of 14 tablets each. Not all pack sizes may be marketed.

No special requirements.