Enpresil Co 20 mg, 12,5 mg Tablet

Enpresil Co is indicated for the treatment of hypertension in patients where fixed combination treatment is considered more appropriate than monotreatment.

Posology
Hypertension
The usual dosage is 1 tablet, administered once daily. If necessary the dosage may be increased to a maximum of 2 tablets, administered once daily.

Special populations
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). Enpresil Co is not be used as initial treatment in any patient with renal insufficiency. In patients with creatinine clearance of >30 and <80 ml/min, Enpresil Co may be used but only after titration of the individual components.

Method of administration
For oral use.

• Hypersensitivity to enalapril maleate and hydrochlorothiazide, or to any of the ingredients listed in section 6.1.
• Severe renal impairment (creatinine clearance u2264 30 ml/min).
• Anuria.
• History of angioneurotic oedema associated with previous ACE-inhibitor treatment or angiotensin receptor blockers (ARBs). These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Hypersensitivity to other sulfonamide-derived medicines.
• Pregnancy and breastfeeding.
• Severe hepatic impairment.
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant treatment with potassium sparing diuretics such as spironolactone, triamterene, amiloride.
• Porphyria.
• Lithium treatment; concomitant administration with Enpresil Co may lead to toxic blood concentrations of lithium.
• The concomitant use of Enpresil Co 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 Enpresil Co within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (See sections 4.4 and 4.5).

Should a woman become pregnant while receiving Enpresil Co, the treatment must be stopped promptly and switched to a different class of antihypertensive medicines. Should a woman contemplate pregnancy, the doctor should institute alternative medications (see section 4.6).

Enalapril Maleate - Hydrochlorothiazide
Hypotension and Electrolyte Fluid Imbalance
Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients. In hypertensive patients receiving Enpresil Co, symptomatic hypotension is more likely to occur if the patient has been volume-depleted or salt-depleted, e.g., by diuretic treatment (which should be discontinued for 2 to 3 days prior to initiation of treatment with Enpresil Co), dietary salt restriction, diarrhoea or vomiting (see sections 4.5 and 4.8). In such patients regular determination of serum electrolytes should be performed at pertinent intervals.

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, treatment should be started under medical supervision and the patients should be followed closely whenever the dose of Enpresil Co and/or diuretic is adjusted.

Similar deliberations 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, further lowering of systemic blood pressure may occur with Enpresil Co. This effect is foreseen, 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 Enpresil Co 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 on time and treated appropriately, renal failure is usually reversible when associated with treatment with enalapril. Enpresil Co should not be administered to patients with renal insufficiency (creatinine clearance 30 ml/min) until titration of enalapril has shown the necessity 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, treatment with Enpresil Co 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 treatment 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 hyperkalaemia developing (see Special warnings and precautions for use, Enalapril Maleate, Hyperkalaemia in section 4.4).

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

Enalapril Maleate-Hydrochlorothiazide
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
In clinical studies, dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren has been shown to be 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 medicine (see sections 4.3, 4.4 and 5.1).

Other Antihypertensive Medicines
Concomitant use of other antihypertensive medicines 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 Enpresil Co with lithium is not recommended (see section 4.4).

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
including selective cyclooxygenase-2 (COX-2) inhibitors may diminish the effect of diuretics and other antihypertensive medicines. 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 worsening of renal function. These effects are usually reversible. Acute renal failure may occur (rarely), especially in patients with compromised renal function (such as the elderly or patients who are volume-depleted, including those on diuretic treatment). Therefore, the combination should be administered with caution in patients with compromised renal function.

Enalapril Maleate
Other Antihypertensive Medicines
Ganglionic blocking medicines or adrenergic blocking medicines in combination with enalapril should only be administered to the patient under careful observation.

Potassium-sparing Diuretics, Potassium Supplements, or other medicines 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 medicines that may increase serum potassium (e.g., heparin, trimethoprim-containing products such as co-trimoxazole) may lead to significant increases in serum potassium (particularly in patients with impaired renal function).

Diuretics (thiazide or loop diuretics)
Prior treatment with high dose diuretic treatment may result in volume depletion and a risk of hypotension when starting treatment 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 medicines, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further lowering of blood pressure (see section 4.4).

Gold
Nitritoid reactions have been reported rarely in patients on treatment with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor treatment. Symptoms of Nitritoid reactions include facial flushing, nausea, vomiting and hypotension.

Mammalian Target of Rapamycin (mTOR) inhibitors
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) treatment may be at increased risk for angioedema (see section 4.4).

Neprilysin Inhibitors
Patients taking concomitant ACE inhibitor and neprilysin inhibitor treatment (e.g., sacubitril, racecadotril) may be at increased risk for angioedema (see section 4.4). The concomitant use of enalapril with sacubitril/valsartan is contraindicated, as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of enalapril. Enalapril treatment must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 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 put forward that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic medicines) 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 u03b2-blockers
Enalapril can be safely administered concomitantly with acetyl salicylic acid (at cardiologic doses), thrombolytics and u03b2-blockers.

Pregnancy
ACE inhibitors: The use of ACE inhibitors is contraindicated in pregnancy, as the safety in this group has not been established. Enpresil Co can cause foetal morbidity and death. Enpresil Co crosses through the placenta and can cause disturbance in foetal blood pressure regulatory mechanisms. The use of Enpresil Co during the first trimester of pregnancy can be associated with an increased risk of birth defects, in particular of the cardiovascular and the central nervous system. Exposure to ACE inhibitor treatment during the second and third trimesters is known to induce human foeto-toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Prematurity and low birth mass can occur. Maternal oligohydramnios, presumably representing decreased foetal renal function, can occur and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Ultrasound check of renal function and skull is recommended in patients where exposure to ACE inhibitors has occurred from the second trimester of pregnancy. Infants (whose mothers have taken ACE inhibitors) should be closely observed for hypotension, oliguria and hyperkalaemia.

Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Thiazides cross the placental barrier and appear in cord blood. Hazards include foetal and neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occur in the adult. 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 treatment should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion. Hydrochlorothiazide treatment should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breastfeeding
ACE inhibitors: The use of ACE inhibitors is contraindicated in breastfeeding as the safety in lactation has not been established. Enalapril: Limited pharmacokinetic data demonstrate very low concentrations in breast milk. Although these concentrations seem to be clinically inconsequential the use of Enpresil Co in breastfeeding 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. Hydrochlorothiazide: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses can cause intense diuresis and can inhibit the milk production. The use of Enpresil Co during breastfeeding is not recommended. Both enalapril and thiazides appear in human milk. If use of Enpresil Co is deemed essential, the patient should stop breastfeeding their infants.

Fertility
No data available.

When driving vehicles or operating machines occasional dizziness or weariness may occur (see section 4.8).

Summary of the safety profile
The most commonly reported side effects for this medicine are headache and cough.

Tabulated summary of adverse reactions
Enalapril maleate / Hydrochlorothiazide
System Organ Class Frequency Side effect
Neoplasms benign, malignant and unspecified (including cysts and polyps) Frequency unknown Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
Blood and lymphatic system disorders Less frequent Decreases in haemoglobin, decreases in haematocrit, decrease in platelets and white cell count, anaemia (including aplastic and haemolytic), neutropaenia, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases
Immune system disorders Less frequent Hypersensitivity, angioedema of the face, extremities, lips, tongue, glottis and/or larynx
Endocrine disorders Frequency unknown Syndrome of inappropriate antidiuretic hormone secretion (SAIDH)
Metabolism and nutrition disorders Less frequent Hyperglycaemia, hyperuricaemia, gout, hypokalaemia, increase of cholesterol, increase of triglycerides, increase in blood glucose, hypercalcaemia
Psychiatric disorders Frequent Depression Less frequent Nervousness, confusion, dream abnormality
Nervous system disorders Frequent Dizziness, insomnia, paraethesia, headache, decreased libido, syncope, sleep disorders, paraesis (due to hypokalaemia) Less frequent Somnolence, vertigo
Eye disorders Frequent Blurred vision
Ear and labyrinth disorders Less frequent Tinnitus
Cardiac disorders Frequent Angina pectoris Less frequent Chest pain, palpitations, tachycardia, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients
Vascular disorders Frequent Orthostatic effects including hypotension, syncope, dizziness, orthostatic hypotension, rhythm disturbances, flushing Less frequent Non-orthostatic hypotension, Raynaudu2019s phenomenon
Respiratory, thoracic and mediastinal disorders Frequent Cough Less frequent Dyspnoea, rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma, pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia
Gastrointestinal disorders Frequent Nausea, diarrhea, vomiting Less frequent Dyspepsia, abdominal pain, constipation, flatulence, dry mouth, pancreatitis, ileus, anorexia, gastric irritations, dry mouth, peptic ulcer, stomatitis/aphthous, ulcerations, glossitis, intestinal angioedema
Hepato-biliary disorders Less frequent Hepatic failure, hepatic necrosis (may be fatal), hepatitis u2013 either hepatocellular or cholestatic, jaundice, cholecystitis (in particular in patients with pre-existing cholelithiasis)
Skin and subcutaneous tissue disorders Frequent Rash, diaphoresis Less frequent Pruritus, Stevens - Johnson syndrome, DRESS (symptoms such as fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive antinuclear antibody, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis), rash, photosensitivity and other dermatologic manifestations, pruritis, urticaria, alopecia, Erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigus
Musculoskeletal and connective tissue disorders Frequent Muscle cramps Less frequent Arthralgia
Renal and urinary disorders Less frequent Renal dysfunction, renal failure, proteinurea, oliguria, interstitial nephritis
Reproductive system and breast disorders Frequent Impotence Less frequent Gynaecomastia
General disorders and administration site conditions Frequent Fatigue, asthenia, chest pain, malaise, fever
Investigations Less common Increases in blood urea, increases in serum creatinine, elevations of liver enzymes, elevations of serum bilirubin, hyperkalaemia, hyponatraemia

Enalapril maleate
System Organ Class Frequency Side effect
Blood and lymphatic system disorders Less frequent Neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, bone marrow depression
Immune system disorders Less frequent Hypersensitivity, angioedema of the face, extremities, lips, tongue, glottis and larynx
Psychiatric disorders Frequent Depression Less frequent Confusion, nervousness, abnormal dreams
Nervous system disorders Frequent Headache Less frequent Somnolence, insomnia, paraesthesia, vertigo
Eye disorders Frequent Blurred vision
Cardiac disorders Frequent Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, chest pain, dysrhythmia, angina pectoris, tachycardia Less frequent Palpitations
Vascular disorders Frequent Dizziness, hypotension (including orthostatic hypotension) Less frequent Orthostatic hypotension, Raynaudu2019s phenomenon
Respiratory, thoracic and mediastinal disorders Frequent Cough, dyspnoea Less frequent Rhinorrhoea, sore throat, hoarseness, bronchospasm/asthma, pulmonary infiltrates
Gastrointestinal disorders Frequent Nausea, diarrhea, abdominal pain, taste alteration Less frequent Ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, dry mouth, stomatitis, glossitis, intestinal angioedema
Hepato-biliary disorders Less frequent Hepatic failure, hepatitis (either hepatocellular or cholestatic), hepatitis (including jaundice)
Skin and subcutaneous tissue disorders Frequent Rash Less frequent Diaphoresis, pruritis, urticaria, alopecia, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, a symptom complex including some or all of the following: fever, serotosis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive antinuclear antibody, elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity and other dermatologic manifestations may occur
Renal and urinary disorders Less frequent Renal dysfunction, renal failure, oliguria
Reproductive system and breast disorders Less frequent Impotence
General disorders and administration site conditions Frequent Asthenia, fatigue Less frequent Muscle cramps, flushing, tinnitus
Investigations Frequent Hyperkalaemia, increases in serum creatinine Less frequent Increases in blood urea, hyponatraemia, elevation of liver enzymes, elevations of serum bilirubin

Hydrochlorothiazide
System Organ Class Frequency Side effect
Infections and infestations Frequency unknown Sialodenitis
Blood and lymphatic system disorders Frequency unknown Leukopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia
Immune system disorders Frequency unknown Anaphylactic reactions
Metabolism and nutrition disorders Frequency unknown Electrolyte imbalance including hyponatraemia
Nervous system disorders Frequency unknown Restlessness
Eye disorders Frequency unknown Transient blurred vision, xanthopsia
Vascular disorders Frequency unknown Necrotising angitis (vasculitis)
Gastrointestinal disorders Frequency unknown Anorexia, gastric irritation
Hepato-biliary disorders Frequency unknown Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders Frequency unknown Toxic epidermal necrolysis, urticaria, purpura, photosensitivity
Musculoskeletal and connective tissue disorders Frequency unknown Muscle spasm
Renal and urinary disorders unknown Glycosuria, interstitial nephritis

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 also sections 4.4 and 5.1).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8. Adverse reactions must also be reported to Unicorn Pharmaceuticals (Pty) Ltd to [email protected].

No precise information is available on the treatment of overdosage with Enpresil Co therefore treatment is symptomatic and supportive. Enpresil Co should be discontinued and the patient should be monitored closely. Measures such as 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, can be introduced within 2 hours after ingestion.

Enalapril Maleate
Symptoms and signs
The most evident symptoms and signs of overdosage are marked hypotension, which occurs approximately six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor.

Management of overdose
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, may also be considered. Enalapril may be removed from the general circulation by haemodialysis (see section 4.4).

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