Enaside 20/12.5 20 mg, 12.5 mg Tablets

Enaside 20/12,5 is indicated for the treatment of hypertension in patients where fixed combination therapy is considered more appropriate than monotherapy.

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
Dosage in Renal insufficiency
Thiazides, including hydrochlorothiazide as contained in Enaside 20/12,5 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). Enaside 20/12,5 is not to be used as initial therapy in any patient with renal insufficiency. In patients with renal clearance of > 30 and < 80 ml/min, Enaside 20/12,5 may be used but only after titration of the individual components.
Paediatric population
Safety and effectiveness in children have not been established.
Method of administration
Oral use.

• Hypersensitivity to enalapril, hydrochlorothiazide, other sulphonamide derived medicines or to any of the excipients of Enaside 20/12,5 (see section 6.1).
• Severe renal impairment (creatinine clearance u2264 30 ml/min).
• Anuria.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive, cardiomyopathy (HOCM).
• Pregnancy and lactation (see section 4.6).
• Severe hepatic impairment.
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant use of Enaside 20/12,5 with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria.
• Lithium therapy: Concomitant administration with Enaside 20/12,5 may lead to toxic blood concentrations of lithium (see section 4.5).
• The concomitant use of Enaside 20/12,5 with aliskiren-containing medicines is contraindicated (see section 4.4).
• Patients with Addisonu2019s disease.
• Concomitant use with fluoroquinolones in patients with moderate to severe renal impairment (creatinine clearance u2264 30 ml/min) and in elderly patients (see section 4.5).
• Combination with sacubitril/valsartan due to increased risk of angioedema. Do not administer Enaside 20/12,5 within 36 hours of switching to or from sacubitril/valsartan, a medicine containing a neprilysin inhibitor (see sections 4.4 and 4.5).
• Patients with a history of previous and/or current basal cell carcinoma and/or squamous cell carcinomas of the skin and lip.

Hypotension and Electrolyte Fluid Imbalance
Symptomatic hypotension is seen in uncomplicated hypertensive patients. In hypertensive patients receiving Enaside 20/12,5, symptomatic hypotension may occur following the initial dose; this 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). Previous diuretic therapy should be discontinued for 2-3 days prior to initiation of treatment with Enaside 20/12,5. Regular determination of serum electrolytes should be performed at appropriate intervals in such patients. Special attention should be paid to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. In hypertensive patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of Enaside 20/12,5 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. Thiazides (including hydrochlorothiazide) can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are xerostomia, thirst, weakness, lethargy, somnolence, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and 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 not usually require treatment. Thiazides may have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia. 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 Enaside 20/12,5. 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 Enaside 20/12,5, may be necessary.
Renal Function Impairment
Renal failure has been reported in association with enalapril and has been observed 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. If this occurs, therapy with Enaside 20/12,5 should be discontinued. This situation should raise the possibility of underlying renal artery stenosis. Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e., moderate or severe renal insufficiency) (see section 4.2). Enaside 20/12,5 should not be administered to patients with renal insufficiency (creatinine clearance 30 ml/min) until titration of the individual components, enalapril and hydrochlorothiazide, have shown the need for the doses present in this combination formulation (see section 4.2).

Enalapril Maleate - Hydrochlorothiazide
Dual blockade of the renin - angiotensin - aldosterone system (RAAS)
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 medicine (see sections 4.3, 4.4 and 5.1).
Other Antihypertensive medicines
Concomitant use of these 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.
Fluoroquinolones
Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).
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 due to reduced renal clearance and enhance the risk of lithium toxicity with ACE inhibitors. Use of Enaside 20/12,5 with lithium is contraindicated (see section 4.3).

Women of child - bearing potential
Patients planning pregnancy should be changed to alternative antihypertensive treatments. When pregnancy is diagnosed, treatment with Enaside 20/12,5 should be stopped immediately, and, if appropriate, alternative therapy should be started.
Pregnancy
Enaside 20/12,5 is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take Enaside 20/12,5 during pregnancy (see section 4.3). Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations. Enaside 20/12,5 passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of ACE inhibitors [as contained in Enaside 20/12,5] during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur.
Breastfeeding
Enaside 20/12,5 is contraindicated during breastfeeding. Both enalapril and thiazides, including hydrochlorothiazide, as in Enaside 20/12,5, appear in human milk. If use of Enaside 20/12,5 is deemed essential, the patient should stop breastfeeding. Hydrochlorothiazide in high doses causing intense diuresis can inhibit the milk production.
Fertility
There are no data on fertility.

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

a. Summary of the safety profile
The most common side effects reported were headache and cough.
b. Tabulated list of adverse reactions
The following undesirable side effects have been reported for enalapril maleate:

System organ class Frequent Less frequent Frequency unknown
Blood and lymphatic system disorders Anaemia (including aplastic and haemolytic), neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, pancytopenia, lymphadenopathy,
Immune system disorders Hypersensitivity/ angio - oedema of the face, extremities, lips, tongue, glottis and/or larynx Autoimmune diseases
Endocrine disorders Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders Hypoglycaemia (see section 4.4), anorexia Gout
Psychiatric disorder Depression Confusion
Nervous system disorders Dizziness, headache, syncope, taste alterations Somnolence, paraesthesia, vertigo, nervousness, insomnia, dream abnormality, sleep disorders
Eye disorders Blurred vision
Ear and labyrinth disorders Tinnitus
Cardiac disorders Chest pain, rhythm disturbances, angina pectoris, tachycardia Palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high risk patients (see section 4.4)
Vascular disorders Hypotension (including orthostatic hypotension) Flushing, orthostatic hypotension, Raynaud's phenomenon
Respiratory, thoracic, and mediastinal disorders Cough, dyspnoea Rhinorrhoea, sore throat and hoarseness, bronchospasm/asthma, pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilia, pneumonia
Gastrointestinal disorders Nausea, diarrhoea, abdominal pain Ileus, pancreatitis, vomiting, dyspepsia, constipation, gastric irritations, dry mouth, peptic ulcer, stomatitis/aphthous ulcerations, glossitis, intestinal angioedema, flatulence
Hepatobiliary disorders Hepatic failure, hepatitis u2013 either hepatocellular or cholestatic, hepatitis including necrosis, cholestasis (including jaundice)
Skin and subcutaneous tissue disorders Rash Diaphoresis, pruritus, urticaria, alopecia, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, erythroderma, pemphigus
A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity or other dermatologic manifestations may occur.
Musculoskeletal, connective tissue, and bone disorder Muscle cramps Arthralgia
Renal and urinary disorder Renal dysfunction, renal failure, proteinuria Oliguria
Reproductive system and breast disorders Impotence, gynecomastia
General disorder and administration site conditions Asthenia, fatigue Malaise, fever
Investigations Hyperkalaemia, increases in serum creatinine Increases in blood urea, hyponatraemia, elevations of liver enzymes, elevations of serum bilirubin

No specific information is available on the treatment of overdosage with Enaside 20/12,5. Treatment is symptomatic and supportive. Therapy with Enaside 20/12,5 should be discontinued and the patient observed closely. Suggested measures include induction of emesis, administration of activated charcoal, and administration of a laxative if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures, introduced within 2 hours of ingestion.
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. 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 ingestion is recent, take measures aimed at eliminating enalapril maleate (e.g., emesis, administration of absorbents, and sodium sulfate). If available, angiotensin II infusion and/or intravenous catecholamines may be beneficial. 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 dysrhythmias.