Acenten 20/12,5 mg Tablets

ACENTEN 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 one tablet, administered once daily. If necessary, the dosage may be increased to a maximum of two tablets, administered once daily.
Special populations
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). ACENTEN is not to be used as initial therapy in any patient with renal insufficiency. In patients with creatinine clearance of greater than 30 and less than 80 mL/min, ACENTEN may be used but only after titration of the individual components.
Use in the elderly
In clinical studies the efficacy and tolerability of enalapril maleate and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.
Paediatric population
Safety and efficacy in children have not been established.
Method of administration
Oral use. The tablet should be swallowed whole.

• Hypersensitivity to any of the active substances or to any of the ingredients of ACENTEN (see section 6.1).
• 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.
• Anuria
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Hypersensitivity to sulfonamide-derived medicines.
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria
• Lithium therapy: Concomitant administration with ACENTEN may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of ACENTEN with aliskiren-containing products is contraindicated (see sections 4.4 and 4.5).
• Severe hepatic impairment.
• Combination with sacubitril/valsartan due to the increased risk of angioedema. Do not administer ACENTEN within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (See sections 4.4 and 4.5).
• Concomitant use of fluoroquinolones with ACE inhibitors/angiotensin receptor blockers in patients with moderate to severe renal impairment and in the elderly (see section 4.4).
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Should a woman become pregnant while receiving ACENTEN, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see section 4.3 and section 4.6).
Enalapril Maleate - Hydrochlorothiazide
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors such as enalapril, 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 and aliskiren is therefore contraindicated (see sections 4.3, 4.5 and 5.1). ACENTEN should not be used concomitantly with aliskiren (see section 4.3).
Hypotension and Electrolyte Fluid Imbalance
Symptomatic hypotension may occur following the initial dose of ACENTEN. In hypertensive patients receiving ACENTEN, symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhoea or vomiting (see sections 4.5 and 4.8). Regular determination of serum electrolytes should be performed at appropriate intervals in such patients. Special attention should be paid to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. In hypertensive patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of ACENTEN 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 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 ACENTEN. 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 ACENTEN may be necessary.
Renal Function Impairment
Renal failure has been reported in association with enalapril, as contained in ACENTEN, 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. ACENTEN should not be administered to patients with renal insufficiency (creatinine clearance 30 mL/min) until titration of enalapril has shown the need for the dose present in this formulation (see section 4.2). Some hypertensive patients with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril has been given concurrently with a diuretic (see Special warnings and precautions for use, Enalapril Maleate, Renal Function Impairment; Hydrochlorothiazide, Renal Function Impairment in section 4.4). If this occurs, therapy with ACENTEN 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).
Hyperkalaemia
The combination of enalapril and a low-dose diuretic cannot exclude the possibility of a hyperkalaemia to occur (see Special warnings and precautions for use, Enalapril Maleate, Hyperkalaemia in section 4.4).
Lithium
The combination of lithium with enalapril and diuretic medicines is generally not recommended (see sections 4.3 and 4.5).
Lactose
ACENTEN contains less than 200 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 such as enalapril, 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 medicines (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.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors such as enalapril. Concomitant use of hydrochlorothiazide diuretics may further increase lithium levels and enhance the risk of lithium toxicity with ACE inhibitors such as enalapril. Use of ACENTEN with lithium is contraindicated (see section 4.3).
Non-Steroidal Anti-Inflammatory Medicines 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 medicines. Therefore, the antihypertensive effect of angiotensin II receptor antagonists, ACE inhibitors such as enalapril 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 such as enalapril, exert an additive effect on the increase in serum potassium, and may result in a deterioration of renal function. These effects are usually reversible. 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.

Pregnancy
The use of ACENTEN is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take ACENTEN during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACENTEN should be stopped immediately and if appropriate, alternative therapy should be started.
ACE inhibitors:
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. ACENTEN 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 ACENTEN during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see section 4.3).
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.
Breastfeeding
This medicine is contraindicated in lactating women (see section 4.3).

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

Side effects reported with enalapril/hydrochlorothiazide combination ACENTEN, enalapril alone or hydrochlorothiazide alone either during clinical studies or after the medicine was marketed include:
System Organ Class
Frequency
Frequent
Less Frequent
Not known
Infections and Infestations
sialadenitis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
Blood and lymphatic system disorders
anaemia (including aplastic and haemolytic), neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases
Immune system disorders
anaphylactic reactions
Endocrine disorders
syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders
hypokalaemia, increase of cholesterol, increase of triglycerides, hyperuricaemia, hypoglycaemia (see section 4.4), hypomagnesemia, gout*, increase in blood glucose, hypercalcaemia (see section 4.4), electrolyte imbalance, including hyponatraemia
Nervous system and psychiatric disorders
headache, depression, syncope, taste alteration, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, decreased libido**, Dream abnormality, sleep disorders, paresis (due to hypokalaemia), restlessness
Eye disorders
blurred vision, xanthopsia
Ear and labyrinth disorders
tinnitus
Cardiac and vascular disorders
dizziness, hypotension, orthostatic hypotension, rhythm disturbances, angina pectoris, tachycardia, flushing, palpitations, myocardial infarction or cerebrovascular accident*, possibly secondary to excessive hypotension in high-risk patients (see section 4.4), Raynaudu2019s phenomenon, necrotising angiitis (vasculitis)
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 angioedema
Hepatobiliary disorders
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
rash (exanthema), hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see section 4.4). diaphoresis, pruritus, urticaria, alopecia, erythema multiforme, stevens-johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigus, a symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive ANA (antinuclear antibody), elevated ESR (erythrocyte sedimentation rate), eosinophilia, and leukocytosis. rash, photosensitivity or other dermatologic manifestations may occur.
Musculoskeletal and connective tissue disorders
muscle crampsu2020, arthralgia**
Renal and urinary disorders
renal dysfunction, renal failure, proteinuria, oliguria, interstitial nephritis, glycosuria
Reproductive system and breast disorders
impotence, gynecomastia
General disorders and administration site conditions
asthenia, chest pain, fatigue, malaise, fever
Investigations
hyperkalaemia, increases in serum creatinine, increases in blood urea, hyponatraemia, elevations of liver enzymes, elevations of serum bilirubin
* Incidence rates were comparable to those in the placebo and active control groups in the clinical trials.
** Only seen with doses of hydrochlorothiazide 12, 5 mg and 25 mg
u2020 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.

No specific information is available on the treatment of overdosage with ACENTEN. Treatment is symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage and correction of dehydration, electrolyte imbalance and hypotension by established procedures introduced within 2 hours after ingestion.
Enalapril Maleate
The most prominent feature of overdosage is hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. The recommended treatment of overdosage is intravenous infusion of normal saline solution. If available, angiotensin II infusion may be beneficial. Enalapril may be removed from the general circulation by haemodialysis (see section 4.4, Haemodialysis patients).
Hydrochlorothiazide
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalaemia may accentuate cardiac dysrhythmias.