Pharmapress Co 20.0mg/12.5 mg Tablet

PHARMAPRESS CO is indicated for the treatment of hypertension in patients where fixed combination therapy is considered more appropriate than monotherapy.

Posology
Hypertension
The usual dose is one tablet, administered once daily. The dosage may be increased to a maximum of two tablets, administered once daily, if appropriate.

Special populations
Renal impairment
For patients with renal impairment, thiazides, including hydrochlorothiazide, as in PHARMAPRESS CO, may not be the appropriate diuretic for use and are ineffective at creatinine clearance values of 30 mL/min or below (i.e. moderate or severe renal insufficiency). In any patient with renal insufficiency, PHARMAPRESS CO must not be used as initial therapy. PHARMAPRESS CO may be used in patients with creatinine clearance of > 30 mL/min and < 80 mL/min, but only after titration of the individual components (see section 4.3).
Paediatric population
No data are available.
Method of administration
PHARMAPRESS CO is taken orally.

PHARMAPRESS CO is contraindicated in:
u2022 Patients with hypersensitivity to enalapril maleate, hydrochlorothiazide, other sulphonamide derived medicines, or any of the excipients in PHARMAPRESS CO (see section 6.1).
u2022 Patients with a history of angioneurotic oedema relating to previous treatment with an ACE-inhibitor or angiotensin receptor blockers (ARBs). These patients must never again be given these medicines.
u2022 Patients with hereditary or idiopathic angioedema.
u2022 Patients with hypertrophic obstructive cardiomyopathy (HOCM).
u2022 Patients with severe renal function impairment (creatinine clearance less than 30 mL/min) or anuria.
u2022 Patients with bilateral renal artery stenosis.
u2022 Renal artery stenosis in patients with a single kidney.
u2022 Patients with aortic stenosis.
u2022 Patients with severe hepatic impairment.
u2022 Concomitant therapy with potassium sparing diuretics such as spironolactone, eplerenone, triamterene and amiloride (see section 4.5).
u2022 Patients with Addisonu2019s disease.
u2022 Concomitant therapy with lithium. Administration of lithium with PHARMAPRESS CO may lead to toxic blood concentrations of lithium (see section 4.5).
u2022 Concomitant use of PHARMAPRESS CO with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1,73 m2) (see section 4.5).
u2022 Concomitant use of PHARMAPRESS CO with fluoroquinolones in patients with moderate to severe renal impairment (creatinine clearance u2264 30 mL/min) and in elderly patients (see section 4.5).
u2022 Combination with sacubitril/valsartan due to the increased risk of angioedema. Do not administer PHARMAPRESS CO within 36 hours of switching to or from sacubitril/valsartan, a medicine containing a neprilysin inhibitor (see sections 4.4 and 4.5).
u2022 Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.
u2022 Pregnancy and lactation (see section 4.6).

Should a woman become pregnant while receiving PHARMAPRESS CO, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6). ACE inhibitors, such as enalapril, as in PHARMAPRESS CO, 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.
Hypersensitivity/angioedema
Angioedema of the extremities, face, lips, glottis and/or larynx and tongue has been reported. PHARMAPRESS CO should be discontinued promptly in such cases and appropriate monitoring should be instituted to ensure complete resolution of symptoms. The condition may resolve without treatment, in those instances where swelling has been confined to the face and lips, although antihistamines have been useful in relieving symptoms. 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. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the glottis, larynx or the tongue, likely to cause airway obstruction, especially those with a history of airway surgery, appropriate therapy such as intravenous epinephrine solution 1:1 000 (0,3 ml to 0,5 ml) and/or measures to ensure a patent airway, should be administered promptly.
Patients from the black ethnicity group receiving ACE inhibitors, such as enalapril, as in PHARMAPRESS CO, have been reported to have a higher incidence of angioedema compared to white patients. However, in general it appears that black patients have an increased risk for angioedema. Patients with a history of angioedema unrelated to ACE inhibitor therapy, may be at increased risk of angioedema, while taking an ACE inhibitor, such as enalapril, as in PHARMAPRESS CO (see section 4.3). Patients receiving co-administration of an ACE inhibitor, such as enalapril, as in PHARMAPRESS CO, and mTOR (mammalian target of rapamycin) inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.
In patients receiving thiazides, such as hydrochlorothiazide, as in PHARMAPRESS CO, sensitivity reactions may occur with or without a history on bronchial asthma or allergy. The use of thiazides such as hydrochlorothiazide, as in PHARMAPRESS CO, has been reported to activate or exacerbate systemic lupus erythematosus (SLE).
Anaphylactoid reactions during hymenoptera desensitisation
Patients receiving ACE inhibitors, such as enalapril, as in PHARMAPRESS CO, during desensitisation with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions are avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.
Anaphylactoid reactions during LDL-Apheresis
Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactic reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, ARBs or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of PHARMAPRESS CO and aliskiren is therefore contraindicated. PHARMAPRESS CO should not be used concomitantly with aliskiren (see section 4.3). ACE-inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
Hypotension and electrolyte fluid imbalances
In some patients, symptomatic hypotension may occur. Patients should be observed for clinical signs of fluid or electrolyte imbalance, e.g. hyponatremia, hypochloraemic alkalosis, volume depletion, hypokalaemia or hypomagnesaemia. This may occur during intercurrent diarrhoea or vomiting, due to dietary salt restriction or diuretic therapy, including hydrochlorothiazide, as in PHARMAPRESS CO. 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. At appropriate intervals, periodic determination of serum electrolytes should be performed in such patients.
Although hypokalaemia may develop during use of thiazide diuretics, such as hydrochlorothiazide, as in PHARMAPRESS CO, concurrent therapy with enalapril, as in PHARMAPRESS CO 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. Hydrochlorothiazide, as in PHARMAPRESS CO, may increase the urinary excretion of magnesium, which may result in hypomagnesemia.
Symptomatic hypotension may occur mainly after the first dose of PHARMAPRESS CO; this is more likely in patients who have received prior diuretic therapy. Prior to initial therapy with PHARMAPRESS CO, diuretic therapy should be discontinued for 2 to 3 days. When therapy is administered to patients with ischaemic heart or cerebrovascular disease, particular consideration should be given, because 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 documented. 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 PHARMAPRESS CO and/or diuretic is adjusted. 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, including enalapril, as in PHARMAPRESS CO (see section 4.3).
The patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline if hypotension occurs. A transient hypotensive response is not a contraindication to further doses. Following the restoration of effective blood volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone. In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with PHARMAPRESS CO. 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 PHARMAPRESS CO may be necessary.
Aortic stenosis and hypertrophic cardiomyopathy
As with all vasodilators, ACE-inhibitors, such as enalapril, as in PHARMAPRESS CO, should be given with caution in patients with left ventricular valvular and outflow tract obstruction and avoided in cases of cardiogenic shock and haemodynamically significant obstruction (see section 4.3).
Renal function impairment
(see Dosage in renal insufficiency under section 4.2) There is an increased risk of renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, are treated with ACE-inhibitors, such as enalapril, as in PHARMAPRESS CO. Loss of renal function may occur with only mild changes in serum creatinine (see section 4.3). In these patients, therapy should be initiated under close medical supervision with low doses, careful titration, and monitoring of renal function. When PHARMAPRESS CO has been given concomitantly with a diuretic, some hypertensive patients, with no apparent pre-existing renal disease have developed minor increases in serum creatinine and blood urea. The combination should be discontinued, if this occurs during therapy with PHARMAPRESS CO. This situation should raise the possibility of underlying renal artery stenosis. Renal failure has been reported in association with enalapril, as in PHARMAPRESS CO, 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, as in PHARMAPRESS CO, is usually reversible. PHARMAPRESS CO 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). Hydrochlorothiazide, as in PHARMAPRESS CO, 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 4.3 and 4.2). The use of enalapril, as in PHARMAPRESS CO, is not indicated in patients requiring dialysis for renal failure. Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor, such as enalapril, as in PHARMAPRESS CO. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive medicine. There is no experience regarding the administration of enalapril, as in PHARMAPRESS CO, in patients with a recent kidney transplantation. Treatment with PHARMAPRESS CO is therefore not recommended. Concomitant use of fluoroquinolones and PHARMAPRESS CO may precipitate acute kidney injury (AKI) in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.4). Renal function should be assessed before initiating treatment, and monitored during treatment, with fluoroquinolones or PHARMAPRESS CO whether used separately and/or concomitantly (see sections 4.3 and 4.5).

Other antihypertensive therapy
Adrenergic blocking medicines or ganglionic blocking medicines combined with enalapril, as in PHARMAPRESS CO, should only be administered under careful observation of the patient. Concomitant use of other antihypertensive medicines may increase the hypotensive effects of PHARMAPRESS CO. Concomitant use with nitro-glycerine and other nitrates, or other vasodilators, may further reduce blood pressure.
Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren
Data has 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 and 4.4).

PHARMAPRESS CO is contraindicated in pregnancy and lactation, and also in patients intending to become pregnant. Pregnant women should be informed of the potential hazards to the foetus and must not take PHARMAPRESS CO 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 PHARMAPRESS CO should be stopped immediately and if appropriate, alternative therapy should be started.
Pregnancy
Enalapril maleate PHARMAPRESS CO passes through the placenta and can cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in new-borns and neonatal toxicity (renal failure, hypotension, and hyperkalaemia) have been reported after administration of PHARMAPRESS CO in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur. In addition, use of PHARMAPRESS CO during the first trimester of pregnancy has been associated with an increased risk of birth defects, in particular of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and the central nervous system (microcephaly, spina bifida) and of kidney malformations. 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 PHARMAPRESS CO have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended (see section 4.3 and 4.4). When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Hydrochlorothiazide
Thiazides, including hydrochlorothiazide, as in PHARMAPRESS CO, cross the placental barrier and appear in cord blood. Hazards include foetal and neonatal jaundice and thrombocytopenia. There is limited experience with hydrochlorothiazide, as in PHARMAPRESS CO, during pregnancy, especially during the first trimester. Based on the pharmacological mechanism of action of hydrochlorothiazide, as in PHARMAPRESS CO, its use during the second and third trimester may compromise foetal-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. PHARMAPRESS CO 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. PHARMAPRESS CO should not be used for essential hypertension in pregnant woman (see section 4.3). Infants whose mothers have taken PHARMAPRESS CO should be closely observed for hypotension, oliguria and hyperkalaemia. There is no experience with the removal of the combination medicine, PHARMAPRESS CO from the neonatal circulation. Enalapril, as in PHARMAPRESS CO, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit. There is no experience with the removal of hydrochlorothiazide, as in PHARMAPRESS CO, which also crosses the placenta, from the neonatal circulation.

PHARMAPRESS CO has moderate influence on the ability to drive and use machines. Since adverse reactions such as somnolence, dizziness and blurred vision have been reported in patients receiving PHARMAPRESS CO, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that PHARMAPRESS CO does not adversely affect their ability to do so (see section 4.8).

a) Tabulated list of adverse reactions
Enalapril maleate and hydrochlorothiazide combination, as in PHARMAPRESS CO.
System organ class Frequent Less frequent Frequency unknown (cannot be estimated from the available data)
Neoplasm benign, malignant and unspecified (including cysts and polyps) Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
Blood and the lymphatic system disorders Decreases in haemoglobin, decreases in haematocrit, decrease in platelets, decrease in white cell count, anaemia (including aplastic and haemolytic), neutropenia, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases
Immune system disorders Hypersensitivity/angioedema (angioedema of the face, extremities, lips, tongue, glottis and/or larynx)
Endocrine disorders Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders Hypokalaemia, increase of cholesterol, increase of triglycerides, hyperuricaemia, hyperglycaemia, hypoglycaemia, gout, hyponatraemia
Nervous system disorders Dizziness, insomnia, paraesthesia, headache, decreased libido, depression, syncope, taste alteration, nervousness, somnolence, vertigo, paresis (due to hypokalaemia), confusion, insomnia, paraesthesia, decreased libido, dream abnormality, sleep disorders
Eye disorders Blurred vision, choroidal effusion
Ear and labyrinth disorders Tinnitus
Cardiac disorders Chest pain, palpitations, tachycardia, rhythm disturbances, angina pectoris, flushing, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, Raynaud's phenomenon
Vascular disorders Hypotension, orthostatic hypotension
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, dyspepsia, constipation, vomiting, flatulence, dry mouth, pancreatitis, ileus, anorexia, gastric irritations, dry mouth, peptic ulcer, stomatitis/aphthous ulcerations, glossitis, intestinal angioedema
Hepato-biliary 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), diaphoresis, pruritus, erythema multiforme, Stevens-Johnson syndrome, symptom complex which may include some or all of the following: syndrome, exfoliative dermatitis, toxic epidermal necrolysis, purpura, cutaneous lupus erythematosus, erythroderma, pemphigus urticaria, alopecia, fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive antinuclear antibody, elevated erythrocyte sedimentation rate, eosinophilia, leukocytosis. Photosensitivity or other dermatologic manifestations may occur (DRESS syndrome)
Musculoskeletal and connective tissue disorders Muscle cramps
Renal and urinary disorders Renal dysfunction, renal failure, proteinuria, oliguria, interstitial nephritis
Reproductive system and breast disorders Impotence, gynaecomastia
General disorders and administrative site conditions Fatigue, asthenia, malaise, fever
Investigations Increases in blood urea, creatinine, elevations of liver enzymes, elevations of serum bilirubin

Treatment
On the treatment of overdosage with PHARMAPRESS CO, no specific information is available. Treatment is symptomatic and supportive. Therapy with PHARMAPRESS CO should be discontinued and the patient observed closely. Suggestive measures include induction of emesis, administration of activated charcoal, administration of a laxative if the ingestion is recent, and correction of electrolyte imbalance, hypotension and dehydration, by established procedures introduced within 2 hours after ingestion.
Symptoms
Hypotension is the most prominent feature of overdosage, 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 such as enalapril, as in PHARMAPRESS CO, may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.
Treatment
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, as in PHARMAPRESS CO (e.g. emesis, gastric lavage, administration of absorbents, and sodium sulphate). Haemodialysis may be used to remove enalapril, as in PHARMAPRESS CO from the general circulation. Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
Hydrochlorothiazide as in PHARMAPRESS CO
Symptoms
The most common signs and symptoms observed are those caused by electrolyte depletion (hypochloraemia, hypokalaemia, hyponatraemia) and from excessive diuresis, dehydration will result. Cardiac dysrhythmias may be accentuated by hypokalaemia, if digoxin has also been administered.