Summary of Product Characteristics, Labelling and Package Leaflet

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SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Femipres Plus 15mg/25mg film-coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 film-coated tablet of Femipres Plus 15mg/25mg contains: moexipril hydrochloride 15mg hydrochlorothiazide 25mg

Excipient(s) with known effects:lactose 0.24 g

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablets. Yellowish, oval film-coated tablets with white core; break score on one side and in the band. Engraved on the upper side with SP and on the lower side with 725.

The tablet can be divided into two equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Femipres Plus is indicated for the treatment of essential hypertension in adults when additional blood pressure control is required over moexipril hydrochloride or hydrochlorothiazide (HCTZ) monotherapy. This fixed dose combination is indicated in patients whose blood pressure has been stabilised on the individual components given in the same proportions.

4.2 Posology and method of administration

Patients whose blood pressure has been stabilised with the free combination consisting of 15mg moexipril hydrochloride and 25mg hydrochlorothiazide should take one film-coated tablet of Femipres Plus 15mg/25mg daily, in the morning. Fixed dose combinations are not recommended for initial therapy. Therefore, a patient whose blood pressure is not adequately controlled with either moexipril or hydrochlorothiazide may be given the fixed combination of moexipril hydrochloride and hydrochlorothiazide, if his/her blood pressure has been stabilised with the free combination of these components given in the same proportions.

Patients with impaired renal function: Femipres Plus must not be given to patients with severely impaired renal function (creatinine clearance <40 ml/min; see section 4.3). In patients with mild to moderate impaired renal function (creatinine clearance of >40 ml/min but <60 ml/min) this fixed combination must be administered very carefully and,if required, dose titration of single components must be requested and must be initiated only under close medical supervision. Additionally, in patients with impaired renal function, close monitoring of kidney function by the treating physician is imperative.

Use in the elderly Dose adjustment is required in elderly patients.

The individual and careful dose titration of single components must be requested and must be initiated only under close medical supervision.

Use in children Femipres Plus must not be given to children.

4.3 Contraindications

Moexiprilhydrochloride/HCTZ must not be used in: - patients with hypersensitivity to the active substances or to any of the excipients listed in section 6.l - patients with hypersensitivity to other sulphonamide-derived drugs - patients with history of angioneuroticedema associated with previous ACE inhibitor therapy - patients with hereditary/idiopathic angioneurotic oedema - patients with renal artery stenosis (bilateral or an anatomic or functional solitary kidney) - patients with diabetes or with moderate to severe kidney impairment treated with aliskiren: the concomitant use of moexipril hydrochloride/HCTZ with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.4, 4.5 and 5.1) - patients with recent kidney transplantation - patients with severely impaired renal function (creatinine clearance <40 ml/min) - patients with severe hepatic impairment - patients with anuria - patients with hemodynamic important aortic or mitral valve stenosis - patients with hypertrophic cardiomyopathy - patients with primary aldosteronism - patients with refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia - the second and third trimesters of pregnancy (see sections 4.4 and 4.6) - children

To avoid the risk of life-threatening anaphylactic reactions, ACE inhibitors must not be used: - during dialysis or hemofiltration with poly-(acrylonitrile, natrium-2-methylallylsulfonat)-high-flux- membranes - during low density lipoprotein (LDL) apheresis with dextrane sulphate - during desensitization therapy versus insect poisons (e.g. bee or wasp stings)

4.4 Special warnings and precautions for use

Moexiprilhydrochloride/HCTZ must only be used with caution in patients with: • clinical important serum electrolyte imbalances • decreased immune response • collagenousvasculardiseases (e.g. lupus erythematosus, sclerodermia) • concomitant systemic drug therapy suppressing the immune response (e.g. corticosteroids, cytostatic agents, antimetabolites) and allopurinol, procainamide, or lithium

Especially at the beginning of the ACE inhibitor therapy the blood pressure and the respective laboratory values must be monitored carefully in patients with: • impaired renal function (creatinine clearance 40 – 60 ml/min) • severe hypertension, renal hypertension • cardiac failure • salt and/or fluid volume depletion • age of more than 65 years

Hypotension: Moexiprilhydrochloride/HCTZ may cause a profound fall of blood pressure especially at the beginning of the therapy with symptoms of dizziness, feeling of weakness and disturbances of vision.Rarely syncope may

4 occur. Symptomatic hypotension was observed in 8% of patients given a combination of moexiprilhydrochloride and HCTZand led to discontinuation of therapy in about 1% of patients. Symptomatic hypotension is rare in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume depleted and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting. Volume and/or salt depletion must be corrected before initiating therapy with moexiprilhydrochloride/HCTZ.

Excessive hypotensioncaused by ACE inhibitor therapy in patients with congestive heart failure with or without concomitant renal insufficiency may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. Those patients must be followed closely at the beginning of the therapy and whenever the dose of moexiprilhydrochloride/HCTZ is increased.

If hypotension occurs, the patient must be placed in a supine position and, if necessary, intravenous sodium chloride solution infusion must be given. Moexiprilhydrochloride/HCTZ treatment usually can be continued following reconstitution of an adequate blood pressure and substitution of the fluid volume.

For patients who experience an excessive reduction in blood pressure with moexipril hydrochloride/HCTZ, dose titration of the individual components must be requested and initiated under close medical supervision.

Dual blockade of the RAAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risk of hypotension compared to monotherapy (see “Dual blockade of the renin-angiotensin- aldosteronesystem (RAAS)” below and section 4.5). Blood pressure, renal function and electrolytes must be closely monitored in patients on moexipril hydrochloride/HCTZ and other agents that affect the RAAS.

Renal vascular hypertension: Before ACE inhibitor therapy is started, renal function has to be controlled. There is an increased risk of severe hypotension and renal insufficiency when patients with renal vascular hypertension are treated with moexiprilhydrochloride/HCTZ. Loss of renal function may occur with only mild changes in serum creatinine. In case of renal artery stenosis (bilateral or stenosis of an anatomic or functional solitary kidney) ACE inhibitors are contraindicated (see section 4.3).

Impaired renal function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including moexipril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when moexipril was given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of moexipril hydrochloride/HCTZ and/or discontinuation of the diuretic may be required.

Dosage recommendation for patients with moderately impaired renal function (creatinine clearance 40 – 60 ml/min or serum creatinine>1.2 mg/dl and <1.8 mg/dl): In patients with mild to moderate impaired renal function, this fixed combination must be administered very carefully and if required dose titration of single components must be requested and must be initiated only under close medical supervision. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, and moexipril hydrochloride/HCTZ is not recommended(see section 4.3). In patients with impaired renal function, close monitoring of kidney function by the treating physician is imperative.

Hepatic diseases: 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. Rarely, ACE inhibitors 5 have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant 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.

Proteinuria: Clinically relevant proteinuria (> 0.5 g/day) may occur, particularly in patients with existing renal function impairment or on relatively high doses of moexipril hydrochloride/HCTZ.

Angioneuroticedema: Angioneuroticedema of the face, lips, mucous membranes, tongue, glottis and/or larynx and of the extremities has been reported in patients treated with ACE inhibitors, especially during the first weeks of treatment. However, in rare cases severe angioneuroticedema may develop even after long-term treatment with an ACE inhibitor. Treatment must promptly be discontinued and replaced by an agent belonging to another class of antihypertensive medicinal products. Symptoms suggestive of angiodema or facial oedema occurred in <0.5% of moexiprilhydrochloride/HCTZ treated patients in placebo controlled trials. None of the cases was considered to be life-threatening.

Angioneuroticedema involving the tongue, glottis or larynx may be fatal due to airway obstruction. Emergency therapy must include intravenous administration of corticosteroids and antihistamines . If the condition of the patient does not ameliorate with the above mentioned therapy, epinephrine must be administered slowly intravenously monitored by ECG control.

In case of hereditary angioneuroticedema due to C1-inactivator deficiency associated with ACE inhibitor therapy, additionally a C1-inactivator must be administered.

Furthermore, intubation or tracheotomy are to be considered (see also section 4.8).

Intestinal angioneurotic edema: Intestinal angioneurotic edema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea and vomiting). In some cases there was no prior history of facial angioneurotic edema and C1-esterase levels were normal. Intestinal angioneurotic edema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery. Symptoms resolved after stopping the ACE inhibitor. Intestinal angioneurotic edema must be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

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).

Cough: During treatment with an ACE inhibitor a dry and non-productive cough may occur which disappears after discontinuation. In controlled trials with a combination of moexiprilhydrochloride and HCTZ cough was present in 5% of patients treated with this combination and in 2% given placebo.

Elderly: In elderly male subjects (>65 years of age) with clinically normal renal and hepatic function, the AUC and Cmax, of moexiprilatare greater than those of younger subjects. The individual and careful dose titration of single components must be requested and must be initiated only under close medical supervision.

Control of renal function before start and during moexiprilhydrochloride/HCTZ therapy is recommended.

Serum electrolyte imbalances: Moexipril

In clinical trials with moexipril hydrochloride, persistent hyperkalaemia (serum potassium >5.4 mEq/l) occurred in approximately 2.6% of hypertensive patients. In clinical trials, 0.1 % of patients (two patients) were discontinued from therapy due to elevated serum potassium.Risk factors for the development of hyperkalaemia with ACE inhibitors include renal insufficiency and/or heart failure, diabetes mellitus and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salt substitutes which have to be used cautiously if at all with moexiprilhydrochloride/HCTZ.

HCTZ/thiazide diuretics Treatment with thiazide diuretics has been associated with hypokalaemia, hyponatraemia and hypochloraemic alkalosis. The risk to develop hypokalaemia is greatest in patients with liver cirrhosis, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH.

In clinical studies with moexiprilhydrochloride/HCTZ, moexipril hydrochloride and HCTZ have been shown to have a counterbalancing effect on serum potassium so that little net effect upon serum potassium will be seen with this combination. However, patients must be told not to use potassium supplements or salt substitutes containing potassium without consulting their physician.

Chloride deficits generally are mild and require specific treatment under extraordinary circumstances only (e.g. in liver disease or renal disease). Dilutionalhyponatremia may occur in oedematous patients. Appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion appropriate replacement is the therapy of choice.

Calcium excretion is reduced by thiazides. In a few patients on prolonged thiazide therapy pathological changes in the parathyroid gland have been observed with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (nephrolithiasis, bone resorption and peptic ulceration) have not been observed.

Thiazides enhance urinary excretion of magnesium and may result in hypomagnesaemia.

Patients receiving thiazide diuretics must be observed for clinical signs of fluid or electrolyte imbalance. Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances as nausea or vomiting.

Metabolic and endocrine effects: ACE inhibitor and thiazide therapy combination may aggravate the glucose intolerance. Dosage adjustment of anti-diabetics agents, including insulin, may be required. In diabetic patients previously treated with oral antidiabetic drugs or insulin, blood glucose levels should be closely monitored during the first month of treatment with an ACE inhibitor. Latent diabetes mellitus may become manifest during thiazide therapy.

Other metabolic disturbances: Thiazide diuretics may reduce glucose tolerance and may raise serum levels of cholesterol and triglycerides. These effects are usually minor. Thiazide diuretics have been associated with the development of hyperuricemia and/or gout in some patients. This effect appears to be dose related.

Surgery and anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, moexiprilhydrochloride/HCTZ will block the effect of compensatory renin release. Hypotension occurring as a result of this mechanism can be corrected by volume expansion (see also section 4.8).

Aortic Stenosis/Mitral stenosis: ACE inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle and mitral stenosis.

Neutropenia/Agranulocytosis: 7

Other ACE inhibitors have been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagenosis such as systemic lupus erythemathosus or dermatosclerosis. Available data from clinical trials of moexipril are insufficient to show that moexipril does not cause agranulocytosis at rates similar as captopril. Although, there were no cases of severe neutropenia (absolute neutrophil count <500/mm3) among patients given moexipril hydrochloride, as with other ACE inhibitors.Monitoring of white blood cell counts must be considered for patients suffering fromcollagenosis, especially if the disease is associated with impaired renal function.

LDL Apheresis/Desensitization: During a LDL (low density lipoprotein) apheresis in the treatment of severe hypercholesterinaemia, life- threatening hypersensitivity reactions may occur in patients receiving ACE-inhibitor therapy.

During a desensitization therapy versus insect poisons (e.g. bee or wasp sting) and concomitant treatment with an ACE-inhibitor, life-threatening hypersensitivity reactions (e.g. fall in blood pressure, difficulty to breath, vomiting, allergic skin reactions) may occur.

In case where a LDL apheresis or a desensitization therapy versus insect poisons is required, the ACE- inhibitor is to be substituted by a different antihypertensive drug temporarily.

Should symptoms such as fever, swelling of the lymph nodes, and/or inflammation of the throat occur in the course of therapy with Femipres Plus, the treating physician must be consulted and the white blood picture investigated immediately.

Lupus: Thiazide diuretics have been reported to exacerbate or activate systemic lupus erythematosus.

Lithium: The combination of ACE inhibitors and lithium is generally not recommended (see section 4.5).

Acute Myopia and Secondary Angle-Closure Glaucoma: HCTZ, a sulphonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue HCTZas rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.

Etnicity: Patients with black skin colour have a higher risk of cardiovascular disease, such as heart failure. ACE inhibitors are less effective as antihypertensives in patients with a black skin colour. These patients also have a higher risk of angioedema.

Dual blockade of the renin-angiotensin-aldosteronesystem (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.

Anti-doping test: The HCTZcontained in this medication could produce a positive analytic result in an anti-doping test.

Associated with excipients: This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactosemalabsorptionmust not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Potassium-sparing diuretics or potassium supplements Moexiprilhydrochloride/HCTZ can increase serum potassium because it decreases aldosterone secretion. As noted above, moexipril and HCTZhave counterbalancing effects on serum potassium, so that little net effect on serum potassium will be seen. Potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements can increase the risk of hyperkalaemia. Therefore, if concomitant use of such agents is indicated, they must be given with caution and the patient’s serum potassium must be monitored.

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 increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Use of moexiprilhydrochloride/HCTZ with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed.

Anaesthetic medicinal products Moexiprilhydrochloride and HCTZ may enhance the hypotensive effects of certain anaesthetic medicinal products.

Narcotic medicinal products/Antipsychotics Potentiation of orthostatic hypotension may occur in patients on thiazide diuretics therapy.

Antihypertensive agents Increase of the hypotensive effect of moexiprilhydrochloride/HCTZ may occur. Concomitant use of thiazide diuretics with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics may enhance the hyperglycaemic effect of diazoxide.

Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide Concomitant administration with moexiprilhydrochloride/HCTZ may lead to an increased risk forleucopenia and may intensify electrolyte depletion, particularly hypokalaemia.

Administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Non-Steroidal Anti-inflammatory medicinal products (NSAID) The administration of non-steroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effect of moexiprilhydrochloride/HCTZ. Furthermore, it has been described that NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium, whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with compromised renal function.

Antacids Decreased bioavailability of ACE inhibitors may be induced.

Sympathomimetics Sympathomimetics may reduce the antihypertensive effects of moexiprilhydrochloride/HCTZ; patients must be carefully monitored to confirm that the desired therapeutic effect is being obtained.

Alcohol Alcohol enhances the hypotensive effectofmoexipril/HCTZ.

Food Food may reduce the bioavailability of ACE inhibitors.

Antidiabetic agents Use of thiazide diuretics and ACE inhibitors concomitantly with antidiabetic agents (oral agents and insulin) may require an adjustment of the posology of the antidiabetic agents. HCTZmay increase the risk for lactic acidosis under treatment with metformin due to a possible functional renal insufficiency.

Vitamin D or calcium salts Administration of thiazide diuretics with vitamin D or with calcium salts may potentiate the rise in serum calcium.

Common salt Common salt may attenuate the antihypertensive effect of moexiprilhydrochloride/HCTZ.

High doses of salicylates High doses of salicylates may potentiate the toxic effect of salicylates on the central nervous system caused by HCTZ.

Kaliuretic diuretics (e.g. furosemide), glucocorticoids, ACTH, carbenoxolone, amphotericin B, penicillin G, salycilates or abuses of laxatives Use of thiazide diuretics concomitantly with these agents may intensify electrolyte depletion, particularly hypokalaemia.

Skeletal muscle relaxants, non-depolarizing Use of HCTZconcomitantly with muscle relaxants may potentiate and prolong the muscle relaxing effect of e.g. tubocurarine (the anaesthetist must be informed about the therapy with moexiprilhydrochloride/HCTZ).

Anticholinergic agents The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.

Catecholamines (e.g. epinephrine) HCTZ administered concomitantly may reduce the efficacy of catecholamines.

Cytostatic agents (e.g. cyclophosphamide, fluorouracil, methotrexate) Use of cytostatic agents may increase toxicity of HCTZ on the bone marrow, especially granulocytopenia.

Non-antiarrhythmic medicinal products inducing torsades de pointes (e.g. astemizole, bepridil, erythromycin i.v., halofantrine, sultopride,terfenadine, vincamine) and anti-arrhythmic medicinal products inducing torsades de pointes HCTZmay increase the risk for torsades de pointes induced by hypokalaemia.

Digitalis glycosides Efficacy and adverse reactions of digitalis glycosides could be potentiated by simultaneous deficiency in potassium and/or magnesium.

Methyldopa Concomitant use of HCTZand methyldopa may cause haemolytic anaemia.

Cholestipol/cholestyramine Absorption of HCTZis impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or cholestipol resins bind HCTZand reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Amantadine 10

Administration of thiazide diuretics may increase the risk of adverse reactions caused by amantadine.

Iodinated contrast media HCTZ may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media.

Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension leading to collapse) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor.

Dual blockade of the renin-angiotensin-aldosteronesystem (RAAS) Clinical trial 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 agent (see sections 4.3, 4.4 and 5.1).

Epoetins Epoetins may cause hypertension and therefore reduce the effect of ACE inhibitors. Hyperkalaemia may be caused on the concurrent use of ACE Inhibitors and Epoetins. ACE inhibitors may antagonise the haematopoietic effects of epoetins.

4.6 Pregnancy and lactation

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 contraindicated during the second and third trimester 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. ACE-inhibitors cross the placenta and can cause foetal and neonatal morbidity and mortality when administered to pregnant women. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation, death), premature labour and neonatal toxicity (renal failure, anuria, hypotension, hyperkalaemia, patent ductusarterious) (See section 5.3.). Limb contractures, craniofacial deformities, bony malformations, hypoplastic lung development, respiratory distress syndrome and intrauterine growth retardation have been reported in association with oligohydramnios. Should exposure to ACE inhibitor 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). Infants exposed in utero to ACE-inhibitors must be closely observed for hypotension, oliguria and hyperkalemia. Oliguria must be treated with support of blood pressure and renal perfusion.

HCTZ: There is limited experience with HCTZduring pregnancy, especially during the first trimester. Animal studies are insufficient. HCTZcrosses the placenta. Based on the pharmacological mechanism of action of

HCTZits 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. HCTZshould 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. HCTZshould not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Women who become pregnant while receiving moexipril hydrochloride and HCTZmust be informed of the potential hazard for the foetus.

Lactation: ACE-inhibitors: Because no information is available regarding the use of moexipril hydrochloride during breastfeeding, the association of moexipril hydrochloride and HCTZ is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

HCTZ: HCTZis excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Femipres Plus during breast feeding is not recommended. If Femipres Plus is used during breast feeding, doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

There are no studies on the effect of this medicine on the ability to drive. When driving vehicles or operating machines it must be taken into account that occasionally dizziness or weariness may occur.

4.8 Undesirable effects

The frequencies of undesirable effects are defined as: 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, including isolated cases (< 1/10,000) not known: cannot be estimated from the available data a. The most commonly reported undesirable effects considered to be possibly or probably related to moexipril hydrochloride/HCTZ, occurring in more than 1% of the patients treated in controlled trials, were cough (3%), dizziness (3%), headache (2%), fatigue (2%) and hyperuricemia (2%). b. In general, the following undesirable effects have been observed associated with moexipril hydrochloride/HCTZ and are specified in the following table:

MedRA Very Common Uncommon Rare Very rare System Organ commo (≥ 1/100 to (≥ 1/1,000 to (≥ 1/10,000 to < including Class n < 1/10) < 1/100) 1/1,000) isolated cases (≥ 1/10) (< 1/10,000) Blood and anemia, neutropenia, hemoconcentration pancytopenia, lymphatic eosinophilia, (caused by HCTZ) agranulocytosi thrombocytopenia s system disorders (especially in patients with impaired renal *see also function or section d1) 12

MedRA Very Common Uncommon Rare Very rare System Organ commo (≥ 1/100 to (≥ 1/1,000 to (≥ 1/10,000 to < including Class n < 1/10) < 1/100) 1/1,000) isolated cases (≥ 1/10) (< 1/10,000) collagenosis or in patients, who simultaneously receive treatment with allopurinol, procainamide or medicinal products suppressing the immune system) Metabolism appetite loss, weight and nutrition loss disorders Psychiatric confusion, depression, disorders anxiety, nervousness

Nervous headache, convulsion, transient system dizziness numbness, ischemic disorders paraesthesia, balance attack (TIA), disturbance,drowsines ischemic s, sleep disturbances, stroke tingling sensations, alteration or loss of taste, paresis (caused by HCTZ induced hypokalemia)

Eye disorders vision disturbances (e.g. blurred vision), decreased production of tear fluid (caused by HCTZ)

Ear and tinnitus labyrinth disorders Cardiac myocardial disorders infarction, angina *see also pectoris, section c1) rhythm disorders, tachycardia, palpitations Vascular Hypotensio syncope embolism (caused by disorders n high doses of HCTZ inducing *see also hemoconcentration, section c2) d2)

Respiratory, cough *airway obstruction respiratory disorders pulmonary thoracic and due to like sinusitis, infiltrates, mediastinal angioneuroticedema pharyngitis, common asthma, disorders involving the tongue, cold (rhinitis) bronchospasm *see also glottis or larynx may , pulmonary section c3)d3) be fatal: for treatment edema see also section c3), (possibly bronchitis caused by an allergic

reaction to HCTZ) Gastrointestin digestive disorders, pancreatitis, al disorders upper abdominal ileus, *see also discomfort, stomatitis, section d4) dyspepsia, diarrhoea, glossitis, constipation, dryness of the meteorism, vomiting, mouth nausea

Hepato-biliary elevation of liver hepatitis, disorders enzymes and/or serum cholestatic bilirubin icterus, *see also disturbances section c4) of liver function Skin and *angioneuroticedema Stevens- subcutaneous (involving the lips, Johnson tissue face and/or syndrome, disorders extremities), urticaria, dermatitis *seealsosection pruritus*seealsosectio exfoliativa, c3) c5)d5) n c3)Respiratory, cutaneous thoracic and lupus

mediastinal disorders: erythematosus recommendations for (with HCTZ), treatment of airway toxic obstruction caused epidermal byangioneuroticedem necrolysis, a; pemphigus, allergic skin reactions erythema e.g. exanthema multiforme, skin reddening

Musculoskelet muscle cramps 14

Renal and polyuria, oliguria, acute renal failure, interstitial urinary system azotemia, deterioration of renal nephritis disorders function, proteinuria (abacterial) Acute renal failure has been reported in patients treated with ACE inhibitors including moexipril (see also section 4.4 Special warnings and special precautions for use) Reproductive impotence system and breast disorders General tiredness feeling of weakness thirst disorders and administration site conditions

Investigations decrease of increase of serum urea *seealsosection haemoglobin, (blood urea nitrogen) c6) haematocrit, white and serum creatinine, blood cell count, and hyperkalemia, platelet count hyponatremia (especially in patients (especially in patients with impaired renal with impaired renal function) function), increased proteinuria, increased

bilirubin, increased liver enzymes

c. This section includes information characterising individual serious and/or frequent adverse reactions, or those where there have been reports of particularly severe cases. Additionally, measures to be taken to avoid specific adverse reactions or actions to be taken, if specific adverse reactions occur, are mentioned below. Supplementary to section b. statements are provided, which particular adverse reaction is usually attributable to which component of the combination product moexipril hydrochloride/HCTZ: c1) Cardiac disorders: ECG changes and cardiac rhythm disorders may be a consequence of HCTZinduced hypokalemia.

15 c2) Vascular disorders: Hypotension caused by moexipril hydrochloride/HCTZ is experienced particularly by certain risk groups (see section 4.4 Special warnings and precautions for use). Symptomatic hypotension caused by moexipril hydrochloride/HCTZ may be associated with dizziness, feeling of weakness, perspiration, vision disturbances, and rarely with loss of consciousness (syncope). Careful monitoring of blood pressure is also recommended in patients with ischemic heart disease, aortic stenosis (see also section 4.3.Contraindications) and cerebrovascular disease, where an excessive hypotension could result in myocardial infarction or cerebrovascular accident. In case of excessive hypotension, the patient must be placed in a supine position and if necessary, fluid must be administered intravenously. Moexipril hydrochloride/HCTZ treatment usually can be continued following reconstitution of an adequate blood pressure and substitution of the fluid volume. c3) Respiratory, thoracic and mediastinal disorders: Angioneuroticedema has been reported in patients treated with ACEinhibitors including moexipril hydrochloride/HCTZ. Angioneuroticedema involving the tongue, glottis or larynx may be fatal due to airway obstruction. Emergency therapy must include intravenous administration of corticosteroids and antihistamines. If the condition of the patient does not ameliorate with the above mentioned therapy, adrenaline must be administered slowly intravenously monitored by ECG control.

In case of hereditary angioneuroticedema due to C1-inactivator deficiency associated with ACE inhibitor therapy, additionally a C1-inactivator must be administered.

Furthermore, intubation or tracheotomy must be considered. (See also section 4.4 Special warnings and precautions for use) c4)Hepatobiliary disorders: In case of significant increase of liver enzymes and in case of icterus, the ACE inhibitor therapy must be stopped and the patients must be monitored carefully. c5) Skin and subcutaneous tissue disorders: Cutaneous alterations caused by ACE inhibitors may be associated with fever, myalgia, arthralgia, vasculitis, serositis and changes in laboratory values (e.g. eosinophilia, leucocytosis, and/or elevation of ESR and/or ANA titres). In case of severe skin reactions a physician must be consulted and, if necessary, moexipril hydrochloride/HCTZ must be discontinued. c6) Investigations: An increase in serum potassium has been observed in patients with manifest diabetes mellitus. Potassium supplements and potassium sparing diuretics must be given with caution in patients with ACE inhibitors and the patient’s serum potassium must be monitored frequently.

HCTZ: Uncommon: hypokalemia, hyponatremia, hypochloremia, hypercalcemia (further diagnostics regarding hyperparathyroidism are considered as necessary) Rare: hyperglycemia, hypercholesterolemia, hypertriglyceridemia, hyperuricemia, increased amylase levels, hypomagnesemia, metabolic alkalosis, hypermagnesiuria, glucosuria. Important note: the above mentioned laboratory values must be monitored before and at regular intervals during the treatment with moexipril hydrochloride/HCTZ. Monitoring of the serum electrolytes, serum creatinine and blood values is indicated for a short period particularly at the start of treatment and in high risk patients (patients with impaired renal function, collagen diseases or patients treated with allopurinol, procainamide, digitalis glycosides, corticosteroids, laxatives or with medicinal products suppressing the immune system). d. In this section, class adverse reactions of ACE inhibitors are mentioned, which have not yet been observed in relation to moexipril hydrochloride/HCTZ: d1) Blood and lymphatic system disorders:

For haemolysis/haemolytic anaemia during treatment with ACE inhibitors - rarely associated with G-6-PDH deficiency - no causal relationship to ACE inhibitor therapy could be established. d2) Vascular disorders: Very rare increased vasospasm in Raynaud’s disease has been observed with ACE inhibitor therapy. d3) Respiratory, thoracic and mediastinal disorders: Very rare eosinophilic pneumonitis has been reported with the use of other ACE inhibitors. d4) Gastrointestinal disorders: Intestinal angioedema has been reported in patients treated with ACE inhibitors. For moexipril hydrochloride, so far, no intestinal angioedema has been reported (see also section 4.4 Special warnings and precautions for use). d5) Skin and subcutaneous tissue disorders: Very rare psoriasiform cutaneous alterations, photosensitivity, alopecia and onycholysis have been observed with ACEinhibitor therapy.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

To date, no case of overdose has been reported.

Symptoms of overdose would be severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure. No specific information is available on the treatment of overdose with moexipril hydrochloride/HCTZ. Treatment must be symptomatic and supportive.

After ingestion of an overdose the patient must be kept under close supervision, preferably in an intensive care unit. Serum electrolytes and creatininemust be monitored frequently. Therapeutic measures depend on the nature and severity of symptoms. Measurements to prevent absorption and hasten elimination such as administration of absorbents and sodium sulphate or gastric lavage must be applied if ingestion is recent, within 1 hour after intake. If hypotension occurs, the patient must be placed in a supine position and salt and volume supplementation must be given rapidly. Treatment with angiotensin II and/or intravenous catecholamines must be considered. Bradycardia or extensive vagal reactions must be treated by administering atropine intravenously. The use of a pacemaker may be considered. It is not yet known whether moexiprilat may be removed by haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic class: ACE-inhibitor and diuretic ATC code: C09BA13 – Moexipril and diuretics

Moexipril hydrochloride: Moexipril hydrochloride is a non-sulfhydryl, orally active, potent and specific competitive inhibitor of angiotensin converting enzyme (ACE). The beneficial effects of ACE inhibitors in hypertension appear to result primarily from the suppression of the plasma renin-angiotensin aldosterone system. Renin is an endogenous enzyme synthesized by the kidneys and released into the circulation where it converts angiotensinogen to angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by ACE, a peptidyldipeptidase, to angiotensin II.

Angiotensin II is a potent vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure, as well as for stimulation of aldosterone secretion by the adrenal gland. Inhibition of ACE results in decreased plasma angiotensin II levels, which lead to decreased vasopressor activity and to a small reduction in aldosterone secretion. In consequence, small increases in serum potassium concentrations may occur along with sodium and fluid loss. The lack of negative feedback by angiotensin II on renin secretion results in an increase in plasma renin activity.

Another function of ACE is to degrade the potent vasodepressor peptide bradykinin to inactive metabolites. Therefore inhibition of ACE results in an increased activity of circulating and local kinin levels which contribute to peripheral vasodilation by activating the prostaglandin and nitric oxide system. It is possible that this mechanism is involved in the hypotensive effect of ACE inhibitors but also may be responsible for certain adverse reactions.

In patients with hypertensionadministration of moexipril results in a similar reduction of supine and standing blood pressure with no compensatory increase in heart rate. Peripheral arterial resistance is reduced.

Although renal blood flow is increased, glomerular filtration rate is usually unchanged.

In most patients studied, onset of antihypertensive activity was seen at approximately 1 hour after oral administration of moexipril with peak reduction of blood pressure achieved at 3 – 6 hours. Maximum antihypertensive efficacy of moexipril was observed after 4 weeks of treatment and sustained during therapy for up to 24 months. At recommended single daily doses antihypertensive efficacy was maintained for at least 24 hours after dosing, although the effect at 24 hours was substantially smaller than at 4 hours after dosing. Abrupt withdrawal of therapy was not associated with a rapid rebound increase in blood pressure.

Moexipril is effective even in patients with low-renin hypertension. Although antihypertensive effects have been observed in all races studied, black hypertensive patients had a smaller average response to moexiprilmonotherapy than non-black patients.

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

HCTZ: Although the exact mechanism of the antihypertensive effect of thiazides is unknown, the diuretic HCTZhas been shown to be an antihypertensive agent. It affects the distal renal tubular mechanism of electrolyte reabsorption and thus increases excretion of sodium and chloride in approximately equivalent amounts. The natriuresis causes a secondary loss of potassium and bicarbonate. Indirectly, the diuretic action of HCTZreduces plasma volume with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss as well as decreases in serum potassium. The renin-aldosterone link is mediated by 18 angiotensin. Therefore, co-administration of an ACE-inhibitor like moexipril hydrochloride tends to reverse the potassium loss seen during treatment with HCTZ.

After oral administration diuresis begins within 2 hours, peaks at 3 – 6 hours and lasts for about 6 – 12 hours. Antihypertensive efficacy of HCTZstarts 3- 4 days after beginning of treatment and may continue up to 1 week after cessation.

Moexipril hydrochloride/HCTZ: The usual daily dose of moexipril hydrochloride/HCTZ is 7.5mg moexipril hydrochloride/12.5mg hydrochlorothiazide or 15 mg moexipril hydrochloride/25mg HCTZ. Doses above 15mg moexipril hydrochloride/25mg HCTZare generally not recommended. A clinical trial has shown that, if the dose was further increased to 30mg moexipril hydrochloride/50mg HCTZper day, the antihypertensive effect seen was comparable to the antihypertensive effect after the administration of 15mg moexipril hydrochloride/25mg HCTZ.

Patients whose blood pressure is adequately controlled with 25mg HCTZdaily, but who experience significant potassium loss with this regimen, may achieve comparable blood pressure control with less electrolyte disturbance if they are treated with 7.5mg moexipril hydrochloride/12.5mg HCTZ.

Use of Femipres Plus in special populations Patients with isolated systolic hypertension have not been studied separately.

Moexiprilmonotherapy (like treatment with other ACE inhibitors) is less effective in blacks than in non- blacks. However, in the 6% black patients treated with moexipril hydrochloride/HCTZ in clinical trials the antihypertensive effect was comparable to that of the whole population.

5.2 Pharmacokinetic properties

Moexipril hydrochloride: The prodrug moexipril is rapidly absorbed and de-esterified to the active metabolite moexiprilat. The pharmacokinetic parameters for moexipril and moexiprilat were similar after both single and multiple doses of moexipril and appeared to be dose-proportional over the dose range of 3.75mg to 30mg moexipril.

Moexipril and moexiprilat are moderately bound to plasma proteins (50 – 70%), predominantly albumin. Therefore, concurrently administered medicinal products are unlikely to interfere with a binding of moexipril and moexiprilat in any clinically significant way. Peak plasma concentration of moexiprilat is detected after about 1.5half-life hours and elimination half-life is estimated at about 10 hours. Like all ACE-inhibitors moexipril has a prolonged terminal elimination phase presumably reflecting slow release of drug bound to the ACE.

Moexipril and its metabolites are eliminated in the urine and in the faeces. After oral administration 52% of the dose is recovered in the faeces as moexiprilat. Only 1–2% appear in urine as unchanged moexipril.

For patients with liver cirrhoses the pharmacokinetics of moexipril and moexiprilat are significantly altered as compared with normal subjects.

HCTZ: After oral administration hydrochlorothiazide is absorbed to 60 – 80%. Its apparent volume of distribution is 3.6-7.8 l/kg and its measured plasma protein binding is approximately 65%.

HCTZis not metabolized. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least, 50-70% of the oral dose is eliminated unchanged by kidney within 24 hours.

In patients with impaired renal function, the half-life of HCTZelimination was lengthened to 21 hours.

Moexipril hydrochloride/HCTZ: The pharmacokinetic parameters of moexipril and HCTZwere unchanged when both medicinal products were co-administered.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies on single and repeated dose toxicity, genotoxicity, carcinogenic potential and safety pharmacology. No teratogenic properties were observed in any of the reproduction studies. At higher doses, there were maternally toxic effect, with an increase in resorptions, mainly in rabbits. Angiotensin converting enzyme inhibitors, as a class, have been shown to be foetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester. Regarding possible reproductive toxic effects: see section 4.3 and 4.6.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The core of the tablet contains: lactose monohydrate; crospovidone, light magnesium oxide, gelatin, magnesium stearate. The film-coat contains: hypromellose, hydroxypropylcellulose, macrogol 6000, magnesium stearate, titanium dioxide (E171), ferric oxide yellow (E172).

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25C. Store in the original package.

6.5 Nature and contents of container

Packs containing 14 film coated tablets, 7 per blister strip.

Blister strips comprising moulded side consisting of soft aluminium foil coated with polyamide on the outside and with PVC-foil, hard on the inner side. Non-moulded side of hard aluminium foil.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

[to be completed locally]

8. MARKETING AUTHORISATION NUMBER(S)

[to be completed locally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[to be completed locally]

10. DATE OF REVISION OF THE TEXT

[to be completed locally]

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton box

1. NAME OF THE MEDICINAL PRODUCT

Femipres Plus 15 mg/25 mg film coated tablets moexipril hydrochloride hydrochlorotiazide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film coated tablet contains: Active substance: moexipril hydrochloride 15 mg hydrochlorotiazide 25 mg

3. LIST OF EXCIPIENTS

Contains also lactose. Read the package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

14 film coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP. The expiry date refers to the product unopened, properly stored.

9. SPECIAL STORAGE CONDITIONS

Do not store above 25°C Store in the original container.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

Do not waste the product in the environment after use.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

12. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

13. BATCH NUMBER

Batch n.

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Femipres Plus 15 mg/25 mg

MINIMUM PARTICULARS TO APPEAR ON BLISTERS

PVC/Al blister

1. NAME OF THE MEDICINAL PRODUCT

Femipres Plus 15 mg/25 mg film coated tablets moexipril hydrochloride/hydrochlorotiazide

2. NAME OF THE MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

3. EXPIRY DATE

EXP.

4. BATCH NUMBER

Batch n.

5. OTHER

PACKAGE LEAFLET

Package leaflet: Information for the user

Femipres Plus 15mg/25mg film coated tablets

Moexipril hydrochloride/hydrochlorotiazide (HCTZ)

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or pharmacist.This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet 1. What Femipres Plus 15mg/25mg is and what it is used for 2. What you need to know before you take Femipres Plus 15mg/25mg 3. How to take Femipres Plus 15mg/25mg 4. Possible side effects 5. How to store Femipres Plus 15mg/25mg 6. Contents of the pack and other information

1. What Femipres Plus 15mg/25mg is and what it is used for

Femipres Plus is a combination of two medicines: - moexipril - hydrochlorothiazide.

Moexipril belongs to a group of medicines called Angiotensin Converting Enzyme (ACE) inhibitors. ACE inhibitors work by widening your blood vessels. This makes it easier for your heart to pump blood around your body and helps lower your blood pressure.

Hydrochlorothiazide (HCTZ) belongs to a group of medicines called thiazide diuretics. Diuretics work by increasing the volume of urine you produce. Diuretics are sometimes called ‘water tablets’. Diuretics reduce the water content of your blood and the volume of blood circulating in your body. This can help lower your blood pressure.

Therapeutic indications

Femipres Plus is used to treat high blood pressure (hypertension) in adult patients who need a combination of drugs to treat their condition. Normally you would not be given Femipres Plus as your first treatment for high blood pressure. Your doctor will probably have first tried to treat your condition with other individual drugs. Your doctor has decided that a fixed combination of these two drugs would be better for you.

2. What you need to know before you take Femipres Plus15mg/25mg

Do not take Femipres Plus:  If you are allergic (hypersensitive) to:  moexipril hydrochloride or hydrochlorothiazide or other sulphonamide-derived drugs  any other ingredients of Femipres Plus (these are listed in section 6 Contents of the pack and other information).  If you have suffered from red, itchy swelling (angioedema) of the face, lips, tongue or throat (angioneurotic oedema) after previous treatment with a ACE inhibitor

 If you or a member of your family have ever suffered from angioneurotic oedema even if the cause is not known (hereditary/idiopathic angioedema)  If you suffer from renal problems: narrowing of the renal artery (bilateral or anatomic or functional solitary kidney)  If you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren  If you are more than 3 months pregnant (it is also better to avoid Femipres Plus in early pregnancy – see pregnancy section)  If you suffer from severe kidney problems. For example if:  your kidney function is severely impaired (your creatinine clearance is less than 40 ml per minute)  you do not produce any urine  If you have recently had a kidney transplant  If your body produces too much of a hormone called aldosterone (primary aldosteronism)  If you suffer from a low concentration of potassium (hypokalaemia), sodium (hyponatraemia) or a high concentration of calcium (hypercalcaemia) in your blood that does not respond easily to treatment  If you suffer from high concentration of uric acid (hyperuricaemia) in the blood which causes symptoms such as painful joints (gout)  If your blood is being cleaned by an artificial kidney machine (on dialysis)  If you suffer from severe hepatic impairment  If yousuffer from heart problems: narrowing of the valves in the heart (aortic stenosis/mitral stenosis); thickening of the heart muscle (hypertrophic cardiomyopathy)  If you are a child.

To avoid the risk of life-threatening allergic (anaphylactic) reactions ACE inhibitors must not be used:  When you are having your blood fat (lipid) levels controlled using a method called low-density lipoprotein (LDL) apheresis  When you are receiving vaccinations to reduce the effects of an allergic reaction, e.g. to bee or wasp stings (desensitisation therapy).

Warnings and precautions Talk to your doctor or pharmacist before taking Femipres Plus

Please tell your doctor if you are suffering or have ever suffered from any of the following conditions or illnesses:

 if you are taking any of the following medicines used to treat high blood pressure: - an angiotensin II receptor blocker (ARBs) (also known as sartans - for example valsartan, telmisartan, irbesartan), in particular if you have diabetes-related kidney problems - aliskiren

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Femipres Plus”

Hypotension (low blood pressure) Femipres Plus may cause a very large fall in your blood pressure (hypotension) especially when you first start this type of treatment. Symptoms of hypotension are:  Dizziness  Feeling of weakness  Sweating (perspiration)  Disturbances of vision  Fainting (syncope) in rare cases. This is more likely to happen if:

 Your body has less water than it needs to work normally (dehydration) because your blood volume has been reduced due to:  water tablets (diuretic therapy)  a low-salt diet  runny stools (diarrhoea) or being sick (vomiting)  You are on dialysis  You have severe heart failure (when the heart cannot pump enough blood) with or without kidney problems (renal insufficiency).  You are alreadytaking either of the following classes of medicines used to treat high blood pressure:  an angiotensin converting enzyme inhibitor such as enalapril, lisinopril, ramipril, etc;  an angiotensin receptor blocker such as valsartan, telmisartan, irbesartan, etc;  a renin inhibitor called aliskiren. Your blood pressure may get too low (hypotension) when you start treatment with Femipres Plus if you have any of these conditions. Before you take Femipres Plus your doctor will need to correct any dehydration and salt deficiency.

If you develop low blood pressure (hypotension) you should lie down and ask someone to inform your doctor.

Kidney disease (impaired renal function) If you have mild to moderate kidney disease (if your creatinine clearance is above 40 but below 60 ml per minute) your doctor will check your kidney function regularly. Your doctor may give you a lower or less frequent dose of Femipres Plus. Femipres Plus should be stopped if you have an impaired renal function (if your creatinine clearance is below 60 ml per minute) and you are treated with aliskiren, a renin inhibitor used to treat high blood pressure.

Liver disease (hepatic disease) Thiazide medicines can cause liver coma and ACE inhibitor medicines have rarely been known to cause a severe liver reaction. This starts with stoppage of the flow of bile (cholestatic jaundice) or inflammation of the liver (hepatitis). This can lead to death of liver tissue (fulminant necrosis) and can sometimes be fatal. If you develop a yellowing of the skin or eyeballs (jaundice) you should stop taking Femipres Plus and see your doctor immediately.

Angioneuroticedema Angioedema (swelling of face, lips, tongue and throat and of the extremities) may occur, especially during the first weeks of treatment. In rare cases, severe angioneuroticedema may occur after long-term treatment with ACE inhibitors. Angioedema involving the tongue and throat can be fatal. If you have sudden swelling of face, lips, tongue or throat you should:  stop taking Femipres Plus immediately  call your doctor or go to your nearest emergency department

Your doctor will give you another type of medicine.

Intestinal angioneuroticedema Intestinal angioneuroticedema (abdominal pain with or without nausea and vomiting) may occur during the treatment with ACE inhibitors. Contact your doctor if you experience symptoms such as abdominal pain with or without nausea and vomiting.

Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Femipres Plus is not recommended in early pregnancy and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Cough 29

You may develop a dry and non-productive cough. This disappears when you stop taking Femipres Plus.

Elderly The doctor will control your renal function before and during the therapy with Femipres Plus if you are an elderly patient.

Electrolyte imbalances You must not take any potassium supplements or salts substitutes containing potassium without having talk to your doctor. Treatment with thiazide diuretics such as hydrochlorothiazide can cause:  Low blood sodium (hyponatraemia)  Low blood potassium (hypokalaemia)  Low blood chloride and low blood acidity (hypochloraemic alkalosis)  Low blood magnesium (hypomagnesaemia)  Low blood phosphate (hypophosphataemia)  High blood calcium (hypercalcaemia)  High blood uric acid levels (hyperuricaemia). This causes gout (pain in the joints).

Your doctor will watch for signs of fluid or electrolyte imbalance and will treat you if necessary. Warning signs of fluid or electrolyte imbalance are:  Dry mouth  Thirst  Weakness  Sluggishness (lethargy)  Drowsiness  Restlessness  Muscle pain or cramps  Muscular fatigue  Low blood pressure (hypotension)  Decreased urine production (oliguria)  Rapid heart beat (tachycardia)  Feeling sick (nausea) or being sick (vomiting).

High blood sugar (diabetes mellitus) Your doctor may need to change the dose of insulin or other medicines you are taking for diabetes.

Surgery and anaesthesia Femipres Plus can cause your blood pressure to fall (hypotension) during surgery or anaesthesia. If you are having an operation, it is very important to tell your doctor that you are taking Femipres Plus.

Heart problems (severe congestive heart failure): If you have a severe congestive heart failure, your doctor will watch your treatment with Femipres Plus more carefully because this treatment may be associated with decreased urine production (oliguria), urea in the blood (azotemia) with (rarely) acute failure and/or death.

Low numbers of neutrophils (neutropenia)/dangerously low white blood cell count (agranulocytosis) You should let your doctor know if you have:  a decreased immune response  a collagen vascular disease such as systemic lupus erythematosus (SLE) or scleroderma. SLE is a disease where your own immune system attacks your body. Scleroderma is hardening of the skin and blood vessels. Other ACE inhibitor medicines can cause a dangerously low white blood cell count (agranulocytosis) and bone marrow depression. This is more common if you have kidney disease, especially if you also have SLE

30 or scleroderma. Bone marrow depression is the reduced activity of the production of new blood cells. This can lead to neutropenia (a low number of white blood cells called neutrophils). This can mean you may get infections more easily.

It is possible that Femipres Plus can also cause neutropenia and agranulocytosis.

Proteinuria You may develop protein in the urine (proteinuria), especially if you have kidney disease or if you are treated with a high dose of Femipres Plus.

Cholesterol / blood lipids Certain lipids in the blood (cholesterol and triglycerids) may be raised when you are treated with Femipres Plus.

Systemic lupus erythematosus (SLE) Femipres Plus may start off, or make this disease worse.

Lithium Lithium is used to treat mental disorders. Please inform your doctor if you are being treated with Lithium.

Acute Myopia and Secondary Angle-Closure Glaucoma Femipres Pluscontains a sulfonamide called hydrochlorothiazide, which can cause certain eye problems (myopia, angle-closure glaucoma). If these eye problems occur, symptoms usually occur within hours to weeks of startingFemipres Plus. Contact your doctor right away if you experience symptoms such as vision changes (eg, decreased vision clearness) or eye pain.Untreated angle-closure glaucoma can lead to permanent vision loss. Your risk may be increased if you are allergic to sulfonamide medicines or to penicillin antibiotics.

Etnicity Your medicine may be less effective if you are black. If you are black you are also at higher risk of angioedema and cardiovascular disease.

Anti-doping test In case of any sport activity: the use of this medicinal product in the absence of a therapeutic need is doping and might cause positivity to anti-doping test.

Children Children must not take Femipres Plus.

Other medicines and Femipres Plus Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines given without a prescription, natural remedies and strong vitamins and minerals.

Your doctor may need to change your dose and/or to take other precautions: If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings “Do not take Femipres Plus” and “Warnings and precautions”).

Medicines which may interact with Femipres Plus 15mg/25mg  Potassium-sparing diuretics or potassium supplements  Lithium (for mental disorders)  Drugs used for surgery (anaesthetics)  Strong pain killers (narcotic drugs)  Medicines for mental illness (antipsychotics, e.g. haloperidol)  Medicines used to treat high blood pressure (antihypertensive agents)

 Drugs containing allopurinol (used to treat gout)  Drugs that suppress the body’s immune defences (immunosuppressive agents)  Anti-inflammationdrugs (systemiccorticosteroids)  Drugs for irregular heart rhythm  Non-steroidal anti-inflammatorymedicinalproducts (e.g. ibuprofen, diclofenac)  Antacids  Drugs that stimulate part of your nervous system (sympathomimetics e.g. pseudoephedrine)  Any medicine containing alcohol (e.g. cough syrup)  Medicines used to treat high blood sugar (antidiabetic agents)  Vitamin D or calcium salts  High doses of salicylates (used as painkillers)  Water tablets that increase the potassium in your urine (kaliuretic diuretics e.g. furosemide)  Glucocorticoids (hormones)  Adrenocorticotropic hormone (ACTH)  Carbenoxolone: a medicine for treating stomach ulcers  Amphotericin B: a medicine used to treat fungal infections  Penicillin G: an antibiotic  Medicines used to help empty your bowels (laxatives)  Muscle relaxants used during operations (non-depolarizing skeletal muscle relaxants)  Certain medicines used to treat Parkinson’s disease (amantadine, anticholinergic agents e.g. biperiden)  Catecholamines (e.g. epinephrine)  A type of cancer drug called cytostatic agents (e.g. cyclophosphamide, fluorouracil, methotrexate)  Medicinal products known to cause a type of rapid heartbeat called ‘torsades de pointes’ (e.g. astemizole, bepridil, intravenous erythromycin, halofantrine, sultopride, terfenadine, vincamine.) Femipres Plus may increase the risk to experience such ‘torsades de pointes’.  Medicines used to treat heart failure (digitalis glycosides e.g. digitoxin)  A medicine called methyldopa used to treat high blood pressure  Certain medicines used to lower cholesterol levels (e.g. cholestipol/cholestyramine)  Dyes used in imaging techniques such as X-rays (iodinated contrast media)  Sodiumaurothiomalate (gold), a medicine to inject against rheumatoid arthritis.  Agents that affects the Renin-Angiotensin System such as angiotensin receptor blockers(e.g. valsartan, telmisartan, irbesartan, etc.), other ACE inhibitors (e.g. enalapril, lisinopril, ramipril, etc.)or aliskiren.  Epoetins

Femipres Plus 15mg/25mg with food and drink  Common salt may reduce the blood pressure lowering effect of Femipres Plus.  When you take this medicine while eating, the blood lowering effect of Femipres Plus may be reduced.  Do not drink alcohol whilst taking this medicine. Alcohol can increase the blood pressure lowering effect.

Pregnancy and breast-feeding If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Femipres Plus before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Femipres Plus. Femipres Plus is not recommended during pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast feeding

Tell your doctor if you are breast feeding or about to start breast feeding. Femipres Plus is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines Femipres Plus can cause dizziness, fainting and tiredness. This is more likely to occur at the start of treatment, when your dose is changed, or if you drink alcohol. Do not drive or operate machinery until this effect has worn off.

Femipres Plus 15mg/25mg contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take Femipres Plus15mg/25mg

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is 1 tablet Femipres Plus 15mg/25mg per day in the morning with a glass of water.

Taking your tablets at the same time each day will have the best effect on your blood pressure. It will also help you to remember when to take the tablets.

Elderly

If you are over 65 years of age your doctor may advise you to take lower doses of the active substances of Femipres Plus 15mg/25mg.

Patients with kidney problems

If you suffer from severe kidney disease you must not take Femipres Plus.

If you suffer from mild to moderate kidney disease your doctor may advise you to take lower doses of the active substances of Femipres Plus 15mg/25mg.

If you take more Femipres Plus 15mg/25mg than you should If you accidentally take too many tablets, contact your doctor or go to your nearest hospital casualty department immediately for advice. Please tell them that you are taking Femipres Plus 15mg/25mg.

The following symptoms may occur after an overdose:  Very low blood pressure (severe hypotension)  Shock  Stupor (loss of consciousness)  Very slow heart rate (bradycardia)  Disturbances of the salts (electrolytes e.g. sodium, potassium) in the blood  Kidney failure (when the kidneys cannot produce enough urine)

If you forget to take Femipres Plus15mg/25mg Do not take a double dose to make up for a forgotten individual dose.

If you stop taking Femipres Plus15mg/25mg Do not stop treatment early without first talking to your doctor. Stopping treatment early can lead to a sudden rise in blood pressure. This can lead to headache or even heart attack or stroke.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 33

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequencies of undesirable effects are defined as: very common (≥ 1/10) common (≥ 1/100 to < 1/10) uncommon (≥ 1/1000 to < 1/100) rare (≥ 1/10000 to < 1/1000) very rare including isolated cases (< 1/10000) not known cannot be estimated from the available data

Common side effects  Cough  Dizziness  Headache  Low blood pressure (hypotension). Symptoms include dizziness, feeling of weakness, sweating (perspiration), vision disturbances, and rarely, fainting (syncope).

Uncommon side effects  Reduction of red blood cells which can make the skin pale and cause weakness or breathlessness (anaemia)  Reduced numbers of a type of white blood cells called neutrophils (neutropenia)  Increased numbers of blood cells called eosinophils (eosinophilia)  Reduced numbers of the blood cells called platelets or thrombocytes (thrombocytopenia) especially if you have kidney disease or collagen disease, or if you are given treatment with allopurinol, procainamide or drugs suppressing the immune system  Loss of appetite  Weight loss  Fainting (syncope)  Swelling of the lips, face and/or extremities (angioneurotic oedema)  Airway obstruction due to angioneurotic oedema involving the tongue, vocal chords (glottis) or voice box (larynx). This may be fatal.  Inflammation of the airways (bronchitis)  Digestive disorders  Upper abdominal discomfort  Indigestion (dyspepsia)  Diarrhoea  Constipation  Excess gas (meteorism)  Being sick (vomiting)  Feeling sick (nausea)  Urticaria (hives)  Itching (pruritus)  Allergic skin reactions (e.g. exanthema)  Increased urine production (polyuria)  Decreased urine production (oliguria)  Excess of nitrogen-containing compounds e.g. urea in the blood (azotemia)  Feeling tired (fatigue)

Rare side effects  Haemoconcentration 34

 Confusion  Feeling very sad or low (depression)  Anxiety  Nervousness  Seizures (convulsions)  Tingling sensations or numbness in the hand or feet (paraesthesia)  Balance disturbance  Drowsiness  Sleep disturbances  Altered taste, or loss of taste  Slight paralysis (paresis)  Vision disturbances (e.g. blurred vision)  Decreased production of tear fluid  Ringing in the ears (tinnitus)  Blockage of a blood vessel with a clot from another part of the body (embolism), especially in older patients suffering from poor circulation in the veins  Blood clot in a blood vessel (thrombosis)  Shock (vascular collapse)  Inflammation of the sinuses (sinusitis)  Inflammation of the throat (pharyngitis)  Common cold (rhinitis)  Raised blood levels of liver enzymes and/or bilirubin (indicators of liver function)  Muscle cramps  Muscle pain (myalgia)  Sudden kidney failure (acute renal failure)  Deterioration of kidney function  Proteins or increased levels of proteins found in urine, e.g. albumin (proteinuria)  Inability to maintain an erection (impotence)  Feeling of weakness  Decreased levels of sodium in the blood (hyponatraemia), especially if you have kidney disease  Increased levels of urea (blood urea nitrogen) in the blood (uraemia)  Increased levels of creatinine in the blood  Increased levels of potassium in the blood (hyperkalaemia)

Very rare side effects  Low numbers of red cells, white cells and platelets at the same time (pancytopenia)  Dangerously low white blood cell count (agranulocytosis)  Temporary stroke sometimes called a ‘mini stroke’ (transient ischaemic attack, TIA)  Loss of brain function due to loss of blood supply (ischaemic stroke)  Heart attack (myocardial infarction)  Chest discomfort caused by poor blood flow through the blood vessels of the heart muscle (angina pectoris)  Abnormal heart rhythms (rhythm disorders)  Abnormally fast heart rate (tachycardia)  Feeling your heartbeat (palpitations)  Inflammation of the lungs (pulmonary infiltrates)  Inflammatory disorder of the airways, which causes shortness of breath, chest tightness and coughing (asthma)  Sudden tightening of the airways causing difficulty in breathing (bronchospasm)  Fluid in the lungs (pulmonary oedema)  Inflammation of the pancreas (pancreatitis)  Intestinal obstruction (ileus)  Inflammation of the mouth (stomatitis)  Tongue inflammation (glossitis)

 Dryness of the mouth (xerostomia)  Inflammation of the liver (hepatitis)  Yellowing of the skin and/or of the whites of the eyes (cholestatic icterus)  Disturbances of liver function  Severe skin disorders including Stevens-Johnson syndrome  Scaling of the skin, often with itching and skin redness (dermatitis exfoliativa)  Cutaneous lupus erythematosus. You may get any of the following symptoms with a skin reaction:  Fever, muscle pain (myalgia), joint pain (arthralgia), inflamed blood vessels (vasculitis), serositis (inflammation of the membranes around the heart and lungs), increased numbers of blood cells called eosinophils (eosinophilia), increased numbers of white blood cells (leukocytosis) and/or increased erythrocyte sedimentation rate (ESR: this is a blood test to measure inflammation) and/or antinuclear antibodies in the blood (ANA titres: these are antibodies against your own cells).  A very serious skin disorder that causes the loss of large areas of skin (toxic epidermal necrolysis)  Blistering rash (pemphigus)  An allergic skin reaction causing spots, red welts or purple or blistered areas. It can also affect the mouth, eyes and other moist body surfaces (erythema multiforme)  Skin reddening  Inflammation of the kidneys not caused by bacteria (abacterial interstitial nephritis)  Thirst.

Reporting of side effects If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible sideeffects not listed in this leaflet. You can also report side effects directly via the national reportingsystem listed in Appendix V. By reporting side effects you can help provide more information on thesafety of this medicine.

5. How to store Femipres Plus15mg/25mg

Keep this medicine out of the sight and reach of children.

Do not store above 25°C.

Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.

Store in the original package.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Femipres Plus 15mg/25mg contains

The active substances are:  moexipril hydrochloride 15 mg  hydrochlorothiazide 25 mg The core of the tablet contains: lactose monohydrate; crospovidone, light magnesium oxide, gelatin, magnesium stearate. The film-coat contains: hypromellose, hydroxypropylcellulose, macrogol 6000, magnesium stearate, titanium dioxide (E171), ferric oxide yellow (E172).

What Femipres Plus 15mg/25mg looks like and contents of the pack

Femipres Plus film-coated tablets are yellowish and oval shaped, with a white core. They have a break score on one side and in the band. They are engraved on the upper side with ‘SP’ and on the lower side with ‘725’.

Femipres Plus 15 mg/25 mg film-coated tablets are available in PVC/aluminium blister packs containing: 14 tablets.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder: [to be completed locally]

Manufacturer: Aesica Pharmaceuticals GmbH Alfred Nobel Strasse, 10 D-40789 Monheim Germany

This leaflet was last revised in {month YYYY}.