SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT ADAPTUS/DELAMAN 30 mg + 10 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30 mg of delapril hydrochloride and 10 mg of manidipine hydrochloride. Excipients with known effect: 67.60 mg lactose monohydrate/tablet 0.08 mg sunset yellow (E110) Aluminum lake/tablet

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Tablet. Salmon-pink, round, scored tablet. The tablet can be divided into equal doses

4. CLINICAL PARTICULARS

4.1 Therapeutic indications Treatment of essential hypertension. ADAPTUS/DELAMAN fixed dose combination (30 mg /10 mg) is indicated in patients whose blood pressure is not adequately controlled on delapril or manidipine alone (see section 4.3, 4.4, 4.5 and 5.1)

4.2 Posology and method of administration Posology Dosage recommendations for adults The usual posology is one tablet of ADAPTUS/DELAMAN once a day. Individual dose titration with the components (delapril 30 mg and manidipine 10 mg) is recommended. If clinically acceptable, a direct switch from delapril or manidipine monotherapy to the fixed combination may be considered (see section 4.3, 4.4, 4.5 and 5.1). Special care should be exercised when ADAPTUS/DELAMAN is used in elderly patients and patients with renal failure or hepatic insufficiency and dose titration should be performed using the single components delapril and manidipine according to the following approach:

Elderly patients: considering the possible impairment of renal function and the slowing down of metabolic processes in elderly patients; dose titration must be approached with caution. After appropriate dose titration with the components, the direct switch to half a tablet of the fixed combination may be considered.

Renal impairment: since in the presence of renal failure a reduced excretion of the component delapril occurs, dose adjustments are needed in patients with serum creatinine >3 mg/dl;

Hepatic impairment: due to the wide hepatic metabolization of the component manidipine, a dose reduction should be considered in patients with hepatic insufficiency, according to the severity of the concomitant disorder;

Pediatricpopulation:

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ADAPTUS/DELAMAN is contraindicated in children and adolescents (see section 4.3 and 4.4);

Method of administration: For oral use. The tablet should be swallowed whole with sufficient water in the morning after breakfast.

4.3 Contraindications  Hypersensitivity to the active substances ‘delapril’ and ‘manidipine’, to any other ACE inhibitors and to other dihydropyridines or to any of the excipients listed in section 6.1.  History of angioneurotic oedema associated with previous ACE inhibitor therapy.  Hereditary/idiopathic angioneurotic oedema.  Severe renal impairment (creatinine clearance  10 ml/min).  Dialysis.  Kidney transplantation.  Severe hepatic impairment.  Bilateral renal artery stenosis or unilateral renal stenosis in cases of a solitary kidney.  Hemodynamically relevant aortic and mitral valve stenosis/hypertrophic cardiomyopathy.  Cardiogenic shock.  Untreated congestive heart failure.  Unstable angina pectoris or myocardial infarction (during first 4 weeks).  Primary hyperaldosteronism.  Second and third trimester of pregnancy (see section 4.4 and 4.6).  Use in children and adolescents ( 18 years).  The concomitant use of ADAPTUS/DELAMAN with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).  Concomitant use with sacubitril/valsartan therapy. ACE inhibitors must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 4.5).

4.4 Special warnings and special precautions for use Symptomatic hypotension: At the beginning of the treatment with ADAPTUS/DELAMAN, patients with increased risk of symptomatic hypotension should be closely monitored for the first two weeks of treatment. The risk of a marked hypotensive response is more probable in some categories of patients, such as those with severe congestive heart failure with or without concomitant renal failure, renovascular hypertension, renal dialysis, intense saline and/or water retention of any aetiology (e.g. intense therapy with loop- diuretics). Sodium depletion and hypovolaemia must be corrected before treatment with ADAPTUS/DELAMAN can be initiated. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. Blood pressure and laboratory parameters should be carefully monitored, especially in patients with: - sodium depletion or hypovolaemia - severe cardiac decompensation - renal impairment - severe hypertension - or older than 65 years In these patients therapy should preferably be initiated in a hospital setting. In case of hypotension, it is recommended to lay the patient in supine position and, if necessary, to administer saline solution by intravenous infusion.

Paediatric population:

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The product is not to be used in children and adolescents on account of inadequate experience in this patient population.

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).

General: Adaptus/Delaman contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Adaptus/Delaman contains sunset yellow (E110 aluminium lake, which may cause allergic reactions).

Patients with renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ADAPTUS/DELAMAN. Treatment with diuretics may be a contributory factor. A renal function reduction may occur even with minor changes in serum creatinine also in patients with unilateral renal artery stenosis. In these patients the treatment should be initiated in hospital under close medical supervision, starting with low doses of the single components followed by a careful dose titration. Diuretic treatment should be discontinued and renal function should be monitored during the first weeks of treatment.

Angioedema: Some cases of angioedema have been reported with the use of ACE inhibitors, especially after the first administrations. Angioedema may occur during the first weeks of treatment. In rare cases, however, angioedema may occur after long-term use. In these cases, treatment should be immediately discontinued and if necessary, antihypertensive therapy should be continued using a drug belonging to an other therapeutic class. The patient should be kept under strict medical control until the oedema disappears. When the oedema is limited to face and lips, this condition is generally resolved without any treatment, though antihistamines are useful as symptomatic treatment. Angioedema involving the tongue, glottis or larynx can be lethal and therefore it requires the prompt institution of suitable therapies, such as the subcutaneous injection of a 1:1000 adrenaline solution (0.3-0.5 ml). Therefore, patients should be duly informed about the importance to promptly report any sign or symptom resembling angioedema (swelling of face, eyes, lips, tongue, difficult breathing) and they should consult the physician before any further drug administration.

Anaphylactic reactions during hymenoptera desensitisation: Rarely patients receiving ACE-inhibitors have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each desensitisation.

Anaphylactoid reactions during LDL aphaeresis: Rarely patients receiving ACE inhibitors during low-density lipoprotein (LDL) aphaeresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each aphaeresis.

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Ethnic differences: ACE-inhibitors more often cause angioedema in black patients than in non-black patients. As with other ACE inhibitors, ADAPTUS/DELAMAN may be less effective in lowering blood pressure in black patients than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Proteinuria: Proteinuria may occur, particularly in patients with existing renal function impairment.

Impaired renal function: in the presence of renal failure, dose adjustments are necessary and renal function must be carefully monitored, even though generally it does not undergo any further worsening. Under treatment with ACE inhibitors, patients with previous congestive heart failure, mono- or bilateral stenosis of the renal artery, renovascular hypertension and intense water or saline depletion, are at higher risk to develop signs of renal impairment (creatinine increase, BUN and serum potassium; proteinuria; alterations of urine volume) and, seldom, acute renal failure. Although not reported with ADAPTUS/DELAMAN, mild increases in BUN and creatinine are occasionally possible even in patients with normal renal function, in particular if under concomitant treatment with diuretics. Should these cases occur, the interruption of the possible diuretic therapy or the reduction or discontinuation of ADAPTUS/DELAMAN are advisable (see also sections 4.2 and 4.3).

Patients under dialysis: In patients treated with ACE inhibitors, anaphylactic-like reactions have been observed during haemodialysis with polyacrylonitrile high-flow membranes (AN69). Therefore, the use of this type of membranes is not recommended in patients treated with ADAPTUS/DELAMAN.

Primary hepatic disease/hepatic failure: Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not known. Patients receiving ADAPTUS/DELAMAN who develop jaundice or marked elevations of hepatic enzymes should discontinue treatment and receive appropriate medical care.

Diabetic patients: In diabetic patients treated with oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first months of treatment with an ACE inhibitor.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Serum potassium: ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, cardiac failure, diabetes mellitus, hypoaldosteronism, impaired renal function and/or patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics or other active substances associated with increases in serum potassium (e.g. trimethoprim or co-trimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers). Potassium supplements or potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5).

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Cough: During treatment with ACE inhibitors, dry and non-productive cough might occur, which disappears with therapy discontinuation. ACE inhibitors-induced cough should be considered as part of the differential diagnosis of cough.

Surgery-anesthesia: ADAPTUS/DELAMAN can strengthen the hypotensive effects of anaesthetic drugs. Hypotension that occurs in these cases can be corrected by expanding volaemia and parenterally rehydrating the patient.

Neutropenia/agranulocytosis: Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. ADAPTUS/DELAMAN must be used with extreme caution in patients with collagen vascular disease, e.g. systemic lupus erythematosus, scleroderma, with immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially in case of pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If ADAPTUS/DELAMAN is used in such patients, regular monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection. The effects are reversible after discontinuation of the ACE inhibitor.

Impaired hepatic function: ADAPTUS/DELAMAN should be cautiously used in patients with hepatic insufficiency, since manidipine antihypertensive effect might be strengthened (see also “Posology and method of administration”) (see also section 4.2 and 4.3).

Patients with heart disease: ADAPTUS/DELAMAN should be used with caution in patients with left ventricular dysfunction, in patients suffering from aortal stenosis or obstruction of the outflow channel of the left ventricle, in patients with isolated right-sided heart failure and in patients with sick sinus (if a pacemaker is not in situ). As no results of studies in stable coronary patients are available, caution is required in such patients because of the possible increased coronary risk (see section 4.8).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade 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.”

Hypersensitivity/angioedema: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of ACE inhibitors. Treatment with ACE inhibitors must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

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Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

4.5 Interaction with other medicinal products and other forms of interaction Antihypertensive agents and diuretics: the antihypertensive effect of ADAPTUS/ DELAMAN can be strengthened by the combination with diuretics, -blockers and in general with other antihypertensive drugs. The antihypertensive effect is usually additive and excessive symptomatic hypotension may occur. Patients on diuretics may experience excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor. The occurrence of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to intake and by initiation of therapy with lower doses of the ACE inhibitor. Further increases in dosage should be performed with caution. Concomitant use of glycerol trinitrate and other nitrates, or other vasodilators may lower the blood pressure further. Alcohol: as with all vasodilating antihypertensive agents caution should be exercised when alcohol is taken concomitantly to ADAPTUS/DELAMAN, as it may potentiate its effect. Sodium chloride: when sodium chloride is taken concomitantly to ADAPTUS /ADAPTUS/DELAMAN, its antihypertensive effect can be decreased. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes: delapril can reduce the potassium loss caused by thiazide diuretics. Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with ACE inhibitors. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when ACE inhibitors are co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the combination of ACE inhibitors with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium. Heparin: Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended. Lithium: in patients under concomitant treatment with ACE inhibitors and lithium, enhancements of lithium blood levels and lithium-toxicity symptoms have been observed. Therefore, the concomitant administration of these drugs should be followed with caution and lithium blood concentration should be frequently checked. Concomitant administration of a diuretic can strengthen lithium toxicity. Concomitant administration with Non steroidal anti-inflammatory drugs (NSAIDs): the concomitant administration of ACE inhibitors with Non steroidal anti-inflammatory drugs (i.e. Cox2- selective inhibitors, acetylsalicylic acid from 325 mg/day and non-selective NSAIDs) may reduce the antihypertensive effect. The concomitant administration of ACE inhibitors with non steroidal anti- inflammatory drugs may increase the risk of renal function worsening including possible acute renal failure and increase in serum potassium especially in patients with pre-existing impaired renal function. These medicinal products should be co-administered with caution particularly in elderly patients. Volume supplementation should be adequately provided to patients and renal function monitoring should be considered at the start of concomitant therapy . Tricyclic antidepressants, antipsychotics, anaesthetics: concomitant use with ACE inhibitors may result in further reduction of blood pressure. Sympathomimetics: sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. Allopurinol, procainamide, cytostatics, immunosuppressive agents, systemic corticosteroids and other medicinal products changing the blood picture: the concomitant treatment with these drugs and ACE inhibitors increases the risk of haematological reactions, especially leukocytosis, leukopenia.

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Hypoglycemic drugs: concomitant administration of ACE-inhibitors and antidiabetic drugs (oral hypoglycaemics or insulin) can potentially lead to an increase of the hypoglycemic effect of the latter, with a higher risk for hypoglycemia, especially during the first weeks of combined treatment and in patients with impaired renal function. Antacids: concomitant administration of antacids can mildly reduce the intestinal absorption of the component delapril. CYP3A4 inhibitors, inducers and substrates: in vitro studies show that the inhibitory potential on cytochrome P450 of manidipine may be clinically insignificant. Similarly to other dihydropyridines calcium-channel blockers, it is likely that manidipine metabolism is catalysed by the cytochrome P4503A4. As in vivo interaction studies on the effect of drugs which inhibit or induce the CYP3A4 on the pharmacokinetics of manidipine are not available, ADAPTUS/DELAMAN should not be administered with CYP3A4 inhibitors, such as antiproteases, cimetidine, ketoconazole, itraconazole, erythromycin and clarithromycin as well as with CYP3A4 inducers, such as phenitoin, carbamazepine, phenobarbital and rifampicine. Caution should be exercised when ADAPTUS/DELAMAN is co- prescribed with other substrates of CYP3A4, like terfenadine, astemizole, class III antiarrythmic drug such as amiodarone and quinidine. Digoxin: concomitant administration of calcium-antagonists and digoxin can bring about an increase in the levels of digoxin. Grapefruit juice: dihydropyridines appear to be particularly sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in their systemic availability and increased hypotensive effect. Therefore ADAPTUS/DELAMAN should not be taken simultaneously with grapefruit juice. ACE-inhibitors, angiotensin II receptor blockers or aliskiren: 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). Medicines increasing the risk of angioedema: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4). Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4). Ciclosporin: Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.

4.6 Fertility, Pregnancy and lactation

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).

Pregnancy 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. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3.) Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is

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recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4). There are no adequate data from the use of Adaptus/Delaman in pregnant women. Studies in animals given the combination of delapril/manidipine (ratio 3:1) have shown reproduction toxicity (see section 5.3). Lactation Because no information is available regarding the use of Adaptus/Delaman during breastfeeding, Adaptus/Delaman is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. Since dizziness might occur due to blood pressure reduction, patients should be warned to pay attention when operating machines and driving.

4.8 Undesirable effects The adverse reactions for ADAPTUS/DELAMAN are consistent with those known for its components or their respective class of medicinal products. Approximately 10% of patients treated with Adaptus/Delaman experienced adverse reactions during clinical studies. The most common (>1%) reported adverse reactions were cough, oedema and headache. The following undesirable effects have been observed and reported during treatment in clinical trials with ADAPTUS/DELAMAN, according to the following frequencies: Very common  1/10 Common  1/100 and 1/10 Uncommon  1/1,000 and 1/100 Rare  1/10,000 and 1/1,000 Very rare  1/10,000 including isolated cases Not known frequency can not be estimated from the available data

System Organ Frequency of adverse reactions Class Very Common Uncommon Rare Very rare Not known common (≥1/100 to (≥1/1,000 to (≥1/10,000 (<1/10,000 (cannot be (≥1/10) <1/10) <1/100) to <1/1,000) ) estimated from the available data) Blood and white blood cells aplastic haemolytic lymphatic system decreased anaemia, anaemia disorders agranulocytos is, thrombocytop enia, neutropenia, anaemia, decreases in haemoglobin and hematocrit

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System Organ Frequency of adverse reactions Class Very Common Uncommon Rare Very rare Not known common (≥1/100 to (≥1/1,000 to (≥1/10,000 (<1/10,000 (cannot be (≥1/10) <1/10) <1/100) to <1/1,000) ) estimated from the available data) Immune system hypersensitivi angioedema disorders ty

Metabolism and anorexia nutrition disorders

Psychiatric apathy confusional libido disorders state,insomnia decrease , mood modifications, nervousness, anxiety Nervous system headache, balance paraesthesia, somnolence disorders disorder, vertigo, dysgeusia dizziness Eye disorders blurred vision

Cardiac disorders palpitations : tachycardia myocardial Very rarely infarction, patients with arrhythmia, pre-existing angina angina pectoris, pectoris chest pain may experience increased frequency, duration or severity of these attacks.Isola ted cases of myocardial infarction may be observed Vascular severe syncope cerebrovascu Raynaud’s disorders hypotension with lar accident phenomenon orthostatic effects, hot flush Respiratory, cough, bronchitis dyspnoea, bronchospas thoracic and sinusitis, m mediastinal rhinitis, disorders pharyngitis

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System Organ Frequency of adverse reactions Class Very Common Uncommon Rare Very rare Not known common (≥1/100 to (≥1/1,000 to (≥1/10,000 (<1/10,000 (cannot be (≥1/10) <1/10) <1/100) to <1/1,000) ) estimated from the available data) Gastrointestinal nausea, abdominal vomiting, gastralgia pancreatitis, disorders pain, dyspepsia diarrhoea, ileus, constipation, glossitis dry mouth Hepatobiliary cholelithiasis, disorders especially with existing cholecystitis Skin and rash, pruritus, urticaria, Stevens- subcutaneous eczema, erythema, Johnson tissue disorders hyperhidrosis angioneurotic syndrome, oedema of alopecia, the face, psoriasis extremities, lips, tongue, glottis, and /or larynx

Musculoskeletal musculoskelet muscle myalgia Formatiert: Englisch (Großbritannien) and connective al stiffness, cramps tissue disorders pain at the extremities Renal and urinary renal acute renal Acute renal disorders impairment, failure, impairment proteinuria uraemia Reproductive impotence gynaecomastia Formatiert: Schriftart: 11 Pt., Nicht Fett, Nicht unterstrichen, system and Englisch (Großbritannien) breast disorders General disorders oedema, fatigue asthenia, irritability and malaise administration site conditions

Investigations increase in SGOT, BUN increase in hyperkalaemia SGPT, gamma- increase bilirubin and GT, LDH, blood CPK alkaline phosphatase and blood potassium

The following undesirable effects have been observed and reported during treatment with delapril and other ACE inhibitors:

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 Infections and infestations: infection  Blood and lymphatic system disorders white blood cells decreased, decreases in haemoglobin and haematocrit, bone marrow depression, agranulocytosis, thrombocytopenia, haemolytic anaemia, neutropenia, anaemia, lymphadenopathy.  Immune system disorders hypersensitivity, autoimmune disorder  Metabolism and nutrition disorders anorexia, gout, hypoglycaemia  Psychiatric disorders depression, insomnia, disorientation  Nervous system disorders vertigo, dizziness, headache, somnolence, paraesthesia, disturbance in attention, dysgeusia.  Eye disorders blurred vision  Ear and labyrinth disorders tinnitus.  Cardiac disorders extrasystoles, tachycardia, palpitations, chest pain, myocardial infarction, arrhythmia, angina pectoris, bradycardia  Vascular disorders orthostatic hypotension, hot flush, Raynaud’s phenomenon, peripheral coldness, syncope.  Respiratory, thoracic and mediastinal cough, dyspnoea, pharyngolaryngeal pain, disorders sneezing, rhinitis, bronchospasm, sinusitis.  Gastrointestinal disorders: nausea, vomiting, epigastralgia, diarrhoea, dyspepsia, constipation, abdominal pain, dry mouth, pancreatitis  Hepatobiliary disorders: hepatic failure, hepatitis-either toxic or cholestatic, jaundice  Skin and subcutaneous tissue disorders: rash, hyperhidrosis, pruritus, erythema, angioneurotic oedema, urticaria, psoriasis, alopecia, toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme.  Musculoskeletal and connective tissue myalgia, muscle cramps, back pain, disorders: musculoskeletal stiffness, joint swelling, pain at the extremities  Renal and urinary disorders: renal impairment, enuresis, pollakiuria, dysuria, acute renal failure, oliguria  Reproductive system and breast erectile dysfunction, menorrhagia, gynecomastia disorders:.

 General disorders and administration site fatigue, asthenia, irritability. conditions:

 Investigations:. increases in SGOT, SGPT, BUN, blood uric acid and blood potassium, increase in serum creatinine, increase in serum bilirubin

The following undesiderable effects have been observed and reported during treatment with manidipine and other dihydropyridines:

 Nervous system disorders: vertigo, dizziness, headache, paraesthesia, somnolence  Cardiac disorders:. palpitations, tachycardia, chest pain, angina pectoris, myocardial infarction. Some

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dihydropyridines may rarely lead to precordial pain. Very rarely patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks  Vascular disorders: hot flush, hypotension, hypertension  Respiratory, thoracic and mediastinal dyspnoea disorders:  Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth, gastrointestinal disorder, gastralgia, abdominal pain.Very rare cases of gingivitis and gingival hyperplasia have been reported, often regressive at therapy withdrawal and requiring a careful dental care.  Skin and subcutaneous tissue disorders: rash, eczema, erythema, pruritus  General disorders and administration site oedema, asthenia, irritability. conditions:

 Investigations: reversible increases in SGOT, SGPT, LDH, gamma-GT, alkaline phosphatase, BUN and serum creatinine

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

4.9 Overdose Symptoms: Possible symptoms of an overdose include hypotension, shock, stupor, bradycardia, electrolyte disturbances, dehydration, and renal failure. Serum electrolytes and creatinine should be monitored frequently. Treatment: After intake of an overdose, the patient should be closely monitored preferably at an intensive care unit. If the tablets were taken recently, recommended measures include induction of vomiting, administration of activated charcoal and administration of a laxative and/or gastric lavage. Any dehydration, disturbances in the electrolyte balance and hypotension should be treated in an appropriate manner, e.g. plasma-substitution or – if the result is insufficient – with catecholamines. Due to the long pharmacological effect of manidipine, the cardiovascular function of patients who have taken an overdose should be monitored for 24 hours at least.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic category:ACE inhibitors and calcium-channel blockers ATC code: C09B B12.

Mechanism of action ADAPTUS/DELAMAN is a combination of delapril, an inhibitor of the angiotensin conversion enzyme, and manidipine, a dyhydropyridine calcium-antagonist with antihypertensive activity and nephroprotecting properties. The combination of these active ingredients through complementary mechanisms of action produces a synergistic antihypertensive effect, reducing blood pressure in a greater measure than with the single constituents.

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Pharmacodynamic effects Delapril brings about the antihypertensive effect by inhibiting the conversion of Angiotensin I to Angiotensin II; due to the lipophilic effect of the combination, the inhibition mainly occurs at the level of the vessel wall. Delapril reduces the peripheral resistances and increases sodium and water elimination by blocking the renin-angiotensin-aldosterone system. Manidipine, whose characteristic is a long-lasting antihypertensive effect, shows vascular selectivity for the renal district, increasing renal blood flow and reducing vascular resistances of afferent and efferent arterioles with reduction of intraglomerular pressure. The effects on the renal haemodynamics allow the glomerular filtering fraction to be maintained over time. This characteristic is associated to the drug diuretic properties, due to the inhibition of water and sodium reabsorption at the tubular level. The combination of the two active ingredients (ADAPTUS/DELAMAN) produced, in pharmacodynamic studies, antihypertensive effects significantly stronger and longer lasting compared to the single components. In hypertensive patients, a clinically significant reduction of blood pressure lasted throughout 24 hours after a single daily dose.

Clinical efficacy and safety In clinical trials ADAPTUS/DELAMAN showed an antihypertensive action higher than the single constituents. In patients not suitably controlled with monotherapy with ACE inhibitors or calcium- channel blockers, the combination of delapril and manidipine led to clinically important reduction of systolic and diastolic blood pressure (-16/-10 mmHg). In a factorial trial designed to assess the dose- response in blood pressure following 6 weeks administration of combinations of delapril and manidipine, both combinations delapril 30 mg + manidipine 10 mg and delapril 15 mg + mandipine 5 mg reduced SBP and DBP significantly compared to placebo and met the efficacy criteria for second line usage (mean reduction vs. baseline with the higher fixed combination: -16.5 mmHg in SBP, -12.8 mmHg in DBP and with the lower fixed combination: -16.0 mmHg in SBP, -10.4 mmHg in DBP). ADAPTUS/DELAMAN’s antihypertensive effect is maintained in long-term treatment. Reduction of blood pressure did not induce any clinically important increase in heart rate both in short- and long-term treatment. Clinical experience is not available in patients aged over 75 years of age. The effect of the combination of delapril and manidipine on morbidity and mortality was not investigated.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan 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

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group than in the placebo group.

Paediatric population Clinical experience is not available in the paediatric population

5.2 Pharmacokinetic properties Delapril Absorption and Biotransformation Pharmacokinetic studies showed that delapril, after rapid absorption by the gastrointestinal tract, is metabolised in the active forms of delapril diacid (MI), and 5-idroxy-delapril diacid (MIII). The main serum metabolite is MI, followed by MIII, while serum levels of MII, a cyclic inactive metabolite, and unchanged delapril are reduced. Metabolite MI shows, compared to the other circulating species, the highest blood concentration values with a peak time of 1.3-1.6 hr. Delapril absorption rate is modestly reduced by the presence of food in the gastrointestinal tract. Since delapril is partly metabolised to active forms in the liver, in subjects with hepatic failure this conversion might be slowed down. There is no clinical experience in patients with hepatic failure or with hepatic cirrhosis. Distribution Delapril and MI bind to human serum proteins by more than 95%. A pharmacokinetic study at steady state in the elderly did not reveal accumulation of delapril. Elimination Approximately 60% of the product is eliminated in the 24-hour urine, mainly in the form of metabolites MI and MIII and in minimum amounts as unchanged delapril and MII. Fecal excretion is complemental to the urinary one. Repeated administration gives no rise to delapril and metabolites’ accumulation phenomena. Studies in special patient populations have shown that the urinary excretion of unmodified delapril and its metabolite MI is considerably reduced in patients with severe renal function impairment (blood creatinine  3 mg/dl).

Manidipine Resorption After oral administration, manidipine shows a plasma concentration peak at 2-3.5 hours, and undergoes a first-passage effect. Manidipine absorption is enhanced by the presence of food in the gastrointestinal tract. Distribution The binding with plasma proteins is of 99%. The product is widely distributed to tissues and widely metabolised, mainly at hepatic level. Biotransformation Since manidipine is metabolised at the hepatic level, a reduction in the liver metabolic function can modify its pharmacokinetics. Patients with mild hepatic impairment did not exhibit significantly altered pharmacokinetics in respect to healthy subjects, while trend towards higher systemic exposure was observed in patients with more severe hepatic impairment. Elimination Elimination chiefly occurs in feces (63%) and partially in urine (31%). After repeated administrations no accumulation phenomenon is observed. Manidipine did not show different pharmacokinetics in patients with renal insufficiency in comparison to healthy volunteers even in case of severe renal insufficiency. In elderly patients the administration of manidipine is associated with increased plasma levels and a longer plasma half-life.

Concomitant administration of delapril and manidipine did not induce any mutual interference on the single components’ pharmacokinetic characteristics. No accumulation of the two active ingredients was observed after repeated administration of the combination. After repeated administration of the combination in the elderly the exposure to the single components was higher in comparison to young subjects expecially for manidipine and metabolite MI of delapril.

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5.3 Preclinical safety data The combination showed a low acute toxicity and after repeated administration in rats and dogs adequate safety margins relating to the recommended therapeutic doses were obtained. The toxic manifestations observed at high doses (mainly decrease in body weight and increase in spontaneous incidence of renal changes in rats; induction of reversible gingival hypertrophy in dogs) were associated to exaggerated pharmacodynamic effects and were consistent with information already known for the single components, this excluding toxicologic interactions. Reproduction toxicity studies have been conducted in rats and rabbits receiving oral doses of the combination of delapril/mandipine (ratio 3:1). In a rat fertility and early embryonic developmental study embryo/fetotoxic effects, including a higher incidence of displaced testis, kinked urether, incomplete ossification of the sternum, and reduced number of live fetuses, were observed. The adverse effects appeared at the lowest dose level of 12 mg/kg/day, the maternal NOAEL. The exposure levels of the combination at this dose was lower than the human exposure levels at the recommended clinical dose. A NOAEL for embryo-/fetotoxic effects could not be established. In a pre-/postnatal study in rats effects on the fetus, including increase in pup loss and decrease in body weight gain, were observed at the highest and maternal toxic dose level. Difficulties in parturition were also seen in rats at higher dose levels. In rabbits no substance-induced effects on embryo-foetal development were observed. No mutagenicity potential was evidenced with the combination and the single components and the available data for the single components do not show potential risks of oncogenicity in man.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Lactose monohydrate, Low-substituted hydroxypropylcellulose, Hydroxypropylcellulose, Magnesium stearate, Riboflavine, Sunset Yellow (E110) Aluminium lake.

6.2 Incompatibilities Not applicable.

6.3 Shelf life 3 years. After first opening: 2 months (14 and 28 tablets) 3.5 months (50 and 100 tablets)

6.4 Special precautions for storage Keep the bottle tightly closed. (Only for 100 tablets pack sizes: Use completely the medicinal product contained in one bottle before opening the other bottle).

6.5 Nature and contents of container Primary container: bottle with child resistant closure. A silica gel tablet is included in the screw cap as dehydrating agent. Final package: printed thin-cardboard box. Pack sizes of 14, 28, 50 tablets of 30mg delapril and 10mg manidipine. Pack sizes of 100 tablets (50x2 bottles) of 30mg delapril and 10mg manidipine.

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Not all pack sizes may be marketed

6.6 Special precautions for disposal No special requirements.

7. MARKETING AUTHORIZATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORIZATION NUMBER

[To be completed nationally]

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

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