Delapril and Manidipine

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.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Concomitant use with ACE inhibitors may result in further reduction of blood pressure.

As with all vasodilating antihypertensive agents caution should be exercised when alcohol is taken concomitantly to delapril/manidipine combination, as it may potentiate its effect.

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.

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.

Concomitant administration of antacids can mildly reduce the intestinal absorption of the component delapril.

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.

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.

The antihypertensive effect of delapril/manidipine can be strengthened by the combination with diuretics, β-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.

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.

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.

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.

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.

The concomitant treatment with these drugs and ACE inhibitors increases the risk of haematological reactions, especially leukocytosis, leukopenia.

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.

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 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). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

When sodium chloride is taken concomitantly to delapril/manidipine combination, its antihypertensive effect can be decreased.

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 delapril/manidipine. 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.

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.

Delapril/manidipine 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.

Delapril/manidipine 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.

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

At the beginning of the treatment with delapril/manidipine, 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 delapril/manidipine 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.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester of 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). 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.

There are no adequate data from the use of delapril/manidipine in pregnant women. Studies in animals given the combination of delapril/manidipine (ratio 3:1) have shown reproduction toxicity.

Because no information is available regarding the use of delapril/manidipine during breast-feeding, delapril/manidipine is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

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.

The adverse reactions for delapril/manidipine are consistent with those known for its components or their respective class of medicinal products. Approximately 10% of patients treated with delapril/manidipine 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 delapril/manidipine, 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.

Blood and lymphatic system disorders

Common: white blood cells decreased

Uncommon: aplastic anaemia, agranulocytosis, thrombocytopenia, neutropenia, anaemia, decreases in haemoglobin and hematocrit

Very rare: haemolytic anaemia

Immune system disorders

Rare: hypersensitivity

Not known: angioedema

Metabolism and nutrition disorders

Uncommon: anorexia

Psychiatric disorders

Common: apathy

Uncommon: confusional state,insomnia, mood modifications, nervousness, anxiety

Rare: libido decrease

Nervous system disorders

Common: headache, balance disorder, vertigo, dizziness

Uncommon: paraesthesia, dysgeusia

Rare: somnolence

Eye disorders

Uncommon: blurred vision

Cardiac disorders

Common: palpitations

Uncommon: tachycardia

Rare: myocardial infarction, arrhythmia, angina pectoris, chest pain

Very rare: very rarely patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks.Isola ted cases of myocardial infarction may be observed

Vascular disorders

Common: severe hypotension with orthostatic effects, hot flush

Uncommon: syncope

Rare: cerebrovascular accident

Very rare: Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders

Common: cough, bronchitis

Uncommon: dyspnoea, sinusitis, rhinitis, pharyngitis

Very rare: bronchospasm

Gastrointestinal disorders

Common: nausea, abdominal pain, dyspepsia

Uncommon: vomiting, diarrhoea, constipation, dry mouth

Rare: gastralgia

Very rare: pancreatitis, ileus, glossitis

Hepatobiliary disorders

Uncommon: cholelithiasis, especially with existing cholecystitis

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, eczema, hyperhidrosis

Rare: urticaria, erythema, angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx

Very rare: Stevens-Johnson syndrome, alopecia, psoriasis

Musculoskeletal and connective tissue disorders

Uncommon: musculoskeletal stiffness, pain at the extremities

Rare: muscle cramps

Not known: myalgia

Renal and urinary disorders

Uncommon: renal impairment, proteinuria

Rare: acute renal failure, uraemia

Reproductive system and breast disorders

Uncommon: impotence

Not known: gynaecomastia

General disorders and administration site conditions Investigations

Common: oedema, fatigue

Uncommon: asthenia, malaise

Rare: irritability

Investigations

Common: increase in SGOT, SGPT, gamma-GT, LDH, blood alkaline phosphatase and blood potassium

Uncommon: BUN increase

Rare: increase in bilirubin and CPK

Not known: hyperkalaemia

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

Infections and infestastions: infection

Blood and lymphatic system disorders: white blood cellss decreased, decreases in haemoglobin and haematocrit, bone marrow depression, agranuloxytosis, thrombocytopenia, heamolytic 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 disorders: cough, dyspnoea, pharyngolaryngeal pain, 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 disorders: myalgia, muscle cramps, back pain, 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 disorders: erectile dysfunction, menorrhagia, gynecomastia

General disorders and administration site conditions: fatigue, asthenia, irritability 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 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 disorders: dyspnoea

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

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