Source: European Medicines Agency (EU)
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:
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 product is not to be used in children and adolescents on account of inadequate experience in this patient population.
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).
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).
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.
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.
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.
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.
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 may occur, particularly in patients with existing renal function impairment.
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).
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.
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.
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.
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
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).
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.
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, 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.
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).
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).
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.
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).
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.
The antihypertensive effect of ADAPTUS/DELAMAN 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.
As with all vasodilating antihypertensive agents caution should be exercised when alcohol is taken concomitantly to ADAPTUS/DELAMAN, as it may potentiate its effect.
When sodium chloride is taken concomitantly to ADAPTUS/ADAPTUS/DELAMAN, its antihypertensive effect can be decreased.
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.
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.
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.
Concomitant use with ACE inhibitors may result in further reduction of blood pressure.
Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.
The concomitant treatment with these drugs and ACE inhibitors increases the risk of haematological reactions, especially leukocytosis, leukopenia.
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.
Concomitant administration of antacids can mildly reduce the intestinal absorption of the component delapril.
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.
Concomitant administration of calcium-antagonists and digoxin can bring about an increase in the levels of digoxin.
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.
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).
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).
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia (see section 4.4).
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
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.
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 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).
Because no information is available regarding the use of Adaptus/Delaman during breast-feeding, 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.
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 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.
Common: white blood cells decreased
Uncommon: aplastic anaemia, agranulocytosis, thrombocytopenia, neutropenia, anaemia, decreases in haemoglobin and hematocrit
Very rare: haemolytic anaemia
Rare: hypersensitivity
Not known: angioedema
Uncommon: anorexia
Common: apathy
Uncommon: confusional state,insomnia, mood modifications, nervousness, anxiety
Rare: libido decrease
Common: headache, balance disorder, vertigo, dizziness
Uncommon: paraesthesia, dysgeusia
Rare: somnolence
Uncommon: blurred vision
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
Common: severe hypotension with orthostatic effects, hot flush
Uncommon: syncope
Rare: cerebrovascular accident
Very rare: Raynaud’s phenomenon
Common: cough, bronchitis
Uncommon: dyspnoea, sinusitis, rhinitis, pharyngitis
Very rare: bronchospasm
Common: nausea, abdominal pain, dyspepsia
Uncommon: vomiting, diarrhoea, constipation, dry mouth
Rare: gastralgia
Very rare: pancreatitis, ileus, glossitis
Uncommon: cholelithiasis, especially with existing cholecystitis
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
Uncommon: musculoskeletal stiffness, pain at the extremities
Rare: muscle cramps
Not known: myalgia
Uncommon: renal impairment, proteinuria
Rare: acute renal failure, uraemia
Uncommon: impotence
Not known: gynaecomastia
Common: oedema, fatigue
Uncommon: asthenia, malaise
Rare: irritability
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
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*.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
