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Hypersensitivity to ramipril, amlodipine, other ACE (Angiotensin Converting Enzyme) inhibitors, dihydropyridine derivatives or to any of the excipients listed in section 6.1.
Related to ramipril:
Related to amlodipine:
Caution is recommended in patients who are being treated concurrently with diuretics since these patients may be volume and/or salt depleted. Renal function and serum potassium level should be monitored.
ACE inhibitors such as ramipril or Angiotension II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.
Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:
Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).
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.
The initial phase of treatment requires special medical supervision.
See section 4.2.
It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.
Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.
Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).
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 ramipril. Treatment with ramipril must not be initiated until 36 hours after taking 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.
In case of angioedema, ramipril must be discontinued. Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms. Intestinal angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of ramipril should be considered prior to desensitization.
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 development of hyperkalaemia include those with renal insufficiency, age (>70 years), uncontrolled diabetes mellitus, and/or patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or cotrimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin-receptor blockers. 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).
Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatraemia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.
Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).
ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.
As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.
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).
Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
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 and vildagliptin, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk for angioedema (see section 4.4).
Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics).
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine,epinephrine) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).
Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.
Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.
Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of ramipril is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.
Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with Ramipril/Amlodipine. 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 Ramipril/Amlodipine is 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 Ramipril/Amlodipine 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 ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.
There is a risk of increased tacrolimus blood levels when co administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate. Mechanistic Target of Rapamycin (mTOR) Inhibitors mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin.
Given the effects of the individual components in this combination product on pregnancy and lactation:
Ramipril/Amlodipine Glenmark is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.
Ramipril/Amlodipine Glenmark is not recommended during lactation. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with Ramipril/Amlodipine Glenmark should be made taking into account the benefit of breastfeeding to the child and the benefit of amlodipine therapy to the mother.
Ramipril/Amlodipine Glenmark is not recommended during the first trimester of pregnancy (see section 4.4) and is contraindicated during the second and third trimesters of pregnancy (see sections 4.3).
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 anti-hypertensive 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 inhibitors 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, oliguria and hyperkalaemia (see sections 4.3 and 4.4).
The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses (see section 5.3).
Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breastfeeding to the child and the benefit of amlodipine therapy to the mother.
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).
Ramipril/Amlodipine Glenmark can have minor or moderate influence on the ability to drive and use machines. Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness, headache, fatigue) may impair the patient’s ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).
This can happen especially at the start of treatment, or when changing over from other preparations. Caution is recommended especially at the start of treatment.
The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.
The most commonly reported adverse reactions during treatment with amlodipine are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.
Adverse reactions frequency is defined using the following convention: 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 (<1/10,000), not known (cannot be estimated from the available data).
The following adverse drug reactions have been reported during the treatment with ramipril and amlodipine independently:
| System organ class | Frequency | Ramipril | Amlodipine |
|---|---|---|---|
| Blood and lymphatic system disorders | Uncommon | Eosinophilia | |
| Rare | White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased | ||
| Very rare | Leukocytopenia, thrombocytopenia | ||
| Not known | Bone marrow failure, pancytopenia, haemolytic anaemia | ||
| Immune system disorders | Very rare | Allergic reactions | |
| Not known | Anaphylactic or anaphylactoid reactions, antinuclear antibody increased | ||
| Endocrine disorders | Not known | Syndrome of inappropriate antidiuretic hormone secretion (SIADH) | |
| Metabolism and nutrition disorders | Common | Blood potassium increased | |
| Uncommon | Anorexia, decreased appetite | ||
| Very rare | Hyperglycaemia | ||
| Not known | Blood sodium decreased | ||
| Psychiatric disorders | Uncommon | Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence | Depression, mood changes (including anxiety), insomnia |
| Rare | Confusional state | Confusion | |
| Not known | Disturbance in attention | ||
| Nervous system disorders | Common | Headache, dizziness | Somnolence, dizziness, headache (especially at the beginning of the treatment |
| Uncommon | Vertigo, paraesthesia, ageusia, dysgeusia | Tremor, dysgeusia, syncope, hypoesthesia, paraesthesia | |
| Rare | Tremor, balance disorder | ||
| Very rare | Hypertonia peripheral neuropathy | ||
| Not known | Cerebral ischemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia | Extrapyramidal disorder | |
| Eye disorders | Common | Visual disturbance (including diplopia) | |
| Uncommon | Visual disturbance including blurred vision | ||
| Rare | Conjunctivitis | ||
| Ear and labyrinth disorders | Uncommon | Tinnitus | |
| Rare | Hearing impaired, tinnitus | ||
| Cardiac disorders | Common | Palpitations | |
| Uncommon | Myocardial ischemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, Oedema peripheral | Arrhythmia, (including bradycardia, ventricular tachycardia and atrial fibrillation) | |
| Very rare | Myocardial infarction | ||
| Vascular disorders | Common | Hypotension, orthostatic blood pressure decreased, syncope | Flushing |
| Uncommon | Flushing | Hypotension | |
| Rare | Vascular stenosis, hypoperfusion, vasculitis | ||
| Very rare | Vasculitis | ||
| Not known | Raynaud’s phenomenon | ||
| Respiratory, thoracic and mediastinal disorders | Common | Non-productive tickling cough, bronchitis, sinusitis, dyspnoea | Dyspnoea |
| Uncommon | Bronchospasm including asthma aggravated, nasal congestion | Cough, rhinitis | |
| Gastrointestinal disorders | Common | Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting | Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea and constipation) |
| Uncommon | Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth | Vomiting, dry mouth | |
| Rare | Glossitis | ||
| Very rare | Pancreatitis, gastritis, gingival hyperplasia | ||
| Not known | Aphthous stomatitis | ||
| Hepatobiliary disorders | Uncommon Hepatic enzymes and/or bilirubin conjugated increased | ||
| Rare | Jaundice cholestatic, hepatocellular damage | ||
| Very rare | Hepatitis, jaundice, hepatic enzymes increased* | ||
| Not known | Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional) | ||
| Skin and subcutaneous tissue disorders | Common | Rash in particular maculo-papular | |
| Uncommon | Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis | Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria | |
| Rare | Exfoliative dermatitis, urticaria, onycholysis | ||
| Very rare | Photosensitivity reaction | Angioedema, erythema, multiforme, exfoliative dermatitis, Stevens- Johnson syndrome, Quincke oedema, photosensitivity | |
| Not known | Toxic Epidermal Necrolysis, Stevens- Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia | Toxic Epidermal Necrolysis (TEN) | |
| Musculoskeletal and connective tissue disorders | Common | Muscle spasms, myalgia | Ankle swelling, muscle cramps |
| Uncommon | Arthralgia | Arthralgia, myalgia, back pain | |
| Renal and urinary disorders | Uncommon | Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased | Micturition disorder, nocturia, increased urinary frequency |
| Reproductive system and breast disorders | Uncommon | Transient erectile impotence, libido decreased | Impotence, gynaecomastia |
| Not known | Gynaecomastia | ||
| General disorders and administration site conditions | Very common | Oedema | |
| Common | Chest pain, fatigue | Fatigue, asthenia | |
| Uncommon | Pyrexia | Chest pain, pain, malaise | |
| Rare | Asthenia | ||
| Investigations | Uncommon | Weight increased, weight decreased |
* most commonly with cholestasis
The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years old, during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:
Tachycardia, nasal congestion and rhinitis, “common” (ie, ≥1/100 to <1/10) in paediatric, and “uncommon” (i.e. ≥1/1,000 to <1/100) in adult population.
Conjunctivitis “common” (ie, ≥1/100 to <1/10) in paediatric and “rare” (i.e. ≥1/10,000 to <1/1,000) in adult population.
Tremor and urticaria “uncommon” (.ie. ≥1/1,000 to <1/100) in paediatric population and “rare” (i.e. ≥1/10,000 to <1/1,000) in adult population.
The overall safety profile for ramipril in paediatric patients does not differ significantly from the safety profile in adults.
Exceptional cases of extrapyramidal syndrome have been reported.
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 [To be completed nationally].
Not applicable.
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