The text with yellow background refers only to full set of strengths applied for in RMS. The text with green background refers only to applications in CMS.
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Capsule, hard
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
Posology Recommended daily dose is one capsule of the given strength.
Patients with hepatic impairment In patients with hepatic impairment, treatment with
Patients with renal impairment In order to find optimal initial and maintenance dose in patients with renal impairment, patients’ dose should be adjusted individually by separate titration of doses of ramipril, amlodipine and hydrochlorothiazide components (regarding details see SmPCs of monocomponent preparations). Daily dose of
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- If creatinine clearance is between 30-60 ml/min, the maximal daily dose of
Renal function and serum potassium should be monitored during treatment with
Elderly patients Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of
Method of administration The capsules should be taken orally each day once at the same time of the day with or without food. It must not be chewed or crushed. It should not be taken with grapefruit juice.
4.3 Contraindications
- history of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or angiotensin-II receptor antagonists (AIIRAs). - shock (including cardiogenic shock). - 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6). - lactation (see section 4.6) - extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5). - significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney. - severe renal impairment (creatinine clearance < 30 ml/min) - in patients with hypotensive or haemodynamically unstable states. - refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia. - obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). - combination with angiotensin II receptor antagonists (ARBs) in patients with diabetic nephropathy (see section 4.4 and 4.5) - Concomitant use with sacubitril/valsartan therapy (see sections 4.4 and 4.5) - The concomitant use of
4.4 Special warnings and precautions for use
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
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Special populations Pregnant woman ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE/AIIRAs 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/AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Patients at particular risk of hypotension - 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: patients with severe hypertension. patients with decompensated congestive heart failure. patients with haemodynamically relevant left-ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve). patients with unilateral renal artery stenosis with a second functional kidney. patients in whom fluid or salt depletion exists or may develop (including patients with diuretics). patients with liver cirrhosis and/or ascites. patients undergoing major surgery or during anaesthesia with agents that produce hypotension. 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 up against the risk of volume overload). - - Patients at risk of cardiac or cerebral ischemia in case of acute hypotension. The initial phase of treatment requires special medical supervision.
Patients with cardiac failure 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.
Patients with impaired hepatic function
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. Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Maximum daily dose of ramipril in patients with hepatic impairment should not exceed 2,5 mg.
Patients with renal impairment
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Renal function should be assessed before and during treatment with
Elderly patients See section 4.2.
Surgery It is recommended that treatment with angiotensin converting enzyme inhibitors, such as ramipril, should be discontinued where possible one day before surgery.
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.
Angioedema Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). This risk may be increased in patients taking concomitant medications such as mTOR (mammalian target of rapamycin) inhibitors (e. g. temsirolismus, everolismus, sirolismus), vildagliptin or neprilysin (NEP) inhibitors (such as racecadotril). The combination of ramipril with sacubitril/valsartan is contraindicated due to the increased angioedema (see sections 4.3 and 4.5) 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).
Anaphylactic reactions during desensitization 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 electrolyte changes Hyperkalaemia has been observed in some patients treated with ACE inhibitors including ramipril. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).
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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,
Treatment with
Serum sodium levels should be monitored prior to initiation of treatment and at regular intervals thereafter. Thiazide diuretics may cause hyponatraemia or exacerbate pre-existing hyponatraemia. In subjects with a significant decrease in serum sodium and / or a significant volume depletion, as observed in patients receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of treatment with the hydrochlorothiazide. The fall in plasma sodium may be initially asymptomatic, regular monitoring is therefore essential and should be even more frequent in populations at risk represented by the elderly, let alone malnourished and cirrhotic patients (see sections 4.8 and 4.9).
Isolated cases of hyponatremia accompanied by neurological symptoms (nausea, progressive disorientation, apathy) were observed. Thiazides should be used only after normalization of any volume and / or existing blood volume. Otherwise, treatment should be initiated under close medical supervision. All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.
Non-melanoma skin cancer An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC. Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).
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Neutropenia/agranulocytosis 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).
Ethnic differences 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 Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non- productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Photosensitivity Cases of photosensitivity reactions have been reported with the use of thiazide diuretics (see section 4.8). In case of occurrence of photosensitivity reaction on treatment, it is recommended to discontinue treatment. If re-administration of treatment is essential, it is recommended to protect areas exposed to the sun or artificial UVA.
Acute Myopia and Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle- closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Glycaemia and lipidaemia Thiazide therapy can decrease glucose tolerance and raise serum levels of cholesterol and triglyceride. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.
Uric acid Hydrochlorothiazide, like other diuretics, can cause increased plasma concentrations of uric acid, due to the decrease in its urinary excretion and consequently promote the development of hyperuricemia or hyperuricemia may aggravate preexisting trigger seizures of gout in susceptible patients. The dosage should be adjusted according to plasma levels of uric acid.
Antihypertensive combinations It is advisable to reduce the dosage when combined with other anti-hypertensive agent, at least initially. The antihypertensive effect of ACE inhibitors, antagonists of angiotensin II or renin inhibitors is potentiated by treatments that increase plasma renin activity (diuretics). Caution is advised when ACE inhibitor, an antagonist of angiotensin II or a direct renin inhibitor is administered in conjunction with hydrochlorothiazide, particularly in patients with sodium chloride depletion and/or in patients with hypovolemia.
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Athletes Athletes should pay particular attention to the fact that this speciality contains an active principle, which may induce a positive reaction in the tests carried out during anti-doping controls.
Other Lupus: Cases of exacerbation or activation of systemic lupus erythematosus have been reported with thiazide diuretics, including hydrochlorothiazide. Hypersensitivity reactions to hydrochlorothiazide are more common with allergies and asthma.
4.5 Interaction with other medicinal products and other forms of interaction
No formal interaction studies with other medicinal products have been performed with
However, it is important to take into account that
Concomitant use not recommended
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patients resulting in increased blood pressure lowering effects.
Precautions for use
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Neprilysin (NEP) inhibitors A potential increased risk of angioedema has been reported for a concomitant use of ACE inhibitors and NEP inhibitor such as racecadotril (see section 4.4). Sacubitril/valsartan The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema. Amlodipine CYP3A4 inhibitors Concomitant use of amlodipine with strong or (i.e. protease inhibitors, azole moderate CYP3A4 inhibitors may give rise to antifungals, macrolides like significant increase in amlodipine exposure. erythromycin, clarithromycin, The clinical translation of these PK variations verapamil or diltiazem) may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required. CYP3A4 inducers There is no data available regarding the effect (i.e. rifampicin, hypericum of CYP3A4 inducers on amlodipine. The perforatum) concomitant use of CYP3A4 inducers may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers. Dantrolene (infusion) In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia 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. Simvastatin 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 to 20 mg daily in patients on amlodipine. Ciclosporin No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of ciclosporin were observed. Consideration should be given for monitoring ciclosporin levels in renal transplant patients on amlodipine, and ciclosporin dose reductions should be made as necessary. Tacrolimus There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. 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.
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HCTZ Drugs that can cause The hypokalaemia is a predisposing factor for hypokalaemia heart rhythm disorders (torsades de pointes, in particular) and increasing the toxicity of certain drugs, such as digoxin. Therefore, drugs that can cause hypokalaemia are involved in a large number of interactions. These are kaliuretic diuretics, alone or combined, stimulant laxatives, glucocorticoids, the tetracosactide and amphotericin B (IV route). Drugs that can cause Some drugs are more frequently involved in hyponatremia the occurrence of hyponatremia. These are diuretics, desmopressin, antidepressants inhibiting serotonin reuptake, carbamazepine and oxcarbazepine. The combination of these drugs increase the risk of hyponatremia. Medicinal products which may Due to the risk of hypokalaemia, cause torsades de pointes hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics. Correct any hypokalaemia before administering the product and carry out clinical, electrolytic and electrocardiographic monitoring. Antidiabetic agents including Hypoglycaemic reactions may occur. insulin Hydrochlorothiazide may attenuate the effect of antidiabetic medicines. Particularly close blood glucose monitoring is therefore recommended in the initial phase of co- administration. Oral anticoagulants Anticoagulant effect may be decreased due to concomitant use of hydrochlorothiazide. Cardiac glycosides, active Their proarrhythmic toxicity may be substances known to prolong increased or their antiarrhythmic effect the QT interval and decreased in the presence of electrolyte antiarrhythmic disturbances (e.g. hypokalaemia, hypomagnesaemia). Monitor serum potassium before, and carry out clinical, electrolytic and electrocardiographic monitoring Potassium-sparing diuretics The rational combination, useful for some (alone or combined) patients, does not exclude the occurrence of hypokalaemia or, particularly in renal insufficiency and diabetes, hyperkalaemia. Monitor serum potassium, perform electrocardiogram, and if appropriate, reconsider the treatment. Calcium salts and plasma Rise in serum calcium concentration is to be calcium increasing medicinal anticipated in case of concomitant products administration of hydrochlorothiazide; therefore, close monitoring of serum calcium is required.
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Drugs causing orthostatic Antihypertensives can cause orthostatic hypotension hypotension. This is the case of nitrates, inhibitors of phosphodiesterase type 5, alpha blockers also those intended for urological use (alfuzosin, doxazosin, prazosin, silodosine, tamsulosin and terazosin), of tricyclic antidepressants and neuroleptic phenothiazines, dopamine agonists, levodopa, baclofen, amifostine Carbamazepine Risk of hyponatraemia due to additive effect with hydrochlorothiazide. Clinical and biological monitoring. Bile acid sequestrants Bile acid sequestrants bind thiazide diuretics (chelating resins), in the gut and impair gastrointestinal (eg. Cholestyramine) absorption by 43-85%. Administration of thiazide 4 hours after a bile acid sequestrant reduced absorption of hydrochlorothiazide by 30-35%. Give thiazide 2-4 hours before or 6 hours after the bile sequestrant. Maintain a consistent sequence of administration. Monitor blood pressure, and increase dose of thiazide, if necessary. Iodine containing contrast In case of dehydration induced by diuretics media including hydrochlorothiazide, there is increased risk of acute renal impairment, when use of important doses of iodine containing contrast media. Rehydration before administration of the iodinated product. Cyclosporine Risk of increase in the creatininemia without modification of the blood concentrations of cyclosporine, even in the absence of sodium depletion. Also risk of hyperuricaemia and gout as complications.
Dual blockade of the RAAS with ARBs, ACE inhibitors 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).
4.6 Fertility, pregnancy and lactation
Pregnancy The use of
Related to ramipril 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
12 safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. ACE inhibitor/ Angiotensin (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (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. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see sections 4.3 and 4.4).
Related to amlodipine 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.
Related to hydrochlorothiazide Hydrochlorothiazide, in cases of prolonged exposure during the third trimester of pregnancy, may cause a foeto-placental ischaemia and risk of growth retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported in case of exposure near term. Hydrochlorothiazide can reduce plasma volume as well as the uteroplacental blood flow.
Ramipril/amlodipine/hydrochlorothiazide There is no experience on the use of
Breastfeeding
Fertility Related to amlodipine 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).
Related to hydrochlorothiazide There is no data on the effect of hydrochlorothiazide on fertility in humans. In studies in animals, hydrochlorothiazide has no effect on fertility or conception (see section 5.3).
4.7 Effects on ability to drive and use machines
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Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) 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. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.
4.8 Undesirable effects
Summary of the safety profile Ramipril The most commonly reported adverse reactions during ramipril treatment are increased blood potassium, headache, dizziness, hypotension, decreased orthostatic blood pressure, syncope, nonproductive tickling cough, bronchitis, sinusitis, dyspnoea, gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting, rash in particular maculopapular, muscle spasms, myalgia, chest pain, fatigue. Serious adverse reactions include agranulocytosis, pancytopenia, haemolytic anemia, myocardial infarction, angioedema, vasculitis, bronchospasm, acute pancreatitis, hepatic failure, acute renal failure, hepatitis, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson-Syndrome and erythema multiforme.
Amlodipine The most commonly reported adverse reactions during amlodipine treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue. Serious adverse reactions include leukopenia, thrombocytopenia, myocardial infarction, atrial fibrillation, ventricular tachycardia, vasculitis, acute pancreatitis, hepatitis, angioedema, erythema multiforme, exfoliative dermatitis and Steven-Johnson-Syndrome.
Hydrochlorothiazide Hydrochlorothiazide active substance may lead to worsening of glucose, lipid and uric acid metabolism and has inverse effects on plasma potassium.
The undesirable effects observed in the course of using active ingredients separately are to be given according to the following frequency grouping:
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). Frequency Ramipril Amlodipine Hydrochlorothiazide Blood and lymphatic system disorders Uncommon Eosinophilia Rare White blood cell count Thrombocytopenia decreased (including (sometimes with purpura) neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased Very rare Leukopenia, Bone marrow depression, thrombocytopenia agranulocytosis,
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haemolytic anaemia, leukopenia Not known Bone marrow failure, aplastic anaemia pancytopenia, haemolytic anaemia Immune system disorders Rare Hypersensitivity reaction 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 Very common hypokalaemia, hyperlipidemia Common: Blood potassium Hyperuricemia, increased hypomagnesemia, hyponatremia Uncommon Anorexia, decreased appetite Rare Hypercalcaemia, hyperglycemia, glycosuria, worsening of metabolic diabetes Very rare Hyperglycaemia hypochloraemic alkalosis Not known Blood sodium decreased Psychiatric disorders Uncommon Depressed mood, Mood changes anxiety, nervousness, (including anxiety), restlessness, sleep insomnia, depression disorder including somnolence Rare Confusional state Confusion Sleep disorders, depression Not known Disturbance in attention Nervous system disorders Common Headache, dizziness Headache, dizziness, somnolence (especially at the beginning of the treatment)
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Uncommon Vertigo, paraesthesia, Tremor, dysgeusia ageusia, dysgeusia syncope, hypoaesthesia, paraesthesia Rare: Tremor, balance Headache, dizziness, disorder paraesthesia Very rare Hypertonia, peripheral neuropathy Not known Cerebral ischaemia Extrapyramidal including ischaemic disorder stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia Eye disorders Common Visual disturbance (including diplopia)
Uncommon Visual disturbance Visual disturbances including blurred vision Rare Conjunctivitis Not known Acute angle-closure glaucoma Ear and labyrinth disorders Uncommon Tinnitus Rare Hearing impaired, tinnitus Cardiac disorders Common Palpitations Uncommon Myocardial ischaemia Arrhythmia including angina (including pectoris or myocardial bradycardia, infarction, tachycardia, ventricular arrhythmia, tachycardia and palpitations, oedema atrial fibrillation) peripheral Rare Arrhythmias Very rare Myocardial infarction
Vascular disorders Common Hypotension, Flushing Orthostatic hypotension orthostatic blood pressure decreased, syncope
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Uncommon Flushing Hypotension Necrotizing angitis (vasculitis, cutaneous vasculitis) Rare Vascular stenosis, hypoperfusion, vasculitis Very rare Vasculitis Not known Raynaud's phenomenon
Respiratory, thoracic and mediastinal disorders Common Non-productive Dyspnoe tickling cough, bronchitis, sinusitis, dyspnoea Uncommon Bronchospasm Cough, rhinitis including asthma aggravated, nasal congestion Very rare Respiratory distress (including pneumonitis and pulmonary edema) Gastrointestinal disorders Common Gastrointestinal Nausea, abdominal Nausea, vomiting, inflammation, digestive pain, dyspepsia, diarrhoea, spasm, loss of disturbances, altered bowel habits apetite abdominal discomfort, (including diarrhoea dyspepsia, diarrhoea, and constipation) nausea, vomiting Uncommon Pancreatitis (cases of Vomiting, dry mouth fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth
Rare Glossitis Abdominal discomfort, constipation Very rare Pancreatitis, Pancreatitis gastritis, gingival hyperplasia Not known Aphtous stomatitis Hepatobiliary disorders Uncommon Hepatic enzymes and/or bilirubin conjugated increased Rare Jaundice cholestatic, Intrahepatic cholestasis, hepatocellular damage jaundice
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Very rare Jaundice, hepatitis, 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 Urticaria and other forms maculo-papular of rash Uncommon Angioedema; very Alopecia, purpura, exceptionally, the skin discolouration, airway obstruction hyperhidrosis, resulting from pruritus, rash, angioedema may have exanthema, urticaria a fatal outcome; pruritus, hyperhidrosis Rare Exfoliative dermatitis, Photosensitivity reaction urticaria, onycholysis Very rare Photosensitivity Angioedema, Type of lupus reaction erythema erythematosus reaction, multiforme, reactivation of lupus exfoliative erythematosus, vasculitis dermatitis, Stevens- necrotising and toxic Johnson syndrome, epidermal necrolysis Quincke oedema, photosensitivity Not known Toxic epidermal Toxic epidermal Erythema multiforme necrolysis, necrolysis StevensJohnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Not known Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)**
Musculoskeletal and connective tissue disorders Common Muscle spasms, Ankle swelling, myalgia muscle cramps Uncommon Arthralgia Arthralgia, myalgia, Muscle cramps back pain
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Not known Renal and urinary disorders Uncommon Renal impairment Micturition disorder, Glycosuria, interstitial including renal failure nocturia, increased nephritis, renal acute, urine output urinary frequency dysfunction, renal failure, increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased Reproductive system and breast disorders Common Impotence Uncommon Transient erectile Impotence, impotence, libido gynecomastia decreased Not known Gynaecomastia General disorders and administration site conditions Very common Oedema Common Chest pain, fatigue Fatigue, asthenia Uncommon Pyrexia Chest pain, pain, Fever malaise Rare Asthenia Not known Weakness Investigations Uncommon Weight increase, weight decrease *In most cases with cholestasis ** Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose- dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).
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
Related to ramipril Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha1- adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.
Related to amlodipine In humans experience with intentional overdose is limited.
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Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported
Related to hydrochlorothiazide In predisposed patients (e.g. prostatic hyperplasia) hydrochlorothiazide overdose may induce acute urinary retention.
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalemia may result in muscle spasms and / or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic drugs.
Treatment Treatment is symptomatic and supportive. Primary detoxification by, for example, administration of adsorbants may be considered. In the event of hypotension, administration of α 1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), must be considered in addition to volume and salt substitution. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. In attempting to eliminate ramipril, or ramiprilat, there is limited/no experience available concerning the efficacy of forced diuresis, altering urine pH, hemofiltration or dialysis. If dialysis or hemofiltration is nevertheless contemplated, consider risks of anaphylactoid reactions with high flux membrane Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. Removal of thiazide diuretics by dialysis is also negligible. The treatment is to restore fluid and electrolyte balance, correction of hyponatremia should be gradual. Active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output should be undertaken.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors, other combinations ATC code: C09BX03
Mechanism of action of ramipril Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (AfroCaribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.
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Pharmacodynamic effects Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate. In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours. The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years. Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.
Clinical efficacy and safety
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 group than in the placebo group.
Mechanism of action of amlodipine Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:
1) Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements. 2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
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In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption. Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
Mechanism of action of hydrochlorothiazide Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide diuretics is not fully known. It inhibits the reabsorption of sodium and chloride in the distal tubule leading to excretion of about 15% of glomerular filtrated sodium and similarly chloride. The increased renal excretion of these ions is accompanied by increased urine output (due to osmotic binding of water). Potassium and magnesium excretion are increased, uric acid excretion is decreased. High doses of hydrochlorothiazide may increase excretion of bicarbonate due to inhibition of carboanhydratase, resulting in an alkaline pH of the urine. Acidosis or alkalosis have no significant effects on the saluretic and diuretic effects of hydrochlorothiazide. Glomerular filtration rate is decreased to a minimal extent at the beginning of therapy. During long-term therapy with hydrochlorothiazide, renal calcium excretion is reduced. This mechanism may result in hypercalcaemia. Possible mechanisms of the antihypertensive action of hydrochlorothiazide could be: the modified sodium balance, the reduction in extracellular water and plasma volume, a change in renal vascular resistance as well as a reduced response to norepinephrine and angiotensin II. Likely, a reduction in peripheral blood vessel resistance is also discussed, probably due to reduction of sodium concentration in the blood vessel walls resulting in a reduced sensibility of the blood vessel walls to norepinephrine.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose- dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose- response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).
Pharmacodynamic effects With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6 to 12 hours. The onset of the antihypertensive effect occurs after 3 to 4 days and can last up to one week after dis- continuation of therapy. During chronic administration, the antihypertensive effect of hydrochlorothiazide is dose dependent in most patients, at doses from 12.5 mg / day to 50-75 mg /day. The blood-pressure-lowering effect is accompanied by slight increases in the filtration fraction, renal vascular resistance and plasma renin activity. Exceeding a certain dosage, the therapeutic effect of thiazide diuretics remains unchanged, while the adverse effects continue to increase: in the case of ineffectiveness, it is not useful, and often badly tolerated, to increase the dosage beyond the recommended dosage. (see section 4.2). In patients with nephrogenic diabetes insipidus, hydrochlorothiazide reduces urine output and increases urine osmolality. Hydrochlorothiazide is not effective in patients with chronic renal impairment (creatinine clearance < 30 ml/min and/or serum-creatinine greater than 1.8 mg/100 ml).
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Paediatric population (aged 6 years and older) The European Medicines Agency has granted of a product-specific waiver for Ramipril/ Amlodipine Hydrochlorothiazide in all subsets of the paediatric population in the treatment of hypertension, on the grounds that the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for paediatric patients. (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Ramipril Absorption Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations of ramipril are reached within one hour. Based on urinary recovery, the extent of absorption is at least 56 % and is not significantly influenced by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45 %. Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril are reached 2-4 hours after ramipril intake. Steady state plasma concentrations of ramiprilat after once daily dosing with the usual doses of ramipril are reached by about the fourth day of treatment.
Distribution The serum protein binding of ramipril is about 73 % and that of ramiprilat about 56 %.
Biotransformation Ramipril is almost completely metabolised to ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.
Elimination Excretion of the metabolites is primarily renal. Plasma concentrations of ramiprilat decline in a polyphasic manner. Because of its potent, saturable binding to ACE and slow dissociation from the enzyme, ramiprilat shows a prolonged terminal elimination phase at very low plasma concentrations. After multiple once-daily doses of ramipril, the effective half-life of ramiprilat concentrations was 13- 17 hours for the 5-10 mg doses and longer for the lower 1.25-2.5 mg doses. This difference is related to the saturable capacity of the enzyme to bind ramiprilat. One single 10 mg oral dose of ramipril produced an undetectable level in breast milk. However the effect of multiple doses is not known.
Patients with renal impairment (see section 4.2) Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.
Patients with hepatic impairment (see section 4.2) In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed, due to diminished activity of hepatic esterases, and plasma ramipril levels in these patients were increased. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.
Amlodipine Absorption, distribution, plasma protein binding After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80 %. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5 % of circulating amlodipine is bound to plasma proteins. The bioavailability of amlodipine is not affected by food intake.
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Biotransformation/elimination The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10 % of the parent compound and 60 % of metabolites excreted in the urine.
Use in hepatic impairment Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60 %.
Use in the elderly The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
Hydrochlorothiazide Absorption After an oral dose of hydrochlorothiazide, absorption is rapid (Tmax about 2 hours). The increase in mean AUC is linear and dose proportional in the therapeutic range. The effect of food on the absorption of hydrochlorothiazide has little clinical impact. After oral administration, the absolute bioavailability of hydrochlorothiazide is 70%. In patients with congestive heart failure, absorption of hydrochlorothiazide is impaired. The continuous administration does not alter the metabolism of hydrochlorothiazide. After 3 months of treatment with a daily dose of 50 mg of hydrochlorothiazide, absorption, elimination or excretion are similar to those seen during short-term treatment.
Distribution Hydrochlorothiazide accumulates in erythrocytes, reaching its maximum concentration 4 hours after oral administration. After 10 hours the concentration in erythrocytes is approximately 3 times that of the plasma. A plasma protein binding of about 40-70% has been reported, and an apparent volume of distribution estimated at 4-8 L / kg. The half-life is highly variable from one subject to another: it is between 6 and 25 hours..
Metabolism Hydrochlorothiazide undergo negligible hepatic metabolism and has not been shown to induce or inhibit any CYP450 isoenzymes.
Excretion Hydrochlorothiazide is eliminated from plasma mainly as unchanged with a half-life of about 6 to 15 h in the terminal elimination phase. In 72 hours, 60 to 80% of a single oral dose is excreted in the urine, 95% unchanged, and 4% as the hydrolyzate 2-amino-4-chloro-m-benzenedisulfonamide (ABCS). Up to 24% of the oral dose is recovered in faeces and a negligible amount is excreted in the bile. In kidney and heart failure, renal clearance of hydrochlorothiazide is reduced, and increased half-life disposal. It is the same in the elderly, with a further increase in the maximum plasma concentration.
Cardiovascular Insufficiency The clearance of hydrochlorothiazide may be decreased in patients with congestive heart failure.
Hepatic Insufficiency No relevant changes in the pharmacokinetics of hydrochlorothiazide have been noted in liver cirrhosis. Hydrochlorothiazide should not be administered in hepatic coma or pre-coma. It should be used only with caution in patients with progressive hepatic disease (see section 4.4)
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5.3 Preclinical safety data
Related to ramipril Reproductive toxicology Reproduction toxicology studies in the rat, rabbit and monkey did not disclose any teratogenic properties. Impairment of fertility Fertility was not impaired either in male or in female rats.
The administration of ramipril to female rats during the fetal period and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at daily doses of 50 mg/kg body weight or higher. Irreversible kidney damage has been also observed in very young rats given a single dose of ramipril.
Related to amlodipine Reproductive toxicology Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
Impairment of fertility There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
*Based on patient weight of 50 kg
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule filling Cellulose, microcrystalline Calcium hydrogen phosphate, anhydrous Maize starch, pregelatinised Sodium starch glycolate (type A) Sodium stearyl fumarate
Capsule shell (2.5 mg/5 mg/12.5 mg) Iron oxide red (E172) Iron oxide yellow (E172) Titanium dioxide (E171) Gelatin
Capsule shell (5 mg/5 mg/25 mg) Iron oxide red (E172) Iron oxide yellow (E172) Titanium dioxide (E171) Gelatin
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Capsule shell (5 mg/10 mg/25 mg) Iron oxide red (E172) Iron oxide black (E172) Titanium dioxide (E171) Gelatin
Capsule shell (10 mg/5 mg/25 mg) Iron oxide red (E172) Iron oxide yellow (E172) Titanium dioxide (E171) Gelatin
Capsule shell (10 mg/10 mg/25 mg) Iron oxide red (E172) Iron oxide yellow (E172) Iron oxide black (E172) Titanium dioxide (E171) Gelatin
Capsule shell (5 mg/5 mg/12.5 mg) Iron oxide red (E172) Iron oxide black (E172) Titanium dioxide (E171) Gelatin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
10, 20, 30, 50, 60, 90 and 100 capsules, hard in PA-Aluminium-PVC (laminate) and aluminium foil blister packs, in carton box. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
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8. MARKETING AUTHORISATION NUMBERS
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
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