Ramipril 2.5mg Capsules
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1. NAME OF THE MEDICINAL PRODUCT
Ramipril 2.5 mg Capsules.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 2.5 mg Ramipril.
For excipients, see 6.1
3. PHARMACEUTICAL FORM
Capsule, hard
Light grey and light green gelatin capsules; marked with “R” on the cap and “2.5” on the body.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
For reducing the risk of myocardial infarction, stroke, cardiovascular death or need for revascularisation procedures in patients of 55 years or more who have clinical evidence of cardiovascular disease (previous MI, unstable angina or multivessel CABG or multivessel PTCA), stroke or peripheral vascular disease.
Also for reducing the risk of myocardial infarction, stroke, cardiovascular death or need for revascularisation procedures in diabetic patients of 55 years or more who have one or more of the following clinical findings: hypertension (systolic blood pressure> 160mmHg or diastolic blood pressure> 90mmHg); high total cholesterol >5.2 mmol/L); low HDL (<0.9 mmol/L); current smoker; known microalbuminuria; clinical evidence of previous vascular disease.
Ramipril is indicated for the treatment of mild to moderate hypertension.
Congestive heart failure as adjunctive therapy to diuretics with or without cardiac glycosides.
Ramipril has been shown to reduce mortality when given to patients surviving acute myocardial infarction with clinical evidence of heart failure.
4.2. Posology and method of administration
Dosage and Administration:
Reducing the risk of myocardial infarction, stroke or cardiovascular death and/or the need for revascularisation procedures: The recommended initial dose is 2.5mg Ramipril once a day. Depending on the tolerability, the dose should be gradually increased. It is therefore recommended that this dose is doubled after about one week of treatment then, after a further 3 weeks, it should be finally increased to 10mg. The usual maintenance dose is 10mg Ramipril once a day. Patients already stabilised on lower doses of Ramipril for other indications where possible should be titrated to 10mg Ramipril once daily.
Hypertension: The recommended initial dosage in patients not on diuretics and without congestive heart failure is 1.25 mg Ramipril once a day. Dosage should be increased incrementally at intervals of 1 - 2 weeks, based on patient response, up to a maximum of 10 mg once a day.
A 1.25 mg dose will only achieve a therapeutic response in a minority of patients. The usual maintenance dose is 2.5 - 5 mg as a single daily dose. If the patient response is still unsatisfactory at a dose of 10 mg Ramipril, combination treatment is recommended.
In diuretic treated patients, the diuretic should be discontinued 2 - 3 days before beginning therapy with Ramipril to reduce the likelihood of symptomatic hypotension. It may be resumed later if required.
In hypertensive patients who also have congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients therapy should be started at a dose of 1.25 mg under close medical supervision in hospital.
Congestive heart failure: Recommended initial dose: In patients stabilised on diuretic therapy the initial dose is 1.25 mg once daily. Depending on the patient's response, the dose may be increased. It is recommended that the dose, if increased, be doubled at intervals of 1 to 2 weeks. If a daily dose of 2.5 mg or more is required, this may be taken as a single dose or as two divided doses. Maximum permitted daily dose: 10 mg.
In order to minimise the possibility of symptomatic hypotension, patients on previous high dose diuretics should have the diuretic dose reduced before starting Ramipril.
Post myocardial infarction: Initiation of therapy: Treatment must be started in hospital between day 3 and day 10 following AMI. The starting dose is 2.5 mg twice a day which is increased to 5 mg twice a day after 2 days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5.0 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn.
Maintenance dose: 2.5 to 5.0 mg twice a day.
Dosage adjustment in renal impairment: The usual dose of Ramipril is recommended for patients with a creatinine clearance> 30 ml/min (serum creatinine < 165 pmol/l). For patients with a creatinine clearance < 30 ml/min (serum creatinine>165 pmol/l) the initial dose is 1.25 mg Ramipril once daily and the maximum dose 5 mg Ramipril once daily.
In patients with severe renal impairment (creatinine clearance < 10 ml/min and serum creatinine of 400-650 pmol/l), the recommended initial dose is also 1.25 mg Ramipril once a day, but the maintenance dose should not exceed 2.5 mg Ramipril once a day.
Dosage in hepatic impairment: In patients with impaired liver function the metabolism of the parent compound ramipril, and therefore the formation of the bioactive metabolite ramiprilat, is delayed due to a diminished activity of esterases in the liver, resulting in elevated plasma ramipril levels. Treatment with ramipril should therefore be initiated at a dose of 1.25 mg under close medical supervision in patients with impaired liver function.
Elderly: Caution in elderly patients with concomitant use of diuretics, congestive heart failure or renal or hepatic insufficiency. The dose should be titrated according to need for the control of blood pressure.
Paediatric population : The safety and efficacy of ramipril in children has not yet been established. Currently available data for ramipril are described in sections 4.8, 5.1, 5.2 & 5.3 but no specific recommendation on posology can be made.
Ramipril capsules should be taken with a glass of water. The absorption of ramipril is not affected by food.
Oral administration.
4.3. Contraindications
Hypersensitivity to ramipril or any of the excipients.
History of angioneurotic oedema, haemodynamically relevant renal artery stenosis, hypotensive or haemodynamically unstable patients.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
4.4. Special warnings and precautions for use
Warnings:
Ramipril should not be used in patients with aortic or mitral valve stenosis or outflow obstruction.
Precautions:
Assessment of renal function: Evaluation of the patient should include assessment of renal function prior to initiation of therapy and during treatment.
Impaired renal function: Patients with renal insufficiency may require reduced or less frequent doses of Ramipril; their renal function should be closely monitored. In the majority, renal function will not alter. There is a risk of impairment of renal function, particularly in patients with renal insufficiency, congestive heart failure, bilateral renal artery stenosis and unilateral renal artery stenosis in the single kidney as well as after renal transplantation. If recognised early, such impairment of renal function is reversible upon discontinuation of therapy.
Patients haemodialysed using high flux polyacrylonitrile ('AN69') membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for dialysis. Similar reactions have been observed during low-density lipoprotein apheresis with dextran sulphate. This method should, therefore, not be used in patients treated with ACE inhibitors.
Some hypertensive patients with no apparent pre-existing renal disease, may develop minor and usually transient increases in blood urea nitrogen and serum creatinine when Ramipril is given, in particular concomitantly with a diuretic. Dosage reduction of Ramipril and/or discontinuation of the diuretic may be required. Additionally, in patients with renal insufficiency, there is a risk of hyperkalaemia.
Impaired liver function: As ramipril is a prodrug metabolised to its active moiety in the liver, particular caution and close monitoring should be applied to patients with impaired liver function. The metabolism of the parent compound, and therefore the formation of the bioactive metabolite ramiprilat, may be diminished resulting in markedly elevated plasma levels of the parent compound (due to the reduced activity of esterases in the liver).
Symptomatic hypotension: In patients with uncomplicated hypertension, symptomatic hypotension has been observed rarely after the initial dose of Ramipril as well as after increasing the dose of Ramipril. It is more likely to occur in patients who have been volume- and salt-depleted by prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea, vomiting or patients with severe heart failure. Therefore, in these patients, diuretic therapy should be discontinued and volume and/or salt depletion should be corrected before initiating therapy with Ramipril.
If symptomatic hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline. Intravenous atropine may be necessary if there is associated bradycardia. Treatment with Ramipril may usually be continued following restoration of effective blood volume and blood pressure.
Surgery/anaesthesia: In patients undergoing surgery or during anaesthesia with agents producing hypotension, Ramipril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by appropriate treatment.
Agranulocytosis and bone marrow depression: In patients on angiotensin converting enzyme inhibitors agranulocytosis and bone marrow depression have been seen rarely, as well as a reduction in red cell count, haemoglobin content and platelet count. These are more frequent in patients with renal impairment, especially if they have a collagen vascular disease. Regular monitoring of white blood cell counts and protein levels in urine should be considered in patients with collagen vascular disease (e.g. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy particularly with corticosteroids and anti metabolites. Patients on allopurinol, immunosuppressants and other substances that may change the blood picture also have increased likelihood of other blood picture changes.
Hyperkalaemia: Elevated serum potassium has been observed very rarely in hypertensive patients. Risk factors for the development of hyperkalaemia include renal insufficiency, potassium sparing diuretics and the concomitant use of agents to treat hypokalaemia.
Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
4.5. Interactions with other medicinal products and other forms of interaction
Combination with diuretics or other antihypertensive agents may potentiate the antihypertensive response to Ramipril. Adrenergic-blocking drugs should only be combined with ramipril under careful supervision.
Potassium sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements may increase the risk of hyperkalaemia. Ramipril may attenuate the potassium loss caused by thiazide-type diuretics. If concomitant use of these agents is indicated, they should be given with caution and serum potassium should be monitored regularly.
When antidiabetic agents (insulin and sulphonylurea derivatives) are used concurrently, the possibility of increased blood-sugar reduction must be considered.
When ACE inhibitors are administered simultaneously with non-steroidal antiinflammatory drugs (e.g. acetylsalicylic acid and indometacin), attenuation of the antihypertensive effect may occur.
If Ramipril is given with lithium, an increase in serum lithium concentration may occur.
The protein binding of ramipril is about 73% and of ramiprilat about 56%.
4.6. Pregnancy and lactation
Pregnancy:
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 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 (see sections 4.3 and 4.4).
Lactation:
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 breastfeeding are preferable, especially while nursing a newborn or preterm infant.
4.7. Effects on ability to drive and use machines
In individual cases, as a result of a reduction in blood pressure, treatment with Ramipril may affect the ability to drive and operate machinery. This occurs especially at the start of treatment, when changing over from other preparations and during concomitant use of alcohol. 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
Generally, adverse reactions have been mild and transient, and do not require discontinuation of therapy. The most frequently reported adverse reactions are nausea, dizziness and headache.
Cardiovascular: Symptomatic hypotension accompanied by dizziness, weakness and nausea may occur after the initial dose of Ramipril and after an increase in the dose of Ramipril. It has been rarely observed, but may occur in severely salt/volume-depleted patients such as those treated with diuretics, patients on dialysis and in patients with severe congestive heart failure. Syncope has also been observed rarely.
Myocardial infarction or cerebrovascular accident possibly secondary to severe hypotension in high risk patients, chest pain, palpitations, rhythm disturbances, angina pectoris may occur.
Renal: Treatment with Ramipril may impair renal function.
Gastrointestinal: Treatment with Ramipril may be associated with symptoms in the digestive tract, e.g. dryness of the mouth, irritation or inflammation of the oral mucosa, digestive disturbances, constipation, diarrhoea, nausea, and vomiting, (gastritis-like) stomach pain, upper abdominal discomfort (sometimes with increased levels of pancreatic enzymes), increases in hepatic enzymes and/or serum bilirubin, jaundice due to impaired excretion of bile pigment (cholestatic jaundice), other forms of impaired liver function, and hepatitis.
Pancreatitis has been reported rarely in patients treated with ACE inhibitors; in some cases this has proved fatal.
Allergic: Hypersensitivity reactions accompanied by pruritus, rash, shortness of breath and sometimes fever may occur, but usually resolve spontaneously after withdrawal of Ramipril.
In addition, the following cutaneous and mucosal reactions may occur: reddening of skin areas with accompanying heat sensation, conjunctivitis, itching, urticaria, other skin or mucosal eruptions (maculo-papular and lichenoid exanthema and enanthema, erythema multiforme), sometimes pronounced hair loss, and precipitation or intensification of Raynaud's phenomenon. With other ACE inhibitors psoriasiform and pemphigoid exanthema and enanthema, hypersensitivity of the skin to light and onycholysis have been observed.
Vasculitis, muscle and joint pains, fever, or eosinophilia may occur. Raised titres of antinuclear antibodies have been seen with other ACE inhibitors.
Angioneurotic oedema: In very rare cases angioneurotic oedema has occurred during therapy with ACE inhibitors including Ramipril. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Ramipril must be discontinued and appropriate therapy instituted immediately.
Respiratory tract: A dry tickling cough may occur. This is possibly due to the desired ACE inhibition as are the following adverse effects: rhinitis, sinusitis, bronchitis and, especially in patients with tickling cough, bronchospasm.
Other adverse reactions: Disturbances of balance, headache, nervousness, restlessness, tremor, sleep disorders, confusion, loss of appetite, depressed mood, feeling of anxiety, paraesthesiae, taste change, taste reduction and sometimes loss of taste, muscle cramps, erectile impotence and reduced sexual desire may occur.
Laboratory test findings: Increases in blood urea nitrogen and serum creatinine may occur, in particular with renal insufficiency or in patients pretreated with a diuretic. Pre-existing proteinuria may deteriorate.
Serum sodium levels may decrease. Elevation of serum potassium may occur, since Ramipril leads to a decrease in aldosterone secretion; potassium-sparing diuretics (spironolactone, amiloride, triamterene) or potassium supplements should therefore be avoided.
Paediatric population
The safety of ramipril was monitored in 325 children and adolescents, aged 216 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" (i.e. > 1/100 to < 1/10) in paediatric while "rare” (i.e. > 1/10,000 to < 1/1,000) in adult population.
• Tremor and urticaria "uncommon" (i.e. > 1/1,000 to < 1/100) in paediatric population while "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.
4.9. Overdose
In case of overdosage prolonged hypotension is to be expected. Treatment with an intravenous infusion of physiological saline and/or angiotensin II may be required.
5.1. Pharmacodynamic properties
ATC Code: C09A A05
Ramipril is a prodrug which, after absorption from the gastrointestinal tract, is hydrolysed in the liver to form the active angiotensin converting enzyme (ACE) inhibitor, ramiprilat which is a potent and long acting ACE inhibitor. Administration of ramipril causes an increase in plasma renin activity and a decrease in plasma concentrations of angiotensin II and aldosterone. The beneficial haemodynamic effects resulting from ACE inhibition are a consequence of the reduction in angiotensin II causing dilatation of peripheral vessels and reduction in vascular resistance. There is evidence suggesting that tissue ACE particularly in the vasculature, rather than circulating ACE, is the primary factor determining the haemodynamic effects.
Angiotensin converting enzyme is identical with kininase II, one of the enzymes responsible for the degradation of bradykinin. There is evidence that ACE inhibition by ramipril appears to have some effects on the kallikrein-kinin-prostaglandin systems. It is assumed that effects on these systems contribute to the hypotensive activity of ramipril.
Administration of Ramipril to hypertensive patients results in reduction of both supine and standing blood pressure. The antihypertensive effect is evident within one to two hours after the drug intake; peak effect occurs 3 - 6 hours after drug intake and has been shown to be maintained for at least 24 hours after therapeutic doses.
In a large endpoint study - HOPE - ramipril significantly reduced the incidence of stroke, myocardial infarction and/or cardiovascular death when compared with placebo. These benefits occurred largely in normotensive patients and were shown, using standard regression analysis techniques, to be only partially due to the relatively modest reductions in blood pressure demonstrated in the study. The 10mg dose, currently the highest safe dose level approved, was selected by the HOPE investigators from previous doseranging studies (SECURE, HEART) and was considered to be the most likely dose to effect full blockade of the renin-angiotensin-aldosterone system. This and other studies suggest that ACE inhibitors like ramipril are likely to have other direct effects on the cardiovascular system. These may include the antagonism of angiotensin II mediated vasoconstriction, the inhibition of proliferating vascular smooth muscle and plaque rupture, the enhancement of endothelial function, the reduction of LV hypertrophy and positive effects on fibrinolysis. Additional effects in diabetic patients may also contribute e.g. effects on insulin clearance and pancreatic blood flow.
Paediatric population
In a randomized, double-blind clinical study involving 244 paediatric patients with hypertension (73% primary hypertension), aged 6-16 years, patients received either low dose, medium dose or high dose of ramipril to achieve plasma concentrations of ramiprilat corresponding to the adult dose range of 1.25 mg, 5 mg and 20 mg on the basis of body weight. At the end of 4 weeks, ramipril was ineffective in the endpoint of lowering systolic blood pressure but lowered diastolic blood pressure at the highest dose. Both medium and high doses of ramipril showed significant reduction of both systolic and diastolic BP in children with confirmed hypertension.
This effect was not seen in a 4 weeks dose-escalation, randomized, doubleblind withdrawal study in 218 paediatric patients aged 6-16 years (75% primary hypertension), where both diastolic and systolic blood pressures demonstrated a modest rebound but not a statistically significant return to the baseline, in all three dose levels tested: low dose (0.625 mg - 2.5 mg), medium dose (2.5 mg - 10 mg) or high dose (5mg - 20 mg) ramipril based on weight. Ramipril did not have a linear dose response in the paediatric population studied.
5.2. Pharmacokinetic properties
Following oral administration ramipril is rapidly absorbed from the gastrointestinal tract; peak plasma concentrations of ramipril are reached within one hour. Peak plasma concentrations of the active metabolite, ramiprilat, are reached within 2 - 4 hours.
Plasma concentrations of ramiprilat decline in a polyphasic manner. The effective half-life of ramiprilat after multiple once daily administration of ramipril is 13 - 17 hours for 5 - 10 mg ramipril and markedly longer for lower doses, 1.25 - 2.5 mg ramipril. This difference is related to the long terminal phase of the ramiprilat concentration time curve observed at very low plasma concentrations. This terminal phase is independent of the dose, indicating a saturable capacity of the enzyme to bind ramiprilat. 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.
Ramipril is almost completely metabolised and the metabolites are excreted mainly via the kidneys. In addition to the bioactive metabolite, ramiprilat, other, inactive metabolites have been identified, including diketopiperazine ester, diketopiperazine acid and conjugates.
Lactation:
One single 10 mg oral dose of ramipril produced an undetectable level in breast milk. However the effect of multiple doses is not known.
Paediatric population
The pharmacokinetic profile of ramipril was studied in 30 paediatric hypertensive patients, aged 2-16 years, weighing >10 kg. After doses of 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Peak plasma concentrations of ramiprilat occurred within 2-3 hours.
Ramiprilat clearance highly correlated with the log of body weight (p<0.01) as well as dose (p<0.001). Clearance and volume of distribution increased with increasing children age for each dose group.
The dose of 0.05 mg /kg in children achieved exposure levels comparable to those in adults treated with ramipril 5mg. The dose of 0.2 mg/kg in children resulted in exposure levels higher than the maximum recommended dose of 10 mg per day in adults.
5.3. Preclinical safety data
Reproduction toxicology studies in the rat, rabbit and monkey did not disclose any teratogenic properties. 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 and higher.
Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Capsule filling:
Pregelatinised starch.
Capsule shell:
Gelatin
Titanium Dioxide (E171)
Black Iron Oxide (E172)
Yellow Iron Oxide (E172)
Indigo Carmine FD & C Blue 2 (E132)
Printing Ink:
Shellac Glaze - 47.5%
Black Iron Oxide (E172)
Soya Leicithin (E322)
Antifoam DC 1510
6.2.
Incompatibilities
Not applicable
6.3. Shelf life
24 months
6.4. Special precautions for storage
Do not store above 25 °C.
Store in the original packaging.
6.5. Nature and contents of container
Al/Al Blister pack.
Pack sizes: 7, 21, 28, 30, 50, 100 capsules. *Not all sizes may be marketed
6.6. Instruction for use and handling (, and disposal)
No special requirements
7. MARKETING AUTHORISATION HOLDER
Waymade Plc trading as Sovereign Medical
Sovereign House
Miles Gray Road
Basildon
Essex
SS143FR
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 06464/2030
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19/10/2005
10 DATE OF REVISION OF THE TEXT
24/05/2013