Therapeutic Category:Cardiovascular drugs
Pharmacologic Category:Angiotensin-Converting Enzyme (ACE) Inhibitor - Thiazide Diuretic
Composition:Ramipril 2.5mg - HydroChlorThiaZide 12.5mg
Ramipril & Hydrochlorothiazide
CO-RAMIPRIL ELSaad: Each capsule contains Ramipril 2.5 mg and Hydrochlorothiazide12.5 mg.
Ramipril is a prodrug of ramiprilate ,which is a potent and long-acting inhibitor of the angiotensin converting enzyme (ACE). Hydrochlorothiazide is a thiazide diuretic and an antihypertensive. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts.
The components have an improved efficacy. Ramipril blocks the counterregulatory rise in angiotensin II triggered by diuretic therapy. Diuretics appear to enhance the antihypertensive action of ACE inhibitors particularly when the renin-angiotensin system is inactive. As a result, patients who do not respond to monotherapy often do respond to combination therapy.
CO-RAMIPRIL ELSaad is indicated for the treatment of mild to moderate hypertension in patients (in whom combination therapy is appropriate) who have been stabilized on the individual components given in the same proportion.
CO-RAMIPRIL ELSaad must not be used in:
Patients with hypersensitivity to ramipril, hydrochlorothiazide or other thiazide diuretics, sulphonamides or any of the excepients
History of hereditary angioneurotic oedema
It is not recommended in patients with severe hepatic and renal impairment.
Haemodynamically relevant unilateral or bilateral renal artery stenosis, mitral stenosis,
aortic stenosis, and in patients with low blood pressure or in patients with an unstable
circulatory situation haemodynamically unstable patients) where there might be a risk of
lifethreatening fall in blood pressure and renal failure.
Clinically electrolyte disturbances e.g. hypokalemia, hyponatremia or hypercalcemia
which may worsen following treatment.
5- PREGNANCY & LACTATION:
CO-RAMIPRIL ELSaad should not be used in pregnancy as it affects development of the foetus. If the patient becomes pregnant during treatment, The drug must be replaced with some other group of antihypertensive agents.
If treatment with CO-RAMIPRIL ELSaad is necessary during the lactation period, the infant should not be breastfed.
Special caution is necessary the treatment of:
patients with severe a malignant hypertension, patients with severe heart failure,
patients with haemodynamically relevant stenosis of coronary arteries or of the blood
vessels supplying the brain.
Patients in whom fluid or salt deficiency exists or may develop as a result of inadequate
fluid or salt intake or as result of diarrhoea, vomiting or exccssivc sweating in cases
where salt and fluid replacement is inadequate.
Patients with haemodynamically relevant renal artery stenosis.
In patients with pre-existing impairment of renal function or in kidney transplant patients.
Pre-existing coronary artery disease or cerebrovascular disease, a sudden fall
in blood pressure may cause perfusion disturbances to the heart (angina
pectoris or myocardial infarction) or the brain (transient ischemic attacks or
Serum sodium, potassium ,calcium, uric acid, and blood sugar should be monitored
regularly. More frequent monitoring of potassium is necessary in patients with impaired
Hydrochlorothiazide may contribute to the development or hypochloremia,
hypomagnesemia as well as hypercalcemia. In addition Co- Ramipril Elsaad may contribute to development or aggravation of metabolic alkalosis.
Ramipril may contribute ,in increase in concentration or serum potassium
while hydrochlorothiazide may contribute to a decrease in serum potassium.
White blood cell count should monitored (more frequent in the initial phase of the treatment) so that leucopenia can be detected.
During treatment with Hydrochlorothiazide and thus, with Co- Ramipril Elsaad increased blood concentrations of uric acid levels may occur. This may lead to attacks particularly in those patients whose uric acid levels are already elevated.
Hydrochlorothiazide might lower the tolerance of glucose, In patients with diabetes mellitus this may lead to deterioration of metabolic control. A latent
diabetes mellitus may become manifest for the first time. Hydrochlorothiazide
may cause an increase in serum cholesterol and triglycerides.
Raised titres of antinuclear antibodies have been seen with other ICE inhibitors.
In temporal relationship with the use of hydrochlorothiazide, the development
of lupus erythematosus has been described.
- The antihypertensive effect may affect the ability to drive therefore caution should be
taken specially at the start of treatment.
7- ADVERSE REACTIONS:
The following adverse effects can be observed during therapy with CO-RAMIPRIL ELSaad:
- Cardiovascular effects: Hypotension characterized in light-headedness, concentration disturbances, fatigue, dizziness, weakness may occur. In excessive hypotension tachycardia, palpitation, orthostatic hypotension, nausea, headache, tiredness, or tinnitus may occur.
- Renal effects: Deterioration in renal function under certain circumstances specially in patients with renovascular diseases and subsequent electrolyte disturbances
- Gastrointestinal reactions: Reactions in digestive tract may develop including dryness of mouth, irritation or inflammation of oral mucosa, constipation, diarrhea, nausea and vomiting, gastritis like abdominal pain, pancreatitis, increase in hepatic enzymes and/or bilirubin, cholestatic jaundice and other forms of impaired liver function.
- Blood profile: Some changes in blood picture may occur such as: a mild to severe reduction in red blood cell count and hemoglobin content, blood platelets and white blood cell count, impaired blood cell formation(bone marrow depression) , pancytopenia.
- There are some other adverse reactions: visual disorders, headache, nervousness, restlessness, tremor, sleep disturbances, loss of appetite, depressed mood, feeling of anxiety and muscle cramps. abnormal sensation Erectile impotence may occur. Muscle and joint pains, fever, eosinophilia may occur. Increased blood concentrations of uric acid levels, lowered glucose tolerance may occur during treatment with hydrochlorothiazide.
- Combination with diuretics or other antihypertensive agents or nitrates and tricyclic antidepressants may potentiate the antihypertensive response to CO-RAMIPRIL ELSaad. Patients previously treated with diuretics may experience a marked drop in blood pressure.
- Potassium-sparing diuretics such as spironolactone, amiloride and triamterene or potassium supplements may increase the risk of hyperkalemia.
- Leukopenia may be aggravated in patients undergoing treatment with immunosuppressants, cytostatic agents, systemic corticosteroids or allopurinol. Concurrant administration of methyldopa may result in hemolysis.
- Co-Ramipril ELSaad may weaken the effectiveness of blood sugar lowering medications
(anti diabetic agents, e.g. insulin and sulphonylurea derivatives).
- ACE inhibitors decrease the excretion of lithium salts, lithium concentrations in the blood should be monitored in patients undergoing such therapy.
- Coadministration with nonsteroidal anti-inflammatory agents (acetyl salicylic acid or indomethacin) it may attenuate the antihypertensive effect or may cause acute renal failure.
- Co-Ramipril ELSaad may potentiate the effects of alcohol.
9- DOSAGE AND ADMINISTRATION
Hypertension: The recommended initial dosage is 1 capsule of CO-RAMIPRIL ELSaad once a day. The dose can be up titrated at intervals of 2-3 weeks to ramipril 5mg and hydrochlorothiazide 12.5mg and then to a maximum of ramipril 10 mg and hydrochlorothiazide 12.5 mg. If required another antihypertensive agent may be added. In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic at least 2-3 days (depending on the duration of action of the diuretic) longer before initiating the treatment
with CO-RAMIPRIL ELSaad. If discontinuation is not possible the treatment should be initiated with the smallest possible dose of ramipril (1.25mg daily) in a free combination. Subsequently a changeover to an initial daily dose of CO-RAMIPRIL ELSaad not exceeding one capsule should be made.
Dosage in patients with impaired renal function:
For patients with creatinine clearance between 60 and 30ml/min/1.73m2 body surface area, treatment is initiated with ramipril alone 1.25mg. After gradually increasing the dose of ramipril, medication with CO-RAMIPRIL ELSaad is initiated at a daily dose of 1 capsule. The maximum permitted daily dose is 2 capsules of CO-RAMIPRIL ELSaad in such patients
* The prescribed daily dose should be taken in the morning as a single dose. They may be taken before during or after a meal.
Absorption: The extent of absorpation is at least 50-60% and is not significantly
influenced by the presence of food in the GI tract, although the rate of absorption is reduced.
Metabolism: Cleavage of the ester group (primarily in the liver) converts ramipril to its
active metabolite ,ramiprilat.
Time to peak serum: Ramipril : 1 hour; Ramiprilat: 2-4 hours
Protein binding: Ramipril: 73%, Ramiprilat: 56%.
Excretion: Urine (60'%) and faces (40%) as parent drug and its mctabolites
Bioavailability Ramipril: 28%, Ramiprilat: 44%.
Plasma levels decline in atriphasic fashion:
The initial rapid decline phase ramipril due to tissue distribution has a half-life of 2-4 hours. The second phase "apparent elimination phase" has a half-life 9-18 hours. The terminal elimination phase has a prolonged half-life (>50 hours).
After multiple daily dose of ramipril 5-10 mg, the half- Life of ramiprilat concentrations within the therapeutic range was 13-17 hours.
The onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours.
The action persists for approximately 6-12 hours. Hydrochlorothiazide is rapidly
absorbed, as indicated by peak plasma concentrations 1-2.5 hours after oral administration.
Plasma levels of the drug are proportional to close: the concentration in whole blood is 1.6-1.8 times than in plasma.
Thiazides are eliminated rapid by the kidney. After oral administration of 12.5 to
100mg doses, 72-97% of dose is excreted in the urine, indicating dose independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a
terminal half-life of 10-17 hours, Plasma protein binding is 67.9%. Plasma clearance is
15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg.
Gastrointestinal absorplloi1 of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the
pharmacokinetics are considerably different in these patients.
11- PACKAGING :
CO-RAMIPRIL ELSaad: A pack of 10 capsules.
12- STORAGE CONDITION:
Store in dry place at temperature between (15-30)ºC.