• Ramipril + hydrochlorothiazide

2.5 mg ramipril/12.5 mg hydrochlorothiazide
5 mg ramipril/12.5 mg hydrochlorothiazide
10 mg ramipril/12.5 mg hydrochlorothiazide
5 mg ramipril/25 mg hydrochlorothiazide
10 mg ramipril/ 25mg hydrochlorothiazide

Therapeutic Categories: Cardiovascular Drugs
Pharmaceutical Form: Tablets

Each tablet contains:
2.5 mg ramipril/12.5 mg hydrochlorothiazide
5 mg ramipril/12.5 mg hydrochlorothiazide
10 mg ramipril/12.5 mg hydrochlorothiazide
5 mg ramipril/25 mg hydrochlorothiazide
10 mg ramipril/ 25mg hydrochlorothiazide

Mechanism of Action

Ramipril is a potent and long-acting inhibitor of the angiotensin converting enzyme(ACE). It is a prodrug, which is hydrolyzed in the liver after absorption from the gastro-intestinal tract to form the active angiotensin converting enzyme inhibitor, ramiprilat. Hydrochlorothiazide (HCTZ) is a thiazide diuretic and an antihypertensive. The components have quite different but complementary antihypertensive mechanisms, and the improved efficacy is not due simply to additive antihypertensive effects. Ramipril blocks the counterregulatory rise in angiotensin II triggered by diuretic therapy. Diuretics appear to enhance the antihypertensive action of ACE inhibitors.



ramipril is rapidly absorbed after oral administration, absorption of ramipril is at least 56%. Administration of ramipril at the same time as food has no relevant effect on absorption., approximately 20% of rally administered ramipril is bioavailable.

 Peak plasma concentrations of ramiprilat are reached 2 to 4 hour.  

The prodrug ramipril undergoes an extensive hepatic first pass metabolism, which is essential for the formation of the sole active metabolite ramiprilat.

Approximately 80 to 90% of the metabolites in urine and bile have been identified as ramiprilat or ramiprilat metabolites. A single daily dose of 2.5 mg ramipril or more yields steady state plasma concentrations of ramiprilat after approximately 4 days. The "effective" half-life, which is relevant for dosage, is 13 to 17 hours under multiple-dose conditions.


 Approximately 70% of hydrochlorothiazide is absorbed after oral administration; the bioavailability of hydrochlorothiazide is approximately 70%, 40% of hydrochlorothiazide is bound to plasma proteins.

Hydrochlorothiazide undergo negligible hepatic metabolism.

Hydrochlorothiazide is excreted almost entirely (more than 95%) by renal route in unchanged form.

The elimination half-life is 5 to 6 hours. In renal insufficiency excretion is reduced and the half-life prolonged.


- Ramithiazid (ramipril/hydrochlorothiazide) is indicated for the treatment of essential hypertension in patients for whom this combination therapy(antihypertensive  and diuretic) is appropriate.

- Ramithiazid is not indicated for initial therapy. Patients in whom ramipril and diuretic are initiated simultaneously can develop symptomatic hypotension.


Ramithiazid (ramipril/hydrochlorothiazide) is contraindicated in:

 • patients who are hypersensitive to any of its constituents: Ramipril (or any ACE inhibitor) or Hydrochlorothiazide or to any ingredient in the formulation

 • patients who have a history of angioedema

• during pregnancy and in breast feeding-women

• Because of the hydrochlorothiazide component,Ramithiazid is contraindicated in patients with anuria or hypersensitivity to thiazides and other sulfonamide-derived drugs


When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected Ramithiazid (ramipril/hydrochlorothiazide) should be discontinued as soon as possible.


Angioedema: If laryngeal stridor or angioedema of the face, extremities, lips, tongue, glottis or difficulty in swallowing or breathing   occurs, Ramithiazid should be discontinued immediately and consult with their physician. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 to 0.5 ml of subcutaneous epinephrine solution 1:1000) should be administered promptly.

If intestinal angioedema which presented with abdominal pain (with or without nausea or vomiting) occurs  Ramithiazid should be stopped.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor

Cough: A dry, persistent cough, which usually disappears only after withdrawal of Ramithiazid, has been reported.

Aortic stenosis: There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop

as much afterload reduction.

Hypotension Symptomatic hypotension has occurred after administration of ramipril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

Because of the potential fall in blood pressure in these patients, therapy with Ramithiazid should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose Of  Ramithiazid is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has

been associated with oliguria, and/or progressive azotemia, and rarely, with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response may not be a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion in hypertensive patients. However, lower doses of Ramithiazid should be considered. In patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of Ramithiazid.

Ramithiazid may lower the state of patient alertness and/or reactivity, particularly at the start of treatment. Patients should be cautioned to report lightheadedness, especially during the first few days of Ramithiazid therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure, patients should be advised to consult with their physician.


Several cases of agranulocytosis, neutropenia or leukopenia have been reported. Periodic monitoring of white blood cell counts should be considered especially in patients with collagen vascular disease and/or renal disease.

Patients should be told to report promptly to their physician any indication of infection (e.g. sore throat, fever) as this may be a sign of neutropenia.


Patients should be advised to return to their physician if they experience any symptoms possibly related to liver dysfunction. This would include "viral-like symptoms" in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy

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. There are no adequate studies in patients with cirrhosis and/or liver dysfunction.

Ramithiazid should be used with particular caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close  monitoring of response and metabolic effects should apply.

Anaphylactoid Reactions to ACE Inhibitors

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes [e.g. polyacrylonitrile (PAN)] and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines.

In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (e.g. bees, wasps) venoma. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Hypersensitivity to Thiazide Diuretics :

Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.


Thiazides, including HCT, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis, hypomagnesemia). Elevated serum potassium was observed in approximately 1% of hypertensive patients in clinical  trials treated with the ACE inhibitor ramipril. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium.

Hyperuricemia may occur, or acute gout may be precipitated. Thiazides may decrease serum PBI (protein-bound iodine) levels.

 Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests of parathyroid function.

Increases in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy.

Dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Administration of ACE inhibitors in patients with diabetes may potentiate the blood glucose lowering effect of oral hypoglycemic agents or insulin.


Thiazides may increase the responsiveness to tubocurarine .

Patients planning to undergo surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor.


As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 mL/min or below (i.e., moderate or severe renal insufficiency).

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.


The most frequent adverse drug reactions: Headache, dizziness, bronchitis, tachycardia, cough, hypotension.


ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, Ramithiazid should be discontinued as soon as possible.

Ramithiazid should not be administered to nursing mothers.


The safety and effectiveness of Ramithiazid in children have not been established; therefore

use in this age group is not recommended.


Because of decreased cardiovascular reserve, greater sensitivity in older patients (> 65 years)

may be expected


concomitant diuretic therapy:
Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was  recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized

Agents increasing serum potassium:
Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of  hyperkalemia. Therefore if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

Agents causing rennin release:
The antihypertensive effect of ramipril is augmented by antihypertensive agents that cause rennin release.

Increase serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors and thiazides during therapy with lithium. These drugs shoud be administered with caution, and frequent monitoring of serum lithium levels is recommended.

The bioavailability of ramipril and the pharmacokinetics profile of ramiprilat were not affected by concomitant administration of antacids.

No changes in serum levels of ramipril, ramiprilat, and digoxin while taking ramipril and digoxin, but digoxin toxicity occur with thiazides. So monitoring of serum electrolytes particularly potassium and magnesium levels, and administer potassium or magnesium supplements as required.

The co-administration of rampril with warfarin did not alter the anticoagulant effects.

Non-steroidal anti-inflammatory agents:
Concomitant treatment with ACE inhibitors and Non-steroidal anti-inflammatory drugs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Possible attenuation of the diuretic, natriuretic, and antihypertensive effects.

No significant change in blood pressure, thrombotest time and coagulation factors with ramipril.

Antidiabetic agents:
Concomitant treatment with ACE inhibitors and antidabetics lead to hypoglycaemic reactions. close glucose monitoring is recommended in initial phase of co-administration.

Concomitant treatment with thiazides and antidiabetics lead to hyperglycemic reactions, so monitor for changes in glycemic control and ensure adequate potassium levels are required.

Skeletal muscle relaxants:
Thiazides may enhance the effects of nondepolarizing skeletal muscle relaxants potentially leading to      prolonged respiratory depression.

May decrease  antihypertensive effect.

Alcohol, barbiturates, narcotics:
Orthostatic hypotension may occur. Alcohol, barbiturates, and narcotics may potentiate the antihypertensive effects.

Hypokalemia may occur and possible reversal of thiazide antihypertensive response via corticosteroid- induce salt and water retention. So monitoring of serum potassium levels and blood pressure are required.

Drug-Laboratory Test Interactions

Tests for Parathyroid Function

Hydrochlorothiazide stimulates renal calcium reabsorption and may cause hypercalcemia. This must be considered when carrying out tests for parathyroid function.


Overdosage may cause persistent diuresis, excessive peripheral vasodilatation (with marked hypotension, electrolyte disturbances, cardiac arrhythmias, impairment of consciousness up to and including coma and cerebral convulsions

Treatment or Management of Overdose

Primary detoxification : administration of adsorbants 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. In attempting to eliminate ramipril, or ramiprilat, limited/no experience is available concerning the efficacy of forced diuresis, altering urine pH, haemofiltration or dialysis. If dialysis or haemofiltration is nevertheless contemplated, consider risks of anaphylactoid reactions with high flux membrane Removal of thiazide diuretics by dialysis is negligible.


Dosing Considerations
- Dosage should be individualized.
- Ramithiazid (ramipril/hydrochlorothiazide) is not for initial therapy.
- The dose of Ramithiazid should be determined by the titration of the individual components.
- Special attention for dialysis patients.

Recommended Dose and Dosage Adjustment
Once the patient has been successfully titrated with the individual components as described below, Ramithiazid may be substituted if the titrated dose and dosing schedule can be achieved by the fixed combination Usual dosage: 2.5 mg ramipril and 12.5 mg hydrochlorothiazide (corresponding to 1 tablet Ramithiazid 2.5/12.5) daily. Generally it is recommended that the daily dose be administered in the morning as a single dose. Maximum daily dose: 10 mg ramipril and 50 mg hydrochlorothiazide (corresponding to 4 tablets Ramithiazid 2.5/12.5 or 2 tablets Ramithiazid 5/25).

Dosage in patients with impaired renal function
Creatinine clearance 30 to 60 ml/min per 1.73 m² body surface area: the maximum recommended daily dose for renally impaired patients is 5 mg ramipril/25 mg hydrochlorothiazide. (corresponding to 2 tablets Ramithiazid 2.5/12.5 or 1 tablet Ramithiazid 5/25).

Missed dose: If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the Regular dosing schedule. Do not double doses.

Administration Ramithiazid tablets should be swallowed with sufficient amounts of liquid (approximately ½ glass). The tablets must not be chewed or crushed. Generally, it is recommended that the daily dose be administered in the morning as a single dose. No substantial food effects is to be expected with Ramithiazid


Store Ramithiazid (ramipril/hydrochlorothiazide) in original container at room temperature.
Presentation: Box contains 30 tablets.