of Ramipri1/12.5 mg hydrochlorothiazide. Ramipril & Hydrochlorothiazide 5 mg/12.5 mg, 5 mg125 mg, 10 mg/12.5 mg and 10 mg/25 mg must not be used in these pat ients.

Dosing in patients pre-treated with diuretics In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic at least 2 to 3 days or (depending on the duration of action of the diuretic) longer before starting treatment with Ramipril & Hydrochlorothiazide or at least to reducing the diuretic dose. Should discontinuation not be possible, it is recommended that treatment be initiated with the smallest possible dosage of Ramipal (1.25 mg daily) in a free combination. It is recommended that, subsequently, a changeover be made to an initial daily dose of not more than 2.5 mg Ramipril /12.5 mg hydrochlorothiazide.

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.

Overdosage Ramipril/Ramipril & Hydrochlorothiazide Overdose may cause excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte disturbances and renal failure. Primary detoxification e.g; gastric lavage, administration of adsorbents, sodium sulfate (if possible during first 30 minutes). In case of hypotension, administration of 1-adrenergic agonists (e.g; norepinephrine, dopamine) and angiotensin II (angiotensinamide) must be considered in addition to volume & salt substitution. Removal of thiazide diuretics by dialysis is negligible.

CONTRAINDICATIONS Ramipril: Ramipril Tablets are contraindicated in patients who are hypersensitive to this product or any other angiotensin converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

Ramipril & Hydrochlorothiazide: Ramipril & hydrochlorothiazide is contraindicated in patients with hypersensitivity to Ramipril, any other angiotensin converting enzyme (ACE) inhibitor, hydrochlorothiazide, other thiazide diuretics, sulfonamides or any of the excipients of Ramipril & Hydrochlorothiazide.

ADVERSE REACTIONS Hypotension, hesdsche, dizziness, vomiting, bronchitis, tachycardia, asthenia (fatigue), neuralgia, vertigo, cough increased, nausea, angina pectoris, syncope, abnormal kidney function, diarrhea, impotence.

WARNINGS & PRECAUTIONS Ramipril/Ramipril & Hydrochlorothiazide Cough A dry, persistent cough, which usually disappears only after withdrawal or lowering the dose of Ramipril &Hydrochlorothiazide, has been reported. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with alisldren containing medicines Dual blockade of the renin-angiotensin-aldosterone system by combining Ramipril & Hydrochlorothiazide with alislciren is not recommended since there is an increased risk of hypotension, syncope, stroke, hyperkalemia and changes in renal function, including renal failure. The use of Ramipril & Hydrochlorothiazide in combination with aliskiren is contraindicated in patients with diabetes mellitus (type 1 or type 2) or with moderate renal impairment (GER<60 ml/min/1.73m2) and is not recommended in other patients.

Aortic Stenosis Patients with aortic stenosis might be at particular risk of decreased coronary perfusion.

Hypotension Patients with severe congestive heart failure with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension.

Agranulocytosis Agranulocytosis and bone marrow depression have been caused by ACE inhibitors.

Hepatic/Biliary Ramipril & Hydrochlorothiazide is not to be used in patients with severe impairment of hepatic function.

Angioedema Intestinal & Laryngeal Angioedema has been reported with the use of Ramipril & Hydrochlorothiazide.

Metabolism HCT, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). It may cause Hyperuricemia, hypomagnesemia, decreased serum PHI (protein-bound iodine) and hypercalcemia.

Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide can cause acute transient myopia and acute angle-closure glaucoma. Surgery/Anesthesia Patients planning to undergo surgery and/or anesthesia should be told to inform their physician that they are taking anACE inhibitor because of the possibility of going in to hypotension.

Renal Ramipril & Hydrochlorothiazide should be used with caution in patients with renal insufficiency.

Pregnancy (Category D) When pregnancy is detected, Ramipril & Hydrochlorothiazide should be discontinued as soon as possible. Nursing Mothers Ratnipril & Hydrochlorothiazide should not be administered to nursing mothers. Pediatrics The safety and effectiveness of Ramipril & Hydrochlorothiazide in children have not been established. Geriatr ics Because of decreased cardiovascular reserve, greater sensitivity in older patients (> 65 years) may be expected. Evaluation of renal function at beginning of treatment is recommended.

DRUG INTERACTIONS Ramipril Aliskiren-containing medicines The combination of ramipril with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or moderate renal impairment (GFR <60 mL/min) and is not recommended in other patients.

Antihypertensive drugs Possible potentiation of the antihypertensive effect must be anticipated when ramipril is administered concurrently with other antihypertensive agents and other substances with antihypertensive potential (eg. nitrates, tricyclic antidepressants, anaesthetics). Regular monitoring of serum sodium is recommended in patients undergoing concurrent diuretic therapy

Vasopressor sympathomimetics The antihypertensive effect of ranapril may be reduced by concurrent administration of vasopressor sympathomimetics. Particularly close blood pressure monitoring is recommended.

Diuretics Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipal. If this is not possible, the starting dose should be reduced. Regular monitoring of serum sodium is necessary in patients undergoing concurrent diuretic therapy.

Potassium supplements, potassium sparing diuretics Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium sparing diuretics (spironolactone, amiloride, trianiterene and others), potassium supplements can increase the risk of hyperkalaemia. Therefore, if concomitant use of such as

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Ramipace®

(Ramipril 1.25, 2.5, 5 & 10mg)RamipaceD®

(Ramipril & Hydrochlorothiazide 2.5/12.5 mg, 5/12.5 & 10/12.5mg)

COMPOSITION:Ramipace (Ramipril)Ramipace ®1.25mg:Each tablet contains Ramipril 1.25mgRamipace ® 2.5mg:Each tablet contains Ramipril 2.5mgRamipace ®5mg:Each tablet contains Ramipril 5mgRamipace ® 10mg:Each tablet contains Ransipril 10mg

Ramipace-D® (Ramipril & Hydrochlorothiazide)Ramipace-D®2.5/12.5mg:Each tablet contains Ramipril 2.5mg/ Hydrochlorothiazide 12.5mgUSPRamipace-D®5/12.5mg:Each tablet contains Ramipril 5mg/ Hydrochlorothiazide 12.5mgUSPRamipace-D®10/12.5mg:Each tablet contains Ramipril 5mg/ Hydrochlorothiazide 12.5mgUSPDESCRIPTIONRamiprilRamipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acidderivative.Ramimil & HydrochlorothiazideRamipril & Hy drochlorothiazide is a combination tabletcontaining two drugs. Ramipril and hydrochlorothiazideHydrochlorothiazide is a thiazide diuretic,

CLINICAL PHARMACOLOGY Mechanism of ActionRamiprilRamnipril and Ramiprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyldipeptidase that catalyzes the conversion of angiotensin Ito thevasoconstrictor substance, angiotensin II. Angiotensin II alsostimulates aldosterone secretion by the adrenal cortex. Inhibitionof ACE results in decreased plasma angiotensin II, which leads o decreased vasopressor activity and to decrease aldosteronesecretion.Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. The effect ofRamipril on hypertension appears to result at least in part frominhibition of both tissue and circulating ACE activity, therebyreducing angiotensin II formation in tissue and plasma. ACE isidentical to kininase, an enzyme that degrades bradylcinin. Whetherincreased levels of bradykinin, a potent vasodepressor peptide,play a role in the therapeutic effects of Ramipril remains to beelucidated. While the mechanism through which Rannipril lowersblood pressure is believed to be primarily suppression of therenin-angiotensin-aldosterone system. Ramipril has anantihypertensive effect even in patients with low-reninhypertension.

Pharmacoldnetics and MetabolismRamiriral:Following oral administration of Ramipril. peak plasma concentrtions of Ramipril are reached within one hour. The extent of absorption is at least 50-60% and is not significantly influenced by the presence of food in the GI tract. Ramipril is almost completely metabolized to Ramiprilat. After oral administration about 60% of the parent drug and its metabolites are eliminated in the urine and about 40% is foundin the feces.

Hydrochlorothiazide:The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax) is reached within 2 to 5 hours after oral administration. There is no clinically- significant effect of food on the bioavailability of hydrochlorothiazide. Hydrochlorothiazide is not metabolized. About 70% of an orally administered dose ofhydrochlorothiazide is eliminated in the urine as unchanged drug.

PharmacodynamicsSingle doses of Ramipril of 2.5-20 mg produce approximately 60-80% inhibition of ACE activity 4 hours after dosing with approximately 40-60% inhibition after 24 hours. Multiple oraldoses of Ramipril of 2.0 mg or more cause plasma ACE activityto fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. Themore prolonged effect of even small multiple doses presumably reflect saturation of ACE binding sites by Ramiprilat andrelatively slow release from those sites.Hydrochlorothiazide:After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12hours.

INDICATIONS AND USAGEFor oral use. Can be taken with or without food.Ramipril:Ramipril is indicated in patients 55 years or older at high risk ofdeveloping a major cardiovascular event to reduce the risk ofmyocardial infarction, stroke or death from cardiovascular causes.Ramipril can be used n addition to other needed treatment (suchas antihypertensive. antiplatelet or lipid-lowering therapy). Ramipril is indicated for the treatment of hypertension. It may be used aloneor in combination with thiazide diuretics.Ramimil is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few daysafter sustaining acute myocardial infarction.

Ramipril & Hydrochlorothiazide:Ramipril & Hydrochlorothiazide is indicated for the treatment of essential hypertension in patients for whom this combinationtherapy is appropriate.Ramipril & Hydrochlorothiazide is not indicated for initial therapy. Patients in whom Ramipril and diuretic are initiated simultaneouslyan develop symptomatic hypotension.

DOSAGEANDADAHNISTRATIONRamipril:Blood pressure decreases associated with any dose of ramiprildepend, in part. on in the presence or absence of volume depletion(e.g., past current diuretic use) or the presence or absenceof renal artery stenosis. If such circumstances are suspected tobe present. the initial starting dose should be 1.25 mg once daily.

Reduction in Risk of Myocardial Infarction, Stroke, andDeath from Cardiovascular CausesRamipril should be given at an initial dose of 2.5 mg, once a dayfor 1 week, 5 mg, once a day for the next 3 weeks. and thenincreased as tolerated, to a maintenance dose of 10 mg, once a day.If the patient is hypertensive or recently post myocardial infarction. itcan also be given as a divided dose.

HypertensionThe recommended initial dose for patients to be treated for hyperten-sion, not receiving a diuretic is 2.5 mg once a day Dosage should be adjusted according to the blood pressure response. The usual maintenance dosage range is 2.5 to 20 mg per dayadministered as a single dose or in two equally divided doses. In some patients treated once daily. the antihypertensive effect may diminish toward the end of the dosing interval. In such patients.an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with Ramipril alone,a diuretic can be added.

Heart Failure Post Myocardial InfarctionFor the treatment of post-infarction patients who have shownsigns of congestive failure. the recommended starting dose of Ramipril is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mgtwice daily, and after one week at the starting dose, patients should

then be titrated (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart. After the initial doseof Ramipril, the patient should be observed under medical supenision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of Ramipril does not preclude subsequent careful dose titrationwith the drug. following effecthe management of the hypotension. The Ramipril tablet is usually swallowed whole. Concomitant administra-tion of Ramipril with potassium supplements. potassium salt substitutes. or potassium-sparing diuretics can lead to increasesof serum potassium. In patients who are currently being treatedwith a diuretic. symptomatic hypotension occasionally can occur following the initial dose of Ramipril. To reduce the likelihood of hypotension, the diuretic should. if possible, be discontinued twoto three days prior to beginning therapy with Rai/lima. Then. ifblood pressure is not controlled with Ramipril alone. diuretictherapy should be resumed. If the diuretic cannot be discontinued.an initial dose of 1.25 mg Rannpril should be used to avoid excesshypotension.

Ramimil & Hydrochlorothiazide:• Dosage should be individualized.• Ramipril & hydrochlorothiazide is not for the initial therapy• The dose of the Ramipril & hydrochlorothiazide should be Determind by the titration of the individual components.• Special attention for dialysis patients.

Recommended Dose & Dosage AdjustmentUsual dosage: 2.5 mg Ramipril and 12.5 m g hydrochlorothiazide (corresponding to 1 tablet Ramipril & Hydrochlorothiazide2.5/12.5) daily. Generally it is recommended that the daily dose be administered in the morning as a single dose. Maximum daily dose: 10 mg Rannpril and 50 mg hydrochlorothiazide (corresponding to4 tablets Ramipril & Hydrochlorothiazide 2.5/12.5 or 2 tabletsRamipril & Hydrochlorothiazide 5/25).

Dosage AdjustmentRamipril:Renal ImpairmentIn patients with creatinine clearance <40 mL/min/1.73 ni2 (serum creatinine approximately >2.5 nag/dL) doses only 25% of those normally used should be expected to induce full therapeutic levelsof Ramiprilat.

Hypertension:For patients with hypertension and renal impairment, thecommended initial dose is 1.25 mg Ramipril once daily Dosagemay be titrated upward until blood pressure is controlled or to amaximum total daily dose of 5 mg.

Heart Failure Post Myocardial InfarctionFor patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg Ramipril once daily Thedose may be increased to 1.25 mg bid, and up to a maximumdose of 2.5 mg b.i.d, depending upon clinical response andtolerability.

Ramipril & Hydrochlorothiazide: Dosage in elderly patientsInitial doses should be lower and subsequent dose titration shouldbe more gradual because of greater chance of undesirable effectsespecially in very old and frail patients.Dosage in patients with impaired renal functionIn patients with moderate renal impairment (creatinine clearance30 to 60 mErnin per 1.73 ne body surface area), treatment is started with Ramipril alone at a daily dose of 1.25 mg. After gradually increasing the dose of Ramipril. medication with the combination preparation is started at a daily dose of 2.5 mg Ramipril /12.5 mg hydrochlorothiazide. Maximum permitted daily dose: 5 mgRamipri1/25 mg hydrochlorothiazide (Ramipril &Hydrochlorothiazide 10 mg/12.5 mg and Ramipril &Hydrochlorothiazide 10 mg/25 mg must not be used in thesepatients).Dosage in patients with impaired hepatic functionIn patients with mild to moderate hepatic impairment, treatmentwith Ramipril & Hydrochlorothiazide must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg

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agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently. Lithium Excretion of lithium may be reduced by ACE inhibitors. Increased serum lithium levels and symptoms of lithium toxicity (eg. cardiotoxic and neurotoxic effects) have been reported in patients receivingACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

NSAIDS As with other ACE inhibitors, the antihypertensive effects of ramipril may be decreased in patients taking non-steroidal anti-inflammatory drugs (eg. acetylsalicylic acid, phenylbutazone, indomethacin). Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening renal function and an increase in serum potassium. Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics Concomitant use of a renin-angiotensin system inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID, including COX-2 inhibitor) and a thiazide diuretic may increase the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. The combination of these agents should be administered with caution, especially in the elderly and in patients with pre-existing renal impairment. Renal function (serum creatinine) should be monitored after initiation of concomitant therapy, and periodically thereafter.

Anaesthetics General anaesthetics or anaesthetics with an antihypertensive action may cause the blood pressure to drop further in patients taking ramipril. Appropriate counter-measures, such as increasing the blood volume or, if necessary, administering angiotensin II, should be taken before or during surgery. Antidiabetic agents ACE inhibitors may reduce insulin resistance. The possibility of an increased blood sugar reduction must be considered in patients treated concurrently with ramipril and antidiabetic agents such as insulin and sulphonylurea derivatives. Particularly close blood glucose monitoring is, therefore, recommended in the initial phase of co-administration. Heparin Arise in serum potassium concentration is possible when ramipril and heparin are administered concurrently Alcohol Concomitant administration with alcohol may lead to increased vasodihtion. Ranapril may potentiate the effect of alcohol. Desensitisation therapy The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom is increased under ACE inhibition. It is assumed that this effect may also occur in connection with other allergens.

Hydrchlorothiazide: When given concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics - potentiation of orthostatic hypotension may occur. Antidiabetic drugs- (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.

Ramipace 1.25mg, 2.5mg, 5mg &10mg are available in pack of 28's. Ramipace-D 2.5/12.5mg, 5/12.5mg &10/12.5mg are availablein pack of 30's.

INSTRUCTIONSTo be sold only on prescription of a medical practitioner.

Protect from heat, light and moisture.

Store between 20 oC to 253 oC.(Excursions permitted between 15 oC to 30 oC)

Keep all medicines out of the reach of children.

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