Find Medicines

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Ophthalmic steroid - antibiotic combined preparations

Dexamethasone is a glucocorticoid. It has an anti-inflammatory and anti-allergic action. It is used topically in the treatment of inflammatory conditions of the anterior segment of the eye. Dexamethasone is absorbed rapidly after oral administration with a half-life of about 190 minutes. Sufficient absorption may occur after topical application to the skin and eye to produce systemic effects.

Chloramphenicol is a broad spectrum bacteriostatic antibiotic active against a wide variety of gram-negative and gram-positive organisms. Chloramphenicol exerts its antibacterial effect by binding to bacterial ribosomes and inhibiting bacterial protein synthesis at an early stage

Eye:

• Bacterial Conjunctivitis: The recommended dosage regimen for the treatment of bacterial conjunctivitis is 1 to 2 drops instilled into the conjunctival sac (s) every 2 hours for 2 days and 1 or 2 drops every 4 hours for the next 5(five days) while awake.
• Corneal Ulcers: The recommended dosage regimen for the treatment of comeal ulcer is 2 drops in the affected eye (s) every 15 minutes for the first 6 hours then 2 drops into the affected eye(s) every 30 minutes for the remainder of first day. On the second day, instill 2 drops in the affected eye (s) hourly. On the 3 to 14 days, place 2 drops in the affected eye (s) every 4 hours. Treatment may be continued after 14 days if corneal re-epithelialization has not occurred.

Ear: For all infections, 2 to 3 drops every 2 to 3 hours initially. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.

Adverse reactions seen with Chloramphenicol are transient ocular burning or discomfort and other reported reactions include stinging, redness, itching, conjunctivitis, foreign body sensation, photophobia, blurred vision, dryness and eye pain. Allergic sensitization may occur with the local use of Chloramphenicol. Elevation of intraocular pressure with possible development of glaucoma, infrequent optic nerve damage and posterior subcapsular cataract formation.

The combination is contraindicated in epithelial herpes simplex cornealis, fungal, viral, tuberculous and other infections of the eye and in glaucoma. Myelosuppression during previous exposure to Chloramphenicol. Hypersensitivity to Chloramphenicol & Dexamethasone Phosphate or to any other ingredients of the preparations.

The possibility of persistent fungal infections of the cornea should be considered after prolonged corticosteroid dosing. Prolonged use of steroids containing products may result in posterior subcapsular cataract formation and glaucoma with optic nerve damage. Intraocular pressure monitoring is needed. Prolonged use of antibiotics may result in the overgrowth of non-susceptible organisms, including fungi. If new infections appear during treatment, the drug should be discontinued and alternative therapy should be instituted.

If Chloramphenicol is absorbed from eye when taking anticoagulants e.g. warfarin, there may be an increase in the effect of this medicine. Action of Chloramphenicol will be inhibited if given simultaneously with Phenobarbital. The therapeutic efficacy of Dexamethasone may be reduced with the concomitant administration of phenytoin, phenobarbitone, ephedrine and rifampicin.

There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when Chloramphenicol and Dexamethasone ophthalmic solution is administered to a nursing mother.

Keep in a cool and dry place, away from light & keep out of the reach of children. Do not use after 30 days of first opening.

Anti-viral drugs

Remdesivir is a preparation of Remdesivir. It is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite. Metabolism of Remdesivir to Remdesivir Triphosphate has been demonstrated in multiple cell types. Remdesivir Triphosphate act as an analogue of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerase with low potential for mitochondrial toxicity.

General Information-

• Adult and pediatric patients (>28 days and old) must have an eGFR determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing of Remdesivir.
• Hepatic laboratory testing should be performed in all patients prior to starting Remdesivir and daily while receiving Remdesivir.
• Remdesivir should be administered via intravenous infusion only. Do not administer as intramuscular injection.

Adult Patients-

• The recommended dosage in adults requiring invasive mechanical ventilation and/or ECMO is a single loading dose of Remdesivir 200 mg on day 1 followed by once daily maintenance dose of Remdesivir 100 mg for 9 days.
• The recommended dose in adults not requiring invasive mechanical ventilation and/or ECMO is a single dose of Remdesivir 200 mg on day 1 followed by once daily maintenance dose of Remdesivir 100 mg for 4 days. If a patient dose not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e. up to a total of 10 days)
• Remdesivir is to be administered via intravenous infusion in a total volume of up to 250 ml 0.9% saline over 30 to 120 minutes.

Pediatric Patients-

• The recommended pediatric dose for pediatric patients weighing between 3.5 kg <40 kg should be calculated using the mg/kg dose according to the patient’s weight.
• For pediatric patients with body weight between 3.5 kg <40 kg use Remdesivir for injection 100 mg lyophilized powder only. Administer a body weight-based dosing regimen of one loading dose of Remdesivir 5 mg/kg IV (infused over 30 to 120 minutes) on day 1 followed by Remdesivir 2.5 mg/kg IV (infused over 30 to 120 minutes) once daily for 9 days (for pediatric patients requiring invasive mechanical ventilation and/or ECMO, days 2 through 5). If a patient dose not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e. up to a total of 10 days)
• For pediatric patients with body weight ≥40 kg requiring invasive mechanical ventilation and/or ECMO, the adult dosage regimen of one loading dose of Remdesivir 200 mg IV (infused over 30 to 120 minutes) on day 1 followed by Remdesivir 100 mg IV (infused over 30 to 120 minutes) once daily for 9 days will be administered.
• For pediatric patients with body weight ≥40 kg requiring invasive mechanical ventilation and/or ECMO, the adult dosage regimen of one loading dose of Remdesivir 200 mg IV (infused over 30 to 120 minutes) on day 1 followed by Remdesivir 100 mg IV (infused over 30 to 120 minutes) once daily for 4 days (days 2 through 5) will be administered. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e. up to a total of 10 days).

The prepared dilution should not be administered simultaneously with any other medication. The compatibility of Remdesivir injection with IV solutions and medications other than saline is not known. Please administered the diluted solution with the infusion rate described in the below table. Recommended Rate of Infusion- Diluted Remdesivir for Injection Lyophilized Powder in Adults and Pediatric Patients Weighing > 40 kg

Infusion bag 250 ml:

• Infusion Time: 30 min, Rate of Infusion: 8.33 ml/min
• Infusion Time: 60 min, Rate of Infusion: 4.17 ml/min
• Infusion Time: 120 min, Rate of Infusion: 2.08 ml/min

Infusion bag 100 ml:

• Infusion Time: 30 min, Rate of Infusion: 3.33 ml/min
• Infusion Time: 60 min, Rate of Infusion: 1.67 ml/min
• Infusion Time: 120 min, Rate of Infusion: 0.83 ml/min

An adverse reaction associated with Remdesivir in clinical trials in healthy adult subjects was increased liver transaminases.

Remdesivir is contraindicated in patients with known hypersensitivity to Remdesivir.

There are limited clinical data available for Remdesivir. Serious and unexpected adverse events may occur that have not been previously reported with Remdesivir use.

No adequate and well controlled studies of Remdesivir use in pregnant women have been conducted. Remdesivir should be used in pregnancy only if the potential benefit justifies the potential risk for the mother fetus. There is no information regarding the presence of Remdesivir in human milk, the effects on the breastfeed infants, or the effects on milk production. Because of the potential for viral transmission of SARS-CoV-2 negative infants and adverse reactions from the drug in breastfeeding infants, the development and health benefits of breastfeeding should be considered along with the mother's clinical need for Remdesivir and any potential adverse effects on the breastfed child from Remdesivir or from the underlying maternal condition.

Reconstitution instructions:

• Aseptically reconstitute Remdesivir lyophilized powder by addition of 19 ml of sterile water for injection using a suitably sized syringe and needle per vial.
• Discard the vial if a vacuum does not pull the sterile water for injection into the vial.
• Immediately shake the vial for 30 seconds.
• Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result.
• If the content of the vial is not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved.
• Following reconstitution, each vial contains 100 mg/20 ml (5 mg/ml).
• Parenteral drug products should be inspected virtually for particulate matter and and discoloration prior to administration, whenever solution and container permit.

Please do not reuse or save unused Remdesivir Lyophilized powder, injection solution or diluted solution for infusion for further use. This product contains no preservatives.

Lyophilized Powder: Please store Remdesivir for injection, 100 mg, vials at temperature not exceeding 30°C in a dry place until required for use. Protect from light & moisture. Do not use after expiration date.

After reconstitution: vials can be stored up to 4 hours at room temperature (20°C-25°C) prior to administration or 24 hours at refrigerated temperature (2°C-8°C). Please dilute within the same day as administration.

Diluted Solution for Infusion: Please store diluted Remdesivir solution for infusion up to 4 hours at room temperature (20°C-25°C) or 24 hours at refrigerated temperature (2°C-8°C).

Ramelteoni s indicated for the treatment of insomnia characterized by difficulty with sleep onset

Miscellaneous sedatives & hypnotics

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2receptors, and lower selectivity for the MT3 receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT1 receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT2 receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT1 and MT2 receptors are associated with the sleep-wake cycle, MT3 has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.

Adult dose: 8 mg taken within 30 minutes of going to bed. Should not be taken with or immediately after a high-fat meal. The total daily dose should not exceed 8 mg.

Most common adverse reactions (≥3% and more common than with placebo) are: somnolence, dizziness, fatigue, nausea, and exacerbated insomnia

Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur.

Need to evaluate for co-morbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment.

Abnormal thinking, behavioral changes, complex behaviors: May include "sleep-driving" and hallucinations. Immediately evaluate any new onset behavioral changes.

Depression: Worsening of depression or suicidal thinking may occur.

CNS effects: Potential impairment of activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, after ingesting the drug. 

Reproductive effects: Include decreased testosterone and increased prolactin levels. Effect on the reproductive axis in developing humans is unknown

Patients with severe sleep apnea: Rozerem is not recommended for use in this population.

Rifampin (strong CYP enzyme inducer): Decreases exposure to and effects of ramelteon.

Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution.

Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. Donepezil increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is co administered with donepezil. Doxepin increases systemic exposure of ramelteon; patients should be closely monitored when ramelteon is co administered with doxepin.

Alcohol: Causes additive psychomotor impairment; should not be used in combination

Pregnancy: Based on animal data may cause fetal harm. Do not use unless the potential benefit justifies the potential risk.

Nursing mothers: Use with caution.

Pediatric use: Safety and effectiveness not established.

Geriatric use: No overall differences in safety and efficacy between elderly and younger adult subjects.

Hepatic impairment: Is not recommended in patients with severe impairment; use with caution in moderate impairment.

Store at 25°C; excursions permitted to 15° to 30°C. Keep container tightly closed and protected from moisture and humidity.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Indicated for the treatment of mild to moderate hypertension in patients (in whom combination therapy is appropriate) who have been stabilised on the individual components given in the same proportion.

Combined antihypertensive preparations

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of Hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of anangiotensin converting enzyme (ACE) inhibitor tends to reverse the potassium loss associated with these diuretics.

Dose Titration Guided by Clinical Effect. A patient whose blood pressure is not adequately controlled with ramipril (or another ACE inhibitor) alone or with hydrochlorothiazide (or another thiazide diuretic) alone may be switched to combination therapy with Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or Ramipril 5 mg + Hydrochlorothiazide 25 mg tablet.

Replacement Therapy: For convenience, patients receiving ramipril and hydrochlorothiazide from separate tablets may instead wish to receive tablets of combination of Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or Ramipril 5 mg + Hydrochlorothiazide 25 mg. If necessary, the dose may be increased to two tablets of Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or Ramipril 5 mg + Hydrochlorothiazide 25 mg once daily.

Maximum daily dose: 10 mg ramipril and 50 mg hydrochlorothiazide (four tablets of Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or two tablets of Ramipril 5 mg + Hydrochlorothiazide 25 mg).

The combination of Ramipril and Hydrochlorothiazide is generally well tolerated. Side effects commonly reported include headache, dizziness, asthenia, nausea, vomiting, hypotension, cough, weakness, diarrhoea, fever, gastric irritation, pulmonary oedema, photosensitivity, electrolyte imbalance, hyperglycaemia, hyperuricaemia and vertigo.

This preparation must not be used in patients with hypersensitivity to ramipril, hydrochlorothiazide or other thiazide diuretics. History of hereditary angioneurotic oedema. Severe impairment of renal function. Haemodynamically relevant unilateral or bilateral renal artery stenosis, mitral stenosis, aortic stenosis, and in patients with low blood pressure (hypotensive patients) or in patients with an unstable circulatory situation (haemodynamically unstable patients) where there might be a risk of life-threatening fall in blood pressure and renal failure. Clinically relevant electrolyte disturbances e.g. hypokalemia, hyponatremia or hypercalcemia which may worsen following treatment.

Treatment with Ramipril and Hydrochlorothiazide combination requires regular medical supervision. Generally dehydration, reduced blood volume (hypovolumia) or salt depletion should be corrected before initiating the treatment (in patients with concomitant heart failure, however, this must be carefully weighed against the risk of volume overload).

Special caution is necessary during the treatment of: Patients with severe and particularly with malignant hypertension. Patients with concomitant and particularly with severe heart failure. Patients in whom fluid or salt deficiency exists or may develop (as a result of inadequate fluid or salt intake) or as a result of diarrhoea, vomiting or excessive 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. White blood cell count should be monitored (more frequent in the initial phase of the treatment) so that leucopenia can be detected. Insufficient experience has been gained concerning the use of Ramipril and Hydrochlorothiazide combination in children.

Combination with diuretics or other antihypertensive agents or nitrates and tricyclic antidepressants may potentiate the antihypertensive response to Ramipril and Hydrochlorothiazide combination. Patients previously treated with diuretics may experience a marked drop in blood pressure. Ramipril / Hydrochlorothiazide may weaken the effectiveness of blood sugar lowering medications (antidiabetic agents, e.g. insulin and sulphonylurea derivatives). When Ramipril/Hydrochlorothiazide is administered simultaneously with acetyl salicylic acid or indomethacin, attenuation of antihypertensive effect and moreover acute renal failure may occur. Ramipril / Hydrochlorothiazide may potentiate the effects of alcohol.

ACE inhibitors can cause foetal and neonatal morbidity and death when administered to pregnant women. Also, thiazides cross the placental barrier and appear in cord blood. There is a risk of foetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. When pregnancy is detected, Ramipril and Hydrochlorothiazide combination should be discontinued as soon as possible. This product is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, women receiving Ramipril and Hydrochlorothiazide combination should not breast feed.

Dosage in renal impairment: In patients with a creatinine clearance between 60 and 30 ml/min, treatment should be initiated with Ramipril 1.25 mg monotherapy. If blood pressure is not adequately controlled, the dose of Ramipril may be increased to 2.5 mg. If blood pressure is still not controlled, patient may be switched to one tablet of Ramoril 2.5 Plus once daily. Dosage may be titrated upward to Ramoril 5 Plus until blood pressure is controlled.

Uue in children: Safety and effectiveness in paediatric patients have not been established

Ramipril: Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Because the hypotensive effect of Ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Ramipril overdosage by infusion of normal saline solution.

Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia, may accentuate cardiac arrhythmias. The degree to which Hydrochlorothiazide is removed by hemodialysis has not been established.

Store in a cool and dry place, protected from light.

Indicated for the treatment of mild to moderate hypertension in patients (in whom combination therapy is appropriate) who have been stabilised on the individual components given in the same proportion.

Combined antihypertensive preparations

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of Hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of anangiotensin converting enzyme (ACE) inhibitor tends to reverse the potassium loss associated with these diuretics.

Dose Titration Guided by Clinical Effect. A patient whose blood pressure is not adequately controlled with ramipril (or another ACE inhibitor) alone or with hydrochlorothiazide (or another thiazide diuretic) alone may be switched to combination therapy with Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or Ramipril 5 mg + Hydrochlorothiazide 25 mg tablet.

Replacement Therapy: For convenience, patients receiving ramipril and hydrochlorothiazide from separate tablets may instead wish to receive tablets of combination of Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or Ramipril 5 mg + Hydrochlorothiazide 25 mg. If necessary, the dose may be increased to two tablets of Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or Ramipril 5 mg + Hydrochlorothiazide 25 mg once daily.

Maximum daily dose: 10 mg ramipril and 50 mg hydrochlorothiazide (four tablets of Ramipril 2.5 mg + Hydrochlorothiazide 12.5 mg or two tablets of Ramipril 5 mg + Hydrochlorothiazide 25 mg).

The combination of Ramipril and Hydrochlorothiazide is generally well tolerated. Side effects commonly reported include headache, dizziness, asthenia, nausea, vomiting, hypotension, cough, weakness, diarrhoea, fever, gastric irritation, pulmonary oedema, photosensitivity, electrolyte imbalance, hyperglycaemia, hyperuricaemia and vertigo.

This preparation must not be used in patients with hypersensitivity to ramipril, hydrochlorothiazide or other thiazide diuretics. History of hereditary angioneurotic oedema. Severe impairment of renal function. Haemodynamically relevant unilateral or bilateral renal artery stenosis, mitral stenosis, aortic stenosis, and in patients with low blood pressure (hypotensive patients) or in patients with an unstable circulatory situation (haemodynamically unstable patients) where there might be a risk of life-threatening fall in blood pressure and renal failure. Clinically relevant electrolyte disturbances e.g. hypokalemia, hyponatremia or hypercalcemia which may worsen following treatment.

Treatment with Ramipril and Hydrochlorothiazide combination requires regular medical supervision. Generally dehydration, reduced blood volume (hypovolumia) or salt depletion should be corrected before initiating the treatment (in patients with concomitant heart failure, however, this must be carefully weighed against the risk of volume overload).

Special caution is necessary during the treatment of: Patients with severe and particularly with malignant hypertension. Patients with concomitant and particularly with severe heart failure. Patients in whom fluid or salt deficiency exists or may develop (as a result of inadequate fluid or salt intake) or as a result of diarrhoea, vomiting or excessive 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. White blood cell count should be monitored (more frequent in the initial phase of the treatment) so that leucopenia can be detected. Insufficient experience has been gained concerning the use of Ramipril and Hydrochlorothiazide combination in children.

Combination with diuretics or other antihypertensive agents or nitrates and tricyclic antidepressants may potentiate the antihypertensive response to Ramipril and Hydrochlorothiazide combination. Patients previously treated with diuretics may experience a marked drop in blood pressure. Ramipril / Hydrochlorothiazide may weaken the effectiveness of blood sugar lowering medications (antidiabetic agents, e.g. insulin and sulphonylurea derivatives). When Ramipril/Hydrochlorothiazide is administered simultaneously with acetyl salicylic acid or indomethacin, attenuation of antihypertensive effect and moreover acute renal failure may occur. Ramipril / Hydrochlorothiazide may potentiate the effects of alcohol.

ACE inhibitors can cause foetal and neonatal morbidity and death when administered to pregnant women. Also, thiazides cross the placental barrier and appear in cord blood. There is a risk of foetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. When pregnancy is detected, Ramipril and Hydrochlorothiazide combination should be discontinued as soon as possible. This product is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, women receiving Ramipril and Hydrochlorothiazide combination should not breast feed.

Dosage in renal impairment: In patients with a creatinine clearance between 60 and 30 ml/min, treatment should be initiated with Ramipril 1.25 mg monotherapy. If blood pressure is not adequately controlled, the dose of Ramipril may be increased to 2.5 mg. If blood pressure is still not controlled, patient may be switched to one tablet of Ramoril 2.5 Plus once daily. Dosage may be titrated upward to Ramoril 5 Plus until blood pressure is controlled.

Uue in children: Safety and effectiveness in paediatric patients have not been established

Ramipril: Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Because the hypotensive effect of Ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Ramipril overdosage by infusion of normal saline solution.

Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia, may accentuate cardiac arrhythmias. The degree to which Hydrochlorothiazide is removed by hemodialysis has not been established.

Store in a cool and dry place, protected from light.

Macrolides

In vitro, chloramphenicol exerts mainly a bacteriostatic effect on a wide range of Gram-negative and Gram positive bacteria and is active against rickettsiae, the lymphogranuloma-psittacosis group and Vibrio cholerae. It is particularly active against Salmonella typhi and Haemophilus influenzae. The mode of actions is through interference or inhibition of protein synthesis in intact cells and cell-free systems. Antagonism has been demonstrated in vitro between chloramphenicol, erythromycin, clindamycin and lincomycin. Chloramphenicol is rapidly absorbed from the GI tract. Chloramphenicol palmitate is hydrolyzed in the GI tract and is absorbed as free chloramphenicol.

Following oral administration of a single one gram dose of chloramphenicol base to healthy adults, average peak plasma chloramphenicol concentrations of about 11 mcg/ml were attained with 1-3 hours. Cumulative dosing gave a peak of 18 mcg/ml after the fifth dose of one gram, every 6 hours. Mean serum levels were 8-14 mcg/ml over a 48 hour period.

Most of the drug is excreted in the urine. Despite the small proportion of unchanged drug excreted in the urine, the concentration of free chloramphenicol in the urine is relatively high. From 8% to 12% of the antibiotic is excreted as free chloramphenicol. The remainder is excreted as inert metabolites, mainly glucuronate. Small amounts of active drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid (CSF). Chloramphenicol enters CSF even in the absence of meningeal inflammation, appearing in concentrations about half of those found in the blood.

Chloramphenicol, like other potent drugs, should be prescribed at recommended doses known to have therapeutic activity. Inhibition of the majority of sensitive organisms may be expected at concentrations of 5 to 20 mcg/ml. The desired concentration of active drug in serum should fall within this range over most of the treatment period. Dosage of 50 mg/kg/day divided into 4 doses at intervals of 6 hours will usually achieve and sustain levels of this order.

Except in certain circumstances (e.g. premature infants and neonates and individuals with hepatic or renal impairment) lower doses may not achieve these concentrations. Close observation of the patient should be maintained and in the event of any adverse reactions, dosage should be reduced or the drug discontinued, if other factors in the clinical situation permit.

Adults: should receive 50 mg/kg/day in divided doses [approximately one 250 mg capsule per each 4.5 kg (10 lbs) of body weight or one 500 mg capsule per each 9 kg (20 lbs) of body weight] in divided doses at 6 hour intervals. In exceptional cases, patients with infections due to moderately resistant organisms may require increased dosage up to 100 mg/kg/day to achieve serum levels inhibiting the pathogen, but these high doses should be decreased as soon as possible.

Adults with impairment of hepatic or renal function, or both, may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted accordingly.

Pediatric patients: Dosage of 50 mg/kg/day divided at 6 hour intervals is effective against most susceptible organisms. Severe infections (eg., bacteremia or meningitis), especially when adequate cerebrospinal fluid concentrations are desired, may require dosage up to 100 mg/kg/day; however, it is recommended that dosage be reduced to 50 mg/kg/day as soon as possible. Children with impaired hepatic or renal function may retain excessive amounts of the drug.

Newborn infants: A total of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces and maintains concentrations in serum and tissues adequate to control most infections for which the drug is indicated.

Chloramphenicol is contraindicated in individuals with a history of hypersensitivity and/or toxic reaction to the product or its components. It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, viral influenza, infections of the throat or as a prophylactic agent to prevent bacterial infections.

It is essential that adequate hematologic functions be closely monitored during treatment with the drug. While hematologic determinations may detect early peripheral hematologic changes, such as leukopenia, reticulocytopenia, or granulocytopenia, before they become irreversible, such determinations cannot be relied on to detect bone marrow depression prior to development of aplastic anemia

Chloramphenicol has been shown to retard the biotransformation of tolbutamide, phenytoin, and dicoumarol in man. Chloramphenicol should be used with caution if administered concomitantly with lincomycin, clindamycin, or erythromycin. In vitro experiments have demonstrated that binding sites for erythromycin, lincomycin, clindamycin and chloramphenicol overlap and competitive inhibition may occur. Rifampin therapy can reduce Chloramphenicol concentrations.

Levels exceeding 25 mcg/ml are frequently considered toxic. Chloramphenicol toxicity can be evidenced by serious hemopoietic effects such as aplastic anemia, thrombocytopenia, leukopenia, as well as increasing serum iron levels, nausea, vomiting and diarrhea. In the case of serious overdosage, charcoal hemoperfusion may be effective in removing chloramphenicol from plasma. Exchange transfusion is of questionable value following massive overdosage, especially in neonates and infants.

Store in a cool dry place. Keep bottle securely closed. Protect from light.

Macrolides

In vitro, chloramphenicol exerts mainly a bacteriostatic effect on a wide range of Gram-negative and Gram positive bacteria and is active against rickettsiae, the lymphogranuloma-psittacosis group and Vibrio cholerae. It is particularly active against Salmonella typhi and Haemophilus influenzae. The mode of actions is through interference or inhibition of protein synthesis in intact cells and cell-free systems. Antagonism has been demonstrated in vitro between chloramphenicol, erythromycin, clindamycin and lincomycin. Chloramphenicol is rapidly absorbed from the GI tract. Chloramphenicol palmitate is hydrolyzed in the GI tract and is absorbed as free chloramphenicol.

Following oral administration of a single one gram dose of chloramphenicol base to healthy adults, average peak plasma chloramphenicol concentrations of about 11 mcg/ml were attained with 1-3 hours. Cumulative dosing gave a peak of 18 mcg/ml after the fifth dose of one gram, every 6 hours. Mean serum levels were 8-14 mcg/ml over a 48 hour period.

Most of the drug is excreted in the urine. Despite the small proportion of unchanged drug excreted in the urine, the concentration of free chloramphenicol in the urine is relatively high. From 8% to 12% of the antibiotic is excreted as free chloramphenicol. The remainder is excreted as inert metabolites, mainly glucuronate. Small amounts of active drug are found in bile and feces. Chloramphenicol diffuses rapidly, but its distribution is not uniform. Highest concentrations are found in liver and kidney, and lowest concentrations are found in brain and cerebrospinal fluid (CSF). Chloramphenicol enters CSF even in the absence of meningeal inflammation, appearing in concentrations about half of those found in the blood.

Chloramphenicol, like other potent drugs, should be prescribed at recommended doses known to have therapeutic activity. Inhibition of the majority of sensitive organisms may be expected at concentrations of 5 to 20 mcg/ml. The desired concentration of active drug in serum should fall within this range over most of the treatment period. Dosage of 50 mg/kg/day divided into 4 doses at intervals of 6 hours will usually achieve and sustain levels of this order.

Except in certain circumstances (e.g. premature infants and neonates and individuals with hepatic or renal impairment) lower doses may not achieve these concentrations. Close observation of the patient should be maintained and in the event of any adverse reactions, dosage should be reduced or the drug discontinued, if other factors in the clinical situation permit.

Adults: should receive 50 mg/kg/day in divided doses [approximately one 250 mg capsule per each 4.5 kg (10 lbs) of body weight or one 500 mg capsule per each 9 kg (20 lbs) of body weight] in divided doses at 6 hour intervals. In exceptional cases, patients with infections due to moderately resistant organisms may require increased dosage up to 100 mg/kg/day to achieve serum levels inhibiting the pathogen, but these high doses should be decreased as soon as possible.

Adults with impairment of hepatic or renal function, or both, may have reduced ability to metabolize and excrete the drug. In instances of impaired metabolic processes, dosages should be adjusted accordingly.

Pediatric patients: Dosage of 50 mg/kg/day divided at 6 hour intervals is effective against most susceptible organisms. Severe infections (eg., bacteremia or meningitis), especially when adequate cerebrospinal fluid concentrations are desired, may require dosage up to 100 mg/kg/day; however, it is recommended that dosage be reduced to 50 mg/kg/day as soon as possible. Children with impaired hepatic or renal function may retain excessive amounts of the drug.

Newborn infants: A total of 25 mg/kg/day in 4 equal doses at 6-hour intervals usually produces and maintains concentrations in serum and tissues adequate to control most infections for which the drug is indicated.

Chloramphenicol is contraindicated in individuals with a history of hypersensitivity and/or toxic reaction to the product or its components. It must not be used in the treatment of trivial infections or where it is not indicated, as in colds, viral influenza, infections of the throat or as a prophylactic agent to prevent bacterial infections.

It is essential that adequate hematologic functions be closely monitored during treatment with the drug. While hematologic determinations may detect early peripheral hematologic changes, such as leukopenia, reticulocytopenia, or granulocytopenia, before they become irreversible, such determinations cannot be relied on to detect bone marrow depression prior to development of aplastic anemia

Chloramphenicol has been shown to retard the biotransformation of tolbutamide, phenytoin, and dicoumarol in man. Chloramphenicol should be used with caution if administered concomitantly with lincomycin, clindamycin, or erythromycin. In vitro experiments have demonstrated that binding sites for erythromycin, lincomycin, clindamycin and chloramphenicol overlap and competitive inhibition may occur. Rifampin therapy can reduce Chloramphenicol concentrations.

Levels exceeding 25 mcg/ml are frequently considered toxic. Chloramphenicol toxicity can be evidenced by serious hemopoietic effects such as aplastic anemia, thrombocytopenia, leukopenia, as well as increasing serum iron levels, nausea, vomiting and diarrhea. In the case of serious overdosage, charcoal hemoperfusion may be effective in removing chloramphenicol from plasma. Exchange transfusion is of questionable value following massive overdosage, especially in neonates and infants.

Store in a cool dry place. Keep bottle securely closed. Protect from light.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.

Angiotensin-converting enzyme (ACE) inhibitors

Ramipril is an angiotensin converting enzyme (ACE) inhibitor, which after hydrolysis to ramiprilat, blocks the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. So, inhibition of ACE by ramipril results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. Thus ramipril exerts its antihypertensive activity. It is also effective in the management of heart failure and reduction of the risk of stroke, myocardial infarction and death from cardiovascular events. It is long acting and well tolerated; so, can be used in long term therapy.

Dosage of Ramipril must be adjusted according to the patient tolerance and response.

Hypertension: For the management of hypertension in adults not receiving a diuretic, the usual initial dose of Ramipril is 1.25-2.5 mg once daily. Dosage generally is adjusted no more rapidly than at 2 week intervals. The usual maintenance dosage in adults is 2.5-20 mg daily given as a single dose or in 2 divided doses daily. If BP is not controlled with Ramipril alone, a diuretic may be added.

Congestive heart failure after myocardial infarction: In this case, Ramipril therapy may be initiated as early as 2 days after myocardial infarction. An initial dose of 2.5 mg twice daily is recommended, but if hypotension occurs, dose should be reduced to 1.25 mg twice daily. Therapy is then titrated to a target daily dose of 5 mg twice daily.

Prevention of major cardiovascular events: In this case, the recommended dose is 2.5 mg once daily for the first week of therapy and 5 mg once daily for the following 3 weeks; dosage then may be increased, as tolerated, to a maintenance dosage of 10 mg once daily.

Dosage in renal impairment:

• For patients with hypertension and renal impairment: The recommended initial dose is 1.25 mg Ramipril once daily. Subsequent dosage should be titrated according to individual tolerance and BP response, up to a maximum of 5 mg daily.
• For patients with heart failure and renal impairment: The recommended dose is 1.25 mg once daily. The dose may be increased to 1.25 mg twice daily and up to a maximum dose of 2.5 mg twice daily depending upon clinical response and tolerability.

Ramipril tablets have to be swallowed with sufficient amounts of liquid. The tablets must not be chewed or crushed. Absorption of Ramipril is not significantly affected by food. Ramipril may, therefore, be taken before, during or after a meal.

Ramipril is generally well tolerated. Dizziness, headache, fatigue and asthenia are commonly reported side effects. Other side effects occurring less frequently include symptomatic hypotension, cough, nausea, vomiting, diarrhoea, rash, urticaria, oliguria, anxiety, amnesia etc. Angioneurotic oedema, anaphylactic reactions and hyperkalaemia have also been reported rarely.

Ramipril must not be used

• in patients with hypersensitivity to ramipril, to any other ACE inhibitor, or any of the excipients of Ramipril.
• in patients with a history of angioedema.
• concomitantly with sacubitril/valsartan therapy. Do not initiate Ramipril until sacubitril/valsartan is eliminated from the body. In case of switch from Ramipril to sacubitril/valsartan, do not start sacubitril/valsartan until Ramipril is eliminated from the body.
• in patients with haemodynamically relevant renal artery stenosis, bilateral or unilateral in the single kidney.
• in patients with hypotensive or haemodynamically unstable states.
• with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (creatinine clearance <60 ml/min).
• with angiotensin II receptor antagonists (AIIRAs) in patients with diabetic nephropathy.
• during pregnancy.

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided, since such use may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-fux (e.g. polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate.

Ramipril should be used with caution in patients with impaired renal function, hyperkalaemia, hypotension, and impaired hepatic function.

Concomitant administration with diuretics may lead to serious hypotension and in addition dangerous hyperkalemia with potassium sparing diuretics. Concomitant therapy with lithium may increase the serum lithium concentration. Reduction in BP may affect the ability to drive and operate machinery and this may be exacerbated by alcohol. NSAIDs may reduce the antihypertensive effect of Ramipril and cause deterioration of renal function.

Ramipril must not be taken during pregnancy. Therefore, pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with ACE inhibitors is indispensable. If the patient intends to become pregnant, treatment with ACE inhibitors must be discontinued, i.e. replaced by another form of treatment. If the patient becomes pregnant during treatment, medication with Ramipril must be replaced as soon as possible by a treatment regimen without ACE inhibitors. Otherwise, there is a risk of harm to the fetus. Ramipril is not recommended during breastfeeding.

Elderly: A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Hepatic impairment: Treatment in these patients must therefore be initiated only under close medical supervision. The maximum permitted daily dose in such cases is 2.5 mg Ramipril.

Renal impairment: With a creatinine clearance between 50 and 20 ml/min per 1.73 m2 body surface area, the initial daily dose is generally 1.25 mg Ramipril. The maximum permitted daily dose, in this case, is 5 mg Ramipril. Patients with incompletely corrected fuid or salt depletion, in patients with severe hypertension, as well as in patients in whom a hypotensive reaction would constitute a particular risk, (e.g., with relevant stenoses of the coronary vessels or those supplying the brain) A reduced initial dose of 1.25 mg Ramipril daily must be considered.

Patients pretreated with a diuretic: Consideration must be given to discontinuing the diuretic for at least 2 to 3 days or- depending on the duration of action of the diuretic- longer before starting treatment with Ramipril, or at least to reducing the diuretic dose. The initial daily dose in patients previously treated with a diuretic is generally 1.25 mg Ramipril.

Sign and symptom: Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management: Primary detoxifcation by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the frst 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

Store at 30° or below, protect from light. Keep out of the reach of children. Do not use later than the date of expiry. To be dispensed only on the prescription of a registered physician.