Hydralazine

Hydralazine

20mg/ml

Solution for Injection (IM/IV)

Drug Category: Direct Vasodilator

Description:

A clear colorless solution to pale yellow solution in USP.

Pharmacokinetics:

Hydralazine given orally is rapidly absorbed from the gastrointestinal tract but undergoes considerable first pass metabolism by acetylation in the gastrointestinal mucosa and liver. The rate of metabolism is genetically determined and depends upon the acetylator status of the individual. The bioavailability of hydralazine has been reported to be about 35% in slow acetylators and less in fast acetylators; thus plasma concentrations after a given dose are higher in slow acetylators. Peak plasma concentrations have been reported to occur after about one hour. Hydralazine is chiefly present in plasma as hydrazone conjugate with pyruvic acid. Plasma protein binding is about 90%. The drug is widely distributed, notably into arterial walls. Systemic metabolism in the liver is by hydroxylation of the ring system and conjugation with glucuronic acid; most sources suggest that N-acetylation is not of major importance in systemic clearance and that therefore acetylator status does not affect elimination. Hydralazine is excreted mainly in urine as metabolites. The apparent average half-life for hydralazine has been reported to vary from about 45 minutes to about 8 hours, with a number of sources giving the average as about 2 to 4 hours. Some of the variation may be due to problems with analytical procedures. The half-life is prolonged in renal impairment and may be up to 16 hours in patients with a creatinine clearance of less than 20 ml/minute. Hydralazine crosses the placenta and is distributed into breast milk.

Indications:

Hydralazine is used for the treatment of hypertension usually with a beta blocker and a thiazide diuretic. It is also used with isosorbide dinitrate in the management of heart failure.

Dosage and Administration

In hypertensive crises, hydralazine hydrochloride is given in doses of 5 to 10 mg by slow intravenous injection, repeated if necessary after 20 to 30 minutes. Alternatively, it may be given by continuous intravenous infusion in an initial dose of 200 to 300 micrograms per minute. The usual maintenance dose range is 50 to 150 micrograms per minute. Hydralazine hydrochloride can be also given by intramuscular injection.

Adverse Effects:

Adverse effects are common with hydralazine, particularly tachycardia, palpitations, angina pectoris, sever headache, and gastrointestinal disturbances such as anorexia, nausea, vomiting, and diarrhea. These adverse effects, and flushing, dizziness, and nasal congestion, which occur less often, may be seen at the start of treatment, especially if the dose is increased quickly. They generally subside with continued treatment. Other less common adverse effects include orthostatic hypotension, fluid retention with edema and weight gain, conjunctivitis, lachrymation, tremor, and muscle cramps. Hydralazine may deplete pyridoxine in the body, and can produce peripheral neuropathy with numbness and tingling of the extremities. Occasionally, hepatotoxicity, blood dyscrasia, hemolytic anemia, difficulty in urinating, glomerulonephritis, constipation, paralytic ileus, depression, and anxiety occur. Hypersensitivity reactions including fever, chills, pruritus, and rashes have been reported, and eosinophilia may occur. Antinuclear antibodies may develop after prolonged use of large doses, and a condition resembling Systemic Lupus Erythematosus may occur. The incidence is greater in slow acetylators, patients with renal impairment, women, and patients taking more than 100mg of hydralazine daily. The symptoms usually disappear when the drug is withdrawn; some patients may require treatment with corticosteroids. Acute overdosage may produce hypotension, tachycardia, myocardial ischemia, arrhythmias, shock and coma.

Carcinogenicity. Although earlier reports suggested that hydralazine might be carcinogenic, there was no evidence from a survey of 1978 patients with lung or colorectal carcer and 6807 controls that there was an increased risk o these neoplasms.

Effects on the blood. Three cases of thrombocytopenia were reported in neonates whose mothers had been treated with hydralazine for some months before deliver. The thrombocytopenia and bleeding was transient with full recovery occurring within a few weeks. No adverse effects were noticed in the mothers.

Effects on the cardiovascular system. Paradoxical sever hypertension developed after oral or intramuscular hydralazine on 3 occasions in a patient with renal artery stenosis.

Effects on the kidney. Rapidly progressive glomerulonephritis with focal and segmental lesions, usually accompanied by necrosis and crescents formation, has been reported in patients given hydralazine. The condition is reported to be associated with the presence of antinuclear antibodies and slow acetylator status, factors associated with the development of hydralazine induced lupus erythematosus. However, renal involvement is much less common in drug-induced lupus, and in a report of 15 such cases men and women and fast and slow acetylators were equally affected. In addition the criteria for Systemic Lupus Erythematosus were not usually fulfilled in these patients and it was suggested withdrawal of hydralazine generally results in some improvement in renal function but complete recovery is uncommon; sever cases may require immunosuppressive therapy.

Effects on the skin. Pruritus and skin rashes have been reported with hydralazine use. A 59-year-old woman who had been taking hydralazine 2t5mg three times daily for 6 months developed sysmtoms of Sweet's syndrome (erythematosus plaques and nodules and hemorrhagic blisters). Symptoms began to subside on withdrawal of the drug but recurred on rechallenge. The condition resolved on discontinuation of hydralazine and treatment with prednisolone.

Lupus erythematosus. Lupus erythematosus is a well-documented adverse effects of hydralazine. Onset is typically delayed from 1 month to 5 years from the start of treatment, and the most common symptoms are arthralgia or arthritis, usually non-deforming, in up to 95% of patients, fever and myalgia in about 50%, and pleuropulmonary involvemnt, manifesting as pleurisy, pleural effusions, or pulmonary infiltrates in up to 30%. Renal involvement is reported to be less common than idiopathic Systemic Lupus Erythematosus and there is some uncertainty as to whether the glomerulonephritis sometimes seen in patients receiving hydralazine should be considered lupus nephritis (see Effects on the Kidneys). Nonetheless, a 20% incidence of renal involvement has been reported. Other complications and symptoms associated with lupus erythematosus in patients taking hydralazine include cutaneous ulceration, bilateral retinal vasculitis, reactive hypoglycemia (although the attribution is uncertain), life-threatening cardiac tamponade, and hoarseness and stridor secondary to vocal cord palsy, which progressed to respiratory arrest. Skin rashes are reported to be less prominent than with the idiopathic from of the disease. Fatalities have occurred, but appear to be rare. Estimates of the overall incidence of hydralazine-associated lupus erythematosus vary from about 1.2 to 5% or more. Th syndrome appear to occur only in patients who develop antinuclear antibodies while receiving hydralazine, but the incidence of positive antinuclear antibody tests is much higher than that of lupus, at up to 60%, so the presence of antinuclear antibodies alone is not diagnostic. There is a strong relationship with drug dose, acetylator status, and patient gender, the syndrome being more common in slow acetylators and women, and in patients receiving 100mg daily or more. Although it has been reported that hydralazine-associated lupus was more frequent in patients with HLA-DR4 antigen this was not confirmed by others and subsequent work has suggested that the association is rather with the non-expressing or null forms of the adjacent complement C4 in vitro and might exacerbate complement deficiency (which is known to be associated with idiopathic Systemic Lupus Erythematosus) in patients with an already low lever of C4 due to a null allele.

Overdosage and Treatment of Adverse Effects

Withdrawal of hydralazine or dosage reduction reverses many of the adverse effects. Peripheral neuropathy has been reported to be alleviated by pyridoxine. If overdose occurs the benefit of gastric decontamination is uncertain, but activated charcoal may be given, If the patient presents within 1 hour of ingestion. Symptomatic and supportive treatment, including plasma expanders for shock and a beta blocker for tachycardia, should be given as necessary. Hypotension may respond to placing the patient in the supine position with the feet raised. If possible, pressor drugs should be avoided. If a pressor is necessary, one should be chosen that will not cause tachycardia or exacerbate arrhythmias; adrenaline should not be used.

Precaution:
Hydralazine is contraindicated in patients with sever tachycardia, dissecting aortic aneurysm, heart failure with high output, cor pulmonale, or myocardial insufficiency due to mechanical obstruction, for example aortic or mitral stenosis or constrictive pericarditis. Hydralazine is also contraindicated in patients with idiopathic Systemic Lupus Erythematosus and related disorders. Hydralazine-induced vasodilation produces myocardial stimulation. It should therefore be used with caution in patients with ischemic heart disease since it can increase angina and it should not be given after myocardial infarction until the patient's condition has stabilized. Patients with suspected or confirmed ischemia heart disease should be given hydralazine under cover of a beta blocker, which should be started a few days before hydralazine, in order to prevent myocardial stimulation. If given to patients with heart failure they should be monitored for orthostatic hypotension and tachycardia during the initial stages of therapy, preferably in hospital. If treatment with hydralazine is to be stopped in patients with heart failure it should generally be withdrawn gradually. Hydralazine should be used with caution in patients with cerebrovascular disorders. The dose of hydralazine should be reduced or the dosage interval prolonged in patients with hepatic or renal impairment. Complete blood counts and antinuclear antibody determinations should be carried out about every 6 months during long term therapy. Urine analysis (for microhematuria and proteinuria) is also recommended. Hydralazine is teratogenic in some species of animals and should therefore be avoided during the first tow trimesters of pregnancy. Patients may experience impaired, especially at the start of therapy, and should not drive or operate machinery if affected.

Breastfeeding. Hydralazine is distributed into mild in small amounts (see Pregnancy) but no adverse effects have been seen in infants and the American Academy of Pediatrics therefore considers hydralazine to be usually compatible with breastfeeding.

Pregnancy. Hydralazine should be avoided during first two trimesters of pregnancy.

Drug Interactions:

The hypotensive effect on hydralazine may be enhanced by other drugs with hypotensive action. Severe hypotension may occur if hydralazine and diazoxide are given together. However, some interactions with an antihypertensive may be beneficial: thiazide diuretics also counteract the fluid retention caused by hydralazine, and beta-blockers diminish the cardiac accelerating effects.

Storage Condition

Store at temperatures not exceeding 25^oC. Protect from light and moisture. The injection should be discharge if any visible article appears.

Pantoprazole Sodium

Pantoprazole Sodium

40mg for Injection IV

Drug Category: Proton Pump Inhibitor

Pharmacological Action:

Mechanism of action:

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H⁺, K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the (H⁺, K⁺)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested.

Pharmacokinetics:

Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following the administration of pantoprazole for injection, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers with normal liver function receiving a 40mg dose of pantoprazole for injection by constant rate over 15 minutes, the peak concentration (C_max) is 5.52 mcg/ml and the total area under the plasma concentration versus time curve (AUC) is 5.4 mcg.hr/ml. The total clearance is 7.6-14.0 L/h and the apparent volume of distribution is 11.0-23.6 L.

The serum protein binding of pantoprazole is about 98%, primarily to albumin. Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system.

After administration of a single intravenous dose of Pantoprazole to healthy, normal metabolizer subjects, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.

Indications:

Pantoprazole for injection is indicated for the treatment of gastric ulcer, duodenal ulcer, moderate and severe reflux esophagitis.

Contraindications:

Pantoprazole for injection is contraindicated in known hypersensitivity to the formulation.

Dosage and Administration:

Dosage:

The recommended dose is intravenous administration of the content of one vial (40mg pantoprazole) once daily for 7 days.

Duodenal Ulcer: Duodenal ulcers generally heal within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Gastric Ulcer and Gastro-esophageal reflux: A 4 week period is usually required for the treatment of gastric ulcers and gastro-esophageal reflux. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Elderly: No dose adjustment is necessary in the elders.

Patient with impaired renal function: No dose adjustment is necessary in patients with impaired renal function.

Patient with impaired hepatic function: In patients with severe liver impairments, the daily dose should be reduced to 20 mg pantoprazole. Also, in these patients the liver enzymes should be monitored during pantoprazole therapy. In cases of a liver enzymes, it should be discontinued.

Administration:

The content of the vial needs to be reconstituted with 10 ml of sodium chloride injection 0.9%w/v before injection.

This freshly prepared solution should be administered intravenously over 2 to 15 minutes, either as a slow injection or it may be further diluted with 100ml of sodium chloride injection 0.9%w/v or 5% glucose injection and administered as a short term infusion.

The duration of administration should be 2 to 15 minutes. The reconstituted solution must be used within 12 hours of preparation.

Warnings and precautions:

Prior to the treatment of gastric ulcer, the possibility of malignancy should be excluded before treatment with pantoprazole is instituted, as treatment may alleviate symptoms and delay diagnosis.

Anaphylaxis has been reported with the use of intravenous pantoprazole. This may require emergency medical treatment.

The diagnosis of an inflammation of the esophagus should be endoscopically confirmed.

Pantoprazole does not affect the ability to drive and use machines.

Pregnancy and Lactation:

Pregnancy: During pregnancy, pantoprazole should be used unless the benefit exceeds the potential risk.

Lactation: There is no information about the safety of pantoprazole during breast feeding in humans. During breast feeding, pantoprazole should not be used unless the benefit exceeds the potential risk.

Adverse Effects:

Treatments with pantoprazole can occasionally lead to headache or diarrhea. Rarely nausea/vomiting, abdominal pain, flatulence, constipation, allergic reactions such as skin rash and pruritus may occur. Individual cases of edema, blurred vision, fever, dizziness, thrombophlebitis, depression or myalgia subsiding after termination of therapy have been reported.

Drug Interactions:

No clinically significant interactions were observed with carbamazepine, caffeine, diazepan, diclofena, digoxin, ethanol, glibenclamide, metoprolol, phenytoin, warfarin and concomitantly administered antacids.

As with other acid secretions inhibitors, changes in absorption may be observed when drugs whose absorption is pH dependent, e.g. ketoconazole are taken concomitantly.

Overdosage and its treatment:

There is no known symptoms of overdosage in human. Doses of up to 240mg IV were administered without adverse effects. Apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

Storage Conditions:

Store in a dry place at a temperature not exceeding 30^oC.

Keep away from direct sunlight.

Keep out reach of children.

Tranexamic Acid

Tranexamic Acid

100mg/ml Injection (I.V.)

Drug Category: Antifibrinolytic agent

Chemical Name and Molecular Formula:

Trans-4-(Aminomethyl) cyclohexanecarboxylic acid. C₈H₁₅NO₂

Pharmacology:

Tranexamic acid is an antifibrinolytic drug, which inhibits breakdown of fibrin clots. It acts primarily by blocking the binding of plasminogen and plasmin to fibrin; direct inhibition of plasmin occurs only to a limited degree. Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ration corresponding to the difference in potency between the compounds.

Pharmacokinetics:

Absorption: Tranexamic acid can be administered by slow intravenous injection or continuous infusion. After an intravenous dose of 1 g, the plasma half-life is about 2 hours for the terminal elimination phase. The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels.

Distribution: Tranexamic acid is widely distributed throughout the body. Tranexamic acid diffuses rapidly into joint fluid, the synovial membrane, CSF, aqueous humor and semen. If diffuses across the placenta and is distributed into breast milk. The concentration in cord blood after an intravenous injection of 10mg/kg to pregnant women is about 30mg/liter, as high as in the maternal blood.

Metabolism: Only a small fraction of the drug is metabolized.

Excretions: It is excreted in the urine mainly in unchanged drug. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10mg/kg body weight.

Indications:

In the treatment and prophylaxis of hemorrhage associated with excessive fibrinolysis. In patients with hemophilia for short term use 2-8 days to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.

Contraindications:

Tranexamic acid is contraindicated in patients with acquired defective color vision, subarachnoid hemorrhage and active intravascular clotting.

Precautions and Warnings:

The dose of tranexamic acid injection should be reduced in patient with renal insufficiency because of the risk of accumulation. Caution should be exercised in the patients with upper urinary tract bleeding which may cause the ureteral obstruction due to clot formation. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid. In addition, cases of central retinal artery and central retinal vein obstruction have been reported.

Used with caution in patients with a previous history of thromboembolic disease which may be at increased risk for venous or arterial thrombosis. Strict supervision by physician should be done while administrating tranexamic acid to the patients with disseminated intravascular coagulation.

An ophthalmic examination, including visual acuity, color vision, eye-ground and visual fields, is advised for patients who are to be treated continually for longer than several days and drug should be discontinued if changes in examination results are found.

Dosage adjustment should be done in the patients with moderate to severe impaired renal function.

Use in Pregnancy and Lactation:

There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Therefore, drug should be used during pregnancy only if clearly needed.

Tranexamic acid is present in the mother's milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when tranexamic acid is administered to a nursing woman.

Drug Interactions:

Caution should be exercised when concomitant administration of drugs with actions on homeostasis is given in the patient with antifibrinolytic therapy. Care should be taken while concurrently administrating of estrogen, because it may increase the potential for thrombus formation. Tranexamic acid should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased.

Adverse Effects:

Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Orthostatic symptoms and hypotension have been reported occasionally. Hypersensitivity skin reactions have also been reported. Hypotension has been observed when intravenous injection is too rapid.

Dosage and Administration:

Adults:

Parenteral Therapy: 10mg/kg 3-4 times daily.

Immediately before dental extraction in patients with hemophilia: 10mg/kg intravenous together with replacement therapy; following surgery, 25mg/kg given orally 3 or 4 times daily for 2-8 days.

Children:

Intravenous therapy: 10mg/kg 2-3 times daily.

Note:

• For intravenous infusion, tranexamic acid injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions and dextran solutions.
• The mixture should be prepared the same day the solution is to be used. Heparin may be added to tranexamic acid injection.
• Tranexamic acid injection should NOT be mixed with blood.
• The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin.

Overdosage:

There is no known case of overdosage of tranexamic acid injection. Symptoms of overdosage may be nausea, vomiting, orthostatic symptoms and/or hypotension. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Shelf-Life:

36 months from the date of manufacturing.

Storage Conditions:

Store at a temperatures not exceeding 30^oC. Protect from direct sunlight. Keep out of reach of children.

Glimepiride

Glimepiride

1mg Tablet

2mg Tablet

3mg Tablet

Drug Category: Oral Hypoglycemic (Sulfonylurea group)

Description:

Glimepiride is an oral blood-glucose-lowering drug of the sulfonylurea class. Chemically, Glimepiride is identified as 1-[{p[2-(3-ethyl-4-methyl-2-oxo-3-pyrolline-1-carboxamido)ethyl]phenyl]-sulfonyl-3-(trans-4-methylcyclhexyl)urea. Its molecular formula is C₂₄H₃₄N₄O₅S and its molecular weight is 490.62.

Mechanism of Action:

The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin.

Pharmacokinetics:

After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Peak levels (Cmax) occur at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under curve) were slightly decreased (8% and 9%, respectively). Protein binding was greater than 99.5%. Glimepiride is completely metabolized by oxidative biotransformation. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxy derivative (M2). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2, by one or several cytosolic enzymes. M1, but no M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinical meaningful is not clear. When ¹⁴C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of the recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces.

Indications:

Glimepiride is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with non-insulin-dependent (Type II) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone.

Contraindications

Glimepiride is not suitable for the treatment of type I diabetes mellitus (eg for the treatment of diabetics with history of ketoacidosis), of diabetic ketoacidosis, or of diabetic precoma or coma.

Glimepiride is contraindicated in patients with known hypersensitivity to glimepiride, other sulfonylureas, other sulfonamides or any of the excipients.

There is insufficient data concerning the use of Glimaryl in patients with severe renal or hepatic impairment. A changeover to insulin is indicated.

Precautions and Warnings:

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy.

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1mg once daily followed by appropriate dose titration is recommended in those patients. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drugs is used. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to add insulin in combination with glimepiride or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. The phenomenon is known as secondary failure to distinguish if from primary failure in which the drug is ineffective in an individual patient when first given. Should secondary failure occur with glimepiride or metformin monotherapy, combined therapy with glimepiride and metformin or glimepiride and insulin may result in a response. Should secondary failure occur with glimepiride/metformin therapy, it may be necessary to initiate insulin therapy.

Usage in pregnancy, lactation and children:

There are no adequate and well-controlled studies in pregnant women. On basis of results from animal studies, Glimepiride should not be used during pregnancy. Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course of pregnancy and lactation.

Because of the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, glimepiride should be discontinued in nursing mothers. Safety and effectiveness of the drug in pediatric patients have not been established.

Adverse Reactions:

The incidence of hypoglycemia with glimepiride, as documented by blood glucose values ,60mg/dhl, has ranged from 0.9-1.7% in most of the clinical trials carried out with the drug. Adverse events, other than hypoglycemia, considered to be possible or probably related to study drug that occurred in more than 1% patients treated with glimepiride are dizziness, asthenia, headache and nausea.

Vomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzymes levels. In isolated instances impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas including glimepiride.

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbiliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of glimepiride. If these hypersensitivity reactions persist, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylurea.

Drug Interactions:

The hypoglycemic action of sulfonylurea may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When these drugs are administered to a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for loss of glycemic control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics and isoniazid. When these drugs are administered to a patient receiving glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed for hypoglycemia.

Dosage and Administration:

The usual starting dose of glimepiride as initial therapy is 1-2mg once daily, administered with breakfast of the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1 mg once daily, and should be titrated carefully. The maximum starting dose of glimepiride should be no more than 2mg.

The usual maintenance dose is 1 to 4 mg once daily. The maximum recommended dose is 8 mg once daily. After reaching a dose of 2 mg, dosage increases should be made in increments of no more than 2 mg at 1-2 week intervals based upon the patients blood glucose response.

If patients do not respond adequately to the maximal dose of glimepiride monotherapy, addition of metformin may be considered. Combination therapy with glimepiride and insulin may also be used in secondary failure patients.

Glimepiride is not recommended for use in pregnancy, nursing mother, or children. In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions.

As with other sulfonylurea hypoglycemic agents, no transition period is necessary when transferring patients to glimepiride. Patients should be observed carefully (1-2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g. chlorpropamide) to glimepiride due to potential overlapping of drug effect. Or as prescribed by a physician.

Overdosage:

Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemia symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a lever above 100mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent recovery.

Storage condition:

Store at temperatures not exceeding 30^oC. Protect from moisture. Store away from heat and direct light.