استطباب: Hypoglycemic. (Sulfonylurea class)

Composition and excipients:
Each ALODOPA F.C. Tablet contains:
– Active ingredients: Methyldopa 125mg or 250mg or 500mg.
– Inactive ingredients:
Core: Povidone, Cutina HR, Sodium starch Glycolate, and Talc.
Film: Eudragit EPO, Talc, Polyethylene Glycol, and Titanium dioxide.
Properties :
Alodopa (methyldopa) is a centrally acting alpha 2-adrenergic agonist which reduces sympathetic tone and produces a fall in
elevated blood pressure .
-Alodopa is decarboxylated in the CNS to alpha-methylnoradrenaline which is thought to stimulate alpha 2-adrenoceptors
resulting in a reduction in sympathetic tone and a fall in blood pressure. It may also act as a false neurotransmitter, and have
some inhibitory action on plasma renin activity
. Alodopa reduces the tissue concentrations of dopamine, noradrenaline, adrenaline, and serotonin.
-When administered by mouth its effects reach a maximum in 4 to 6 hours following a single dose, although the maximum
hypotensive effect may not occur until the second or third day of continuous treatment. Blood pressure returns to its
pretreatment levels usually apparent 24-48 hours after withdrawal of methyldopa.
-To reduce the side effects. Smaller doses of methyldopa may be given in conjunction with thiazide diuretic, which would also
reduce the oedema that sometimes occur with methyldopa therapy and reduces development of tolerance .
-Side effects are minimized if the daily dose is kept below 1g .
Indications :
Alodopa is used in the treatment and control of moderate to severe hypertension, usually in combination , but other agents with
fewer adverse effects are generally preferred. It reduces the standing, and to a lesser extent the supine blood pressure.
Pharmacokinetics :
-Following oral administration, methyldopa is variably and incompletely absorbed, apparently by an amino-acid active
transport system. The mean bio-availability has been reported to be about 50%. It is extensively metabolized and is excreted in
urine mainly as unchanged drug and the O-sulphate conjugate. It crosses the blood brain barrier and decarboxylated in the
central nervous system to active alpha methyl noradrenaline .
-The elimination is biphasic with a half-life of about 1.7 hours in the initial phase; the second phase is more prolonged.
Clearance is decreased and half-life prolonged in renal insufficiency. Plasma protein bindings is reported to be minimal.
Methyldopa crosses the placenta, small amounts are distributed into breast milk.
Contraindications :
-Alodopa is contraindicated in patients hypersensitive to methyldopa or any of its components, renal or hepatic insufficiency,
porphyria, and active hepatitis, anuria, and active cirrhosis.
-Concomitant administration of Alodopa with MAOIs and L-dopa-, and patients with pheochromocytoma.
-In patients with liver diseases previously associated with methyldopa therapy .
Precautions :
-Periodic Coombs test and blood test should be performed during therapy to detect hemolytic anemia. It may be useful to do a
Coombs test before therapy and at 6-12 months after the start of therapy.
-Since concomitant administration of methyldopa is associated with liver disorders. It may be useful to do periodic
determination of hepatic function before therapy and during 6-12 months after the start of therapy .
-Some patients experience clinical edema or weight gain which may be controlled by use of diuretic. Methyldopa should not
be cotinued if edema progresses or signs of heart failure appears .
-Treatment should be discontinued if patients experience involuntary choreoathetotic movements in subjects with severe
bilateral cerebrovascular disease.
Drug Interactions :
-The hypotensive effects of methyldopa are enhanced by diuretics and other anti-hypotensive agents .
-Absorption of methyldopa was reduced by 73% and 61 %. respectively when taken with a dose of ferrous sulfate and ferrous
gluconate .
-Concurrent administration methyldopa with lithium may lead to lithium toxicity, therefore, patients taking both medicines
should be carefully monitored .
Pregnancy and Lactation: Pregnancy category C:
-There are no adequate and well-controlled studies with methyldopa in pregnant woman. Methyldopa should be used during
pregnancy and lactation only if clearly needed and under medical observation.
Side Effects :
-Few adverse effects may occur including, dizziness, headache, weakness, and parkinsonism when higher doses are
administered .
-Orthostatic hypotension, bradycardia.
-Hematological alterations including hemolytic anemia, positive Coombs test, allergic reaction, and impotence have rarely
been reported .
-CNS: – Alodopa may cause sedation, it is advisable not to drive or operated machineries when taking the drug .
-Less common side effects including nasal congestion, drug fever, failure of ejaculation, decreased libido, thrombocytopenia,
leukopenia, jaundice, and pancreatitis .
Dosage and Administration :
Dosge of Alodopa should be individualized .
Adults: The usual initial dose by mouth is 250 mg 2-3 times daily. Then adjusted by small increments or decrements not more
frequently than every 2 days according to the response of the patient. Maximum dose is 3 g. daily.
-The usual maintenance dosage is the equivalent of 0.5 to 2 g. daily in 2-4 divided doses .
-Elderly: Initially 125 mg twice daily, increased gradually: Maximum 2 g. daily.
-Children: A suggested initial dose of 10 mg per kg body -weight daily in 2-4 divided doses. Increased as necessary until
adequate response is achieved to maximum of 65 mg per kg or 3 g. daily whichever is less .
-Dosage reduction should be considered in patients with renal insufficiency .
Packing :
Box containing Alodopa ( 125 mg -250 mg – 500 mg ) 30- 50 F.C. Tablets.
Storage :Store at temperature (15-30)° C.

Composition: each tablet contains glimepiride 1mg- 2mg- 4mg.

Pharmacological properties:

AMARAX (glimepiride) is an oral blood-glucose-lowering drug of the sulfonylurea class. 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. Studies with single oral doses in normal subjects and with multiple oral doses in patients with Type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. After intravenous (IV) dosing in normal subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%, Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). 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 that 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.

Indications:

AMARAX is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications:

AMARAX is contraindicated in patients with:

1.Known hypersensitivity to the drug.

2.Diabetic ketoacidosis, with or without coma.

3. Sulphonylureas should be avoided where possible in severe hepatic impairment and in acute porphyria
4. they shouldn’t be used during pregnancy and while breast-feeding .

Warnings and precautions:

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.

Persons allergic to other sulfonamide derivatives may develop an allergic reaction to glimepiride as well.

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 AMARAX. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

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 AMARAX or even use insulin monotherapy.

The effectiveness of any oral hypoglycemic drug, including AMARAX, in lowering blood glucose to a desired level decreases 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. This phenomenon is known as secondary failure, Should secondary failure occur with AMARAX or metformin monotherapy, combined therapy with AMARAX and metformin or AMARAX and insulin may result in a response.

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Since AMARAX belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered.

Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycemic control.

Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite adequate attempts at dieting. Metformin is considered the drug of choice in obese patient . Caution is needed in the elderly and in those with mild to moderate hepatic impairment because of hazard of hypoglycaemia .

Use in pregnancy:

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, AMARAX (glimepiride) should not be used during pregnancy. Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities.

Nursing mothers:

Because the potential for hypoglycemia in nursing infants may exist AMARAX should be discontinued in nursing mothers.

Pediatrics:

Data are insufficient to recommend pediatric use of AMARAX.

Drug interactions:

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs, clarithromycin, disopyramide, fluoxetine,cimetidine , testosterone , and quinolones 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 AMARAX, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving AMARAX, the patient should be observed closely for loss of glycemic control.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported.

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, progestogens , phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving AMARAX, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving AMARAX, the patient should be observed closely for hypoglycemia.

Coadministration of aspirin (1 g tid) and AMARAX led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean Cmax had a decrease of 4%.

Concomitant administration of propranolol (40 mg tid) and AMARAX significantly increased Cmax, AUC, and T½ of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/f by 18%.

There is a potential interaction of glimepiride with inhibitors (e.g. fluconazole) and inducers (e.g. rifampicin) of cytochrome P450 2C9..

Plasma concentration of sulphonylureas increased by fluconazole, miconazole and voriconazole.

Requirements for sulphonylureas possibly reduced by lanreotide and octreotide .

Adverse reactions:

The administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.

The incidence of  hypoglycemia with amarax (blood glucose values <60mg/dl ) ranged from 0.9-1.7% .dizziness, asthenia ,headache , nausia and vomiting, gastrointestinal pain, and diarrhea. In rare cases, there may be an elevation of liver enzyme 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  , Allergic skin reactions, e.g., pruritus, erythema, urticaria, Porphyria, photosensitivity reactions, and allergic vasculitis, Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, , Hepatic porphyria reactions and disulfiram-like reactions, hyponatremia, (SIADH)The syndrome of inappropriate antidiuretic hormone , Changes in accommodation and/or blurred vision.

Severe allergic reactions (difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain or irregular heartbeat; dark urine; fainting; fever, chills, or persistent sore throat.

Overdosage:

Overdosage of sulfonylureas, including AMARAX, can produce hypoglycemia. Mild hypoglycemic 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 a 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 level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.

Dosage:

Usual Starting Dose: The usual starting dose of AMARAX as initial therapy is 1-2 mg once daily, administered with breakfast or 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 AMARAX should be no more than 2 mg.

Usual Maintenance Dose :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 patient’sblood glucose response  long term efficacy should be monitored by measurement of HbA1c levels, for example, every 3 to 6 months.

AMARAX-Metformin Combination Therapy: If patients do not respond adequately to the maximal dose of AMARAX monotherapy, addition of metformin may be considered. With concomitant AMARAX and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.

AMARAX-Insulin Combination Therapy:

Combination therapy with AMARAX and insulin may also be used in secondary failure patients. The fasting glucose level for instituting combination therapy is in the range of > 150 mg/dL in plasma or serum depending on the patient. The recommended AMARAX dose is 8 mg once daily administered with the first main meal. After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily. Periodic adjustments of insulin may also be necessary during maintenance as guided by glucose and HbA1c levels.

packing:

• AMARAX 1 contains glimepiride 1 mg.: pack of 20-30 tablets.
• AMARAX 1 contains glimepiride 2 mg.: pack of 20-30 tablets.
• AMARAX 1 contains glimepiride 4 mg.: pack of 20-30 tablets.

Storage: Store between  (15 and 30 ° C).