Actine

Uses

Actine is used for an adjunct to diet for the control of hyperglycaemia and its associated symptomatology in the treatment of non-insulin-dependent diabetes mellitus (NIDDM type II) when diet modification has not been proved effective on its own. In certain patients who are receiving insulin, the concurrent use of Actine would allow a reduction in the daily dose of insulin.

Use of Actine must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, short term administration may be required if diet control alone results in transient control of blood glucose level.

During maintenance, if satisfactory lowering of blood glucose is no longer achieved, use of Actine should be discontinued.

Actine is also used to associated treatment for these conditions: Type 2 Diabetes Mellitus

How Actine works

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence worldwide. Characterized by higher-than-normal levels of blood glucose, T2DM is a complex disorder that arises from the interaction between genetic, environmental and behavioral risk factors. Insulin is a peptide hormone that plays a critical role in regulating blood glucose levels. In response to high blood glucose levels, insulin promotes the uptake of glucose into the liver, muscle cells, and fat cells for storage. Although there are multiple events occurring that lead to the pathophysiology of T2DM, the disorder mainly involves insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual failure of beta cells of pancreatic islets that normally produce insulin. Early management with lifestyle intervention, such as controlled diet and exercise, is critical in reducing the risk of long-term secondary complications, such as cardiovascular mortality.

Actine, like other sulfonylurea drugs, is an insulin secretagogue, which works by stimulating the insulin release from the pancreatic beta cells thereby increasing the plasma concentrations of insulin. Thus, the main therapeutic action of the drug depends on the functional beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor expressed on the pancreatic beta-cell plasma membrane, leading to the closure of the ATP-sensitive potassium channel and reduced potassium conductance. This results in depolarization of the pancreatic beta cell and opening of the voltage-sensitive calcium channels, promoting calcium ion influx. Increased intracellular concentrations of calcium ions in beta cells stimulates the secretion, or exocytosis, of insulin granules from the cells. Apart from this main mechanism of action, the blood-glucose-lowering effect of glipizide involves increased peripheral glucose utilization via stimulating hepatic gluconeogenesis and by increasing the number and sensitivity of insulin receptors.

Dosage

Actine dosage

Like any other oral hypoglycaemic agent, dosage of Actine is not fixed and may be adjusted through periodic monitoring of blood glucose level. Short term administration of Actine may be sufficient during periods of transient loss of control of blood glucose in patients, usually controlled well on diet.

In general, Actine should be given approximately 30 minutes before a meal to achieve the maximum reduction in postprandial hyperglycaemia.

• Initial dose: The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg.
• Dosage adjustments: Dosage adjustment may be done at intervals of several days by an increment of 2.5-5 mg, as determined by blood glucose response. If response to a single dose is not satisfactory, dividing that dose might prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate calorie content. The maximum recommended total daily dose is 40 mg.
• Maintenance: Some patients may be effectively controlled on a once daily regimen, while others show better response with divided dosing. Total daily dose above 30 mg have been safely given on bid basis to long term patients. Patients can usually be stabilized on a dosage ranging from 2.5 to 30 mg daily.

In elderly, debilitated or malnourished patients, and patients with impaired renal or hepatic function:

The initial and maintenance dosing should be conservative to avoid hypoglycaemic reactions.

Patients receiving insulin: Many stable non-insulin-dependent diabetic patients receiving Insulin may be safely placed on Actine if the physician decides to do so.

Patients receiving other oral hypoglycaemic agents: As with other sulphonylurea, no transition period is necessary while transferring patients to Actine. Patients should be observed carefully for any possible hypoglycaemic effect due to overlapping of drug effects.

Side Effects

The most potential adverse reaction is hypoglycemia (1% to 3.4%). Other side effects reported were asthenia, headache, dizziness, nervousness, tremor, diarrhea, flatulence.

Toxicity

In rats, the oral LD₅₀ is reported to be greater than 4000 mg/kg and the intraperitoneal LD₅₀ is 1200 mg/kg. The lowest published toxic dose (TDLo) via oral route in child was 379 μg/kg.

Symptoms of overdose in sulfonylureas, including glipizide, may be related to severe hypoglycemia and may include coma, seizure, or other neurological impairment. These are symptoms of severe hypoglycemia and require immediate treatment with glucagon or intravenous glucose and close monitoring for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose.

Precaution

Hypoglycaemia: All sulphonylurea drugs are capable of producing severe hypoglycaemia. Proper patient selection, dosage and instructions are important to avoid hypoglycaemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of Actine and the latter may also diminis gluconeogenic capacity, both of which increase the risk of serious hypoglycaemic reactions. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycaemic actions of glucose lowering drugs. Patients should be instructed to take their meals regularly and not to exercise excessively without additional calorie intake.

Renal and hepatic disease: The metabolism and excretion of Actine may be slowed in patients with impaired renal and/or hepatic function. These patients may suffer from prolonged hypoglycaemia and appropriate measures should be instituted.

Loss of control on blood glucose: When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control on blood glucose may occur. At that time it may be necessary to discontinue Actine and administer Insulin.

The effectiveness of any oral hypoglycaemic drug including Actine, in lowering blood glucose to a desired level, decreases in many patients over a period of time, which may be due to secondary failure, i.e., progression of the severity of the diabetes or diminished responsiveness to the drug.

Interaction

The hypoglycaemic action of sulphonylurea may be potentiated by certain drugs including non-steroidal anti inflammatory agents and other drugs that are highly protein bound e.g., Salicylates, Sulphonamides, Chloramphenicol, Probenecid, Coumarins, Monoamine Oxidase Inhibitors, and β adrenergic blocking agents. When such drugs are administered to a patient receiving Actine, the patients should be observed closely for hypoglycaemia. When such drugs are withdrawn from a patient receiving Actine, the patient should be observed closely for loss of control on blood glucose.

Certain drugs tend to produce hyperglycaemia and may lead to loss of control on blood glucose. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, oestrogens, oral contraceptives, Phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and Isoniazid. When such drugs are administered to or withdrawn from a patient receiving Actine, the patient should be closely observed for loss of control on blood glucose. Diabetic control may be altered also in patients treated with cyclophosphamide.

Food Interaction

• Avoid excessive or chronic alcohol consumption. The risk of hypoglycemia is increased when alcohol is ingested.
• Take before a meal. Take 30-60 minutes before breakfast.

[Moderate] GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes.

Hypoglycemia most frequently occurs during acute consumption of alcohol.

Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise.

The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia.

Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion.

By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia.

Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes.

A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis.

Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan.

Alcohol should not be consumed on an empty stomach or following exercise.

Actine Drug Interaction

Moderate: aspirin, aspirin, aspirin, aspirin, sitagliptin, sitagliptin, insulin glargine, insulin glargine, metoprolol, metoprolol, metoprolol, metoprololUnknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, atorvastatin, atorvastatin, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Actine Disease Interaction

Major: cardiovascular risk, DKA, renal/liver diseaseModerate: GI narrowing, hypoglycemia, G6PD deficiency, hyponatremia

Volume of Distribution

The mean volume of distribution was approximately 10 L following administration of single intravenous doses in patients with type 2 diabetes mellitus. In mice and rat studies, the presence of the drug and its metabolites was none to minimal in the fetus of pregnant female animals. Other sulfonylurea drugs were shown to cross the placenta and enter breast milk thus the potential risk of glipizide in fetus or infants cannot be excluded.

Elimination Route

Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. The absolute bioavailability of glipizide in patients with type 2 diabetes receiving a single oral dose was 100%. The maximum plasma concentrations are expected to be reached within 6 to 12 hours following initial dosing. The steady-state plasma concentrations of glipizide from extended-release oral formulations are maintained over the 24-hour dosing interval. In healthy volunteers, the absorption of glipizide was delayed by the presence of food but the total absorption was unaffected.

Half Life

The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus.

Clearance

The mean total body clearance of glipizide was approximately 3 L/hr following administration of single intravenous doses in patients with type 2 diabetes mellitus.

Elimination Route

Actine is mainly eliminated by hepatic biotransformation, where less than 10% of the initial dose of the drug can be detected in the urine and feces as unchanged glipizide. About 80% of the metabolites of glipizide is excreted in the urine while 10% is excreted in the feces.

Pregnancy & Breastfeeding use

Pregnancy: Actine should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Prolonged severe hypoglycaemia (4-10 days) has been reported in neonates born to mothers who were receiving sulphonylurea (e.g., Actine) at the time of delivery. So, if Actine is used during pregnancy, it should be discontinued at least one month before the expected delivery date.

Lactation: Although it is not known whether Actine is excreted in human milk, some sulphonylurea drugs are known to be so. Breast feeding is not therefore recommended while taking this medication.

Contraindication

Actine is contraindicated in the following conditions :

• Patients who are hypersensitive to Actine or any component of the product
• Juvenile onset diabetes
• Severe or unstable ‘brittle’ diabetes
• Diabetes complicated by ketosis and acidosis, major surgery, severe sepsis or severe trauma
• Severe renal, hepatic or thyroid impairment, co-existent renal and hepatic disease

Special Warning

Pediatric Use: Safety and effectiveness in children have not been established.

Geriatric Use: There were no overall differences in effectiveness or safety between younger and older patients.

Renal Impairment: Severe: Contraindicated.

Hepatic Impairment: Severe: Contraindicated.

Acute Overdose

There is no well-documented experience with Actine tablets overdosage in humans.

Storage Condition

The tablets should be protected from moisture and humidity and stored at room temperature (below 30° C).

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