|| See TERMINOLOGY & ABBREVIATIONS ||
Content & Indication(s)
Biphasic insulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Biphasic insulin is a mixture of 70% Human Insulin Isophane Suspension and 30% Human Insulin Injection (rDNA origin). It is an intermediate-acting insulin combined with the more rapid onset of action of Regular human insulin. The duration of activity may last up to 24 hours following injection. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Biphasic insulin is dependent on dose, site of injection, blood supply, temperature, and physical activity. Biphasic insulin is a sterile suspension and is for subcutaneous injection only. It should not be used intravenously or intramuscularly.
This product may be available in following composition & strengths:
Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates, proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur and thus to prevent the production of ketone bodies by the liver. Some patients might develop severe insulin resistance such that daily doses of several hundred units of insulin or more are required.
Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibit lipolysis, proteolysis, and gluconeogenesis, and enhance protein synthesis and conversion of excess glucose into fat.
Administered insulin, including Biphasic human insulin, substitutes for inadequate endogenous insulin secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals to patients with diabetes mellitus, Biphasic insulin restores their ability to metabolize carbohydrates, proteins and fats.
As with all insulin preparations, the duration of action of Biphasic insulin is dependent on dose, site of injection, blood supply, temperature, and physical activity. Clinical experience has shown that it frequently has time action characteristics reflecting both prandial and basal activity.
Biphasic insulin is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 1 and type 2 diabetes mellitus. Furthermore indicated for the initial stabilisation of diabetes, during treatment of diabetic ketoacidosis and the hyperosmolar non ketotic syndrome, and during stress situations such as severe infections and major surgery in diabetic patients.
How to use
Please carefully read & follow manufacturer's Patient Instruction Leaflet (PIL) for detailed direction of chosen brand. A generalized guideline may be as follows.
9. Remove the needle from the bottle and lay the syringe down so that the needle does not touch anything.
For detail description, please see the manufacturer's Patient Instruction Leaflet.
Do not use Biphasic insulin:
Dosage and Administration
Dosage is individualized and determined by the physician in accordance with the needs of the patient.
Usual dose of Biphasic insulin may be affected by changes in diet, activity, or work schedule.
The average range of total daily insulin requirement for maintenance therapy in insulin-treated patients without severe insulin resistance lies between 0.5 and 1.0 unit/kg/day. However, in pre-pubertal children it usually varies from 0.7 to 1.0 unit/kg/day, but can be much lower during the period of partial remission. In situations of insulin resistance, e.g., during puberty or due to obesity, the daily insulin requirement may be substantially higher. Initial dosages for type 2 diabetes patients are often lower, e.g., 0.3 to 0.6 units/kg/day.
An injection should be followed by a meal or snack containing carbohydrates within approximately 30 minutes of administration.
This insulin should be administered by subcutaneous injection in the abdominal wall, the thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Injection sites should be rotated within the same region. As with all insulin, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity.
Insulin should only be administered subcutaneously and do not administer intravenously or intramuscularly.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the content and container permit. Never use the product if it has lost its usual color & consistency. Insulin should not be used after the printed expiration date. Careful attention to manufacturers' packaging leaflet is recommended.
Biphasic insulin is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Biphasic insulin or any of its excipients.
Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species, or method of administration may result in the need for a change in dosage. For Biphasic insulin, extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia.
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists: Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Biphasic insulin, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Dosing Confusion/Dosing Errors
Medication errors associated with Biphasic insulin have occurred and resulted in patients experiencing hyperglycemia, hypoglycemia or death. The majority of errors occurred due to errors in dispensing, prescribing or administration. Careful attention to the above details may prevent the errors significantly.
Manufacturer's instructions for use should always be read and followed before use. The patient should be instructed to inform hospital or emergency department staff of the dose of Biphasic insulin prescribed, in the event of a future hospitalization or visit to the Emergency Department.
Hypoglycemia is the most common adverse reaction of all insulin therapies, including Biphasic insulin. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Biphasic insulin. As with all insulin preparations, the time course of Biphasic insulin action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. Concomitant oral antidiabetic treatment may need to be adjusted.
Any patient who requires Biphasic insulin for control of diabetes should be under close observation until appropriate dosage is established. The response will vary among patients. Most patients will require 2 or 3 injections per day. Insulin resistance, in some patients is transitory; after several weeks or months during which high dosage is required, responsiveness to the pharmacologic effect of insulin may be regained and dosage can be reduced. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may prevent a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia may develop 18 to 24 hours after the original injection of Biphasic insulin.
Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Non-Ketotic Syndrome
Hyperglycemia, diabetic ketoacidosis, or hyperosmolar coma may develop if the patient takes less Biphasic insulin than needed to control blood glucose levels. This could be due to increases in insulin demand during illness or infection, neglect of diet, omission or improper administration of prescribed insulin doses or use of drugs that affect glucose metabolism or insulin sensitivity. Early signs of diabetic ketoacidosis include glycosuria and ketonuria. Polydipsia, polyuria, loss of appetite, fatigue, dry skin, abdominal pain, nausea and vomiting and compensatory tachypnea come on gradually, usually over a period of some hours or days, in conjunction with hyperglycemia and ketonemia. Severe sustained hyperglycemia may result in hyperosmolar coma or death.
Insulin stimulates potassium movement into the cells, possibly leading to hypokalemia, that left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Biphasic insulin. Localized reactions and generalized myalgias have been reported with the use of metacresol as an injectable excipient.
Renal or Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment.
Some medications may alter insulin requirements and the risk for hypoglycemia and hyperglycemia.
Pregnancy Category (FDA)and use in Specific Population
Pregnancy Category B All pregnancies have background risk of birth defects, miscarriage, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and is decreased with good glucose control. It is important for patients to maintain good control of diabetes before conception and during pregnancy. Special attention should be paid to diet, exercise and insulin regimens. Insulin requirements may decrease during the first trimester, usually increase during the second and third trimesters and rapidly decline after delivery. Careful glucose monitoring is essential in these patients. Female patients should be advised to tell their physician if they intend to become, or if they become pregnant. Studies show that endogenous insulin only crosses the placenta in minimal amounts. While there are no adequate and well-controlled studies in pregnant women, an extensive body of published literature demonstrates the maternal and fetal benefits of insulin treatment in patients with diabetes during pregnancy. Biphasic insulin is a recombinant human insulin that is identical to the endogenous hormone; therefore, reproduction and fertility studies were not performed in animals.
Labor and Delivery
Careful glucose monitoring and management of patients with diabetes during labor and delivery are required.
Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the gastrointestinal tract. In lactating infants, no adverse reactions have been associated with maternal use of insulin. In a study of eight preterm infants between 26 to 30 weeks gestation, enteral administration of Humulin R did not result in hypoglycemia. Good glucose control supports lactation in patients with diabetes. Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.
There are no well-controlled studies of use of Biphasic insulin in children.
Hypoglycemia is one of the most frequent adverse events experienced by insulin users.
It can be brought about by:
Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:
- sweating - drowsiness - dizziness - sleep disturbances - palpitation - anxiety - tremor - blurred vision - hunger - slurred speech - restlessness - depressed mood - tingling in the hands, feet, lips, or tongue - irritability - lightheadedness - abnormal behavior - inability to concentrate - unsteady movement - headache - personality changes
Signs of severe hypoglycemia can include:
- disorientation - seizures - unconsciousness - coma - death
Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, autonomic diabetic neuropathy, use of medications such as beta adrenergic blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes.
Without recognition of early warning symptoms, the patient may not be able to take steps to avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose more frequently, especially prior to activities such as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy, non-diet carbohydrate-containing drinks or glucose tablets.
Hypokalemia: See Precautions
Lipodystrophy: Administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue).
Allergy: Local Allergy Patients occasionally experience erythema, local edema, and pruritus at the site of injection. This condition usually is self-limiting. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.
Systemic Allergy Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be life threatening.
Weight gain: Weight gain can occur with some insulin therapies and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
Peripheral Edema: Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
The concurrent use of oral anti-hyperglycemic diabetes agents with Biphasic insulin is not recommended since there are limited data to support such use. A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.
Drugs that may increase the blood-glucose-lowering effect of Biphasic insulin and susceptibility to hypoglycemia:
- Oral antihyperglycemic diabetes agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors [SSRIs]), pramlintide, disopyramide, fibrates, fluoxetine, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol.
Drugs that may reduce the blood-glucose-lowering effect:
- Corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents, somatropin, atypical antipsychotics, glucagon, protease inhibitors and thyroid replacement therapy.
Drugs that may increase or decrease blood-glucose-lowering effect:
- Beta-adrenergic blockers, clonidine, lithium salts, and alcohol.
- Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Drugs that may mask the signs of hypoglycemia:
- Beta-adrenergic blockers, clonidine, guanethidine, and reserpine.
Excess insulin may cause hypoglycemia and hypokalemia. Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
|Brand Name||Manufacturer/Marketer||Composition||Dosage Form||Pack Size & Price|
|ANSULIN 30/70 100||Square Pharmaceuticals Ltd.||Insulin Human (rDNA) 100 IU/ml||SC Injection||10 ml: 415.00 MRP|
|ANSULIN 30/70 40||Square Pharmaceuticals Ltd.||Insulin Human (rDNA) 40 IU/ml||SC Injection||10 ml: 195.00 MRP|
|ANSULIN 30/70 PEN||Square Pharmaceuticals Ltd.||Insulin Human (rDNA) 100 IU/ml||SC Injection||3 ml: 222.00 MRP|
|ANSULIN 50/50 INJ||Square Pharmaceuticals Ltd.||Insulin Human (rDNA) 100 IU/ml||SC Injection||10 ml: 415.00 MRP|
|ANSULIN 50/50 PEN||Square Pharmaceuticals Ltd.||Insulin Human (rDNA) 100 IU/ml||SC Injection||3 ml: 222.00 MRP|
|HUMULIN 30/70||Eli Lilly/International Agencies (Bd.) Ltd.||Biphasic premix human insulin (rDNA) 100 IU/ml||Injection||4ml & 10ml vial x1's; 3ml cartridge x5's: 316.00 & 666.00; 1957.30 MRP|
|INSUL 30/70||Popular Pharmaceuticals Ltd.||Biphasic premix human insulin (rDNA) 40 IU/ml,100 IU/ml||Injection||40 IU: 195.00; 100 IU 10ml vial x1's & 3ml cartridge x5's: 415.00 & 1110.00 MRP|
|INSUL 50/50||Popular Pharmaceuticals Ltd.||Biphasic premix human insulin (rDNA) 100 IU/ml||Injection||10ml vial x1's, 3ml cartridge x5's: 415.00 & 1110.00 MRP|
|INSULET 30/70||Aristopharma Ltd.||Biphasic premix human insulin (rDNA) 100 IU/ml||Injection||4ml & 10ml vial: 169.70 & 415.00 MRP|
|INSULET 50/50||Aristopharma Ltd.||Biphasic premix human insulin (rDNA) 100 IU/ml||S/C Injection||4ml & 10ml vial: 169.70 & 415.00 MRP|
|INSUMAN Comb 25||Sanofi||Biphasic (25% Soluble/75% Isophane) premix human insulin (rDNA) 100 IU/ml Penfill||Injection||5ml vial: 281.70 MRP|
|MAXSULIN 30/70||Incepta Pharmaceuticals Limited||Human Insulin (rDNA) BP 40 & 100 IU/ml as 30% Soluble Human Insulin (Regular) + 70% Isophane Human Insulin (NPH)||Injection||10ml vial each: 195.00 & 415.00 MRP|
|MAXSULIN 30/70 Penset||Incepta Pharmaceuticals Limited||Human Insulin (rDNA) BP 100 IU as 30% Soluble Human Insulin (Regular) + 70% Isophane Human Insulin (NPH) per ml||Injection||4's: 888.00 MRP|
|MAXSULIN 50/50||Incepta Pharmaceuticals Limited||Human Insulin (rDNA) BP 100 IU/ml as 50% Soluble Human Insulin (Regular) and 50% Isophane Human Insulin (NPH)||Injection||10ml: 415.00 MRP|
|MAXSULIN 50/50 Penset||Incepta Pharmaceuticals Limited||Human Insulin (rDNA) BP 100 IU/ml as 50% Soluble Human Insulin (Regular) and 50% Isophane Human Insulin (NPH), Penset||Injection||4's: 888.00 MRP|
|MIXTARD 30||Novo Nordisk Pharma (Private) Ltd.||Biphasic (30% Soluble/70% Isophane) premix human insulin (rDNA) 100 IU/ml||Injection||10ml vial: 415.00 MRP|
|MIXTARD 30 HM Penfill||Novo Nordisk Pharma (Private) Ltd.||Biphasic (30% Soluble/70% Isophane) premix human insulin (rDNA) 100 IU/ml Penfill||S/C Injection||3ml cartridge: 1830.00 MRP|
|MIXTARD 50 HM Penfill||Novo Nordisk Pharma (Private) Ltd.||Biphasic (50% Soluble/50% Isophane) premix human insulin (rDNA) 100 IU/ml Penfill||S/C Injection||3ml cartridge: 1830.00 MRP|
|NOVOMIX 30 Flexpen||Novo Nordisk Pharma (Private) Ltd.||Pre-mixed neutral suspension consisting of rapid acting insulin aspart (rys) (30%) and intermediate-acting protamine insulin aspart (rys) (70%), S/C Injection||Injection||3ml pre-filled Flexpen: 860.00 MRP|
|NOVOMIX 30 Penfill||Novo Nordisk Pharma (Private) Ltd.||Pre-mixed neutral suspension consisting of rapidacting insulin aspart (rys) (30%) and intermediate-acting protamine insulin aspart (rys) (70%)||S/C Injection||3ml cartridge x5's: 3850.00 MRP|