Insunova

Regular, or isophane or biphasic isophane human insulin of recombinant DNA origin, glargine (rDNA).

Insunova-R (Regular): Insunova-R is a soluble, short-acting insulin. It is a sterile, clear solution of human insulin. One (1) IU (International Unit) of insulin is equivalent to human insulin 0.035 mg. It also contains m-cresol 0.25% w/v as a preservative, and water for injection. The cartridge also contains the following excipients: Zinc oxide, glycerol, sodium hydroxide or hydrochloric acid (for pH adjustment). Insunova-R (Regular) is for SC and IV use only.
Insunova-N (NPH): Insunova-N is an intermediate-acting isophane (NPH) insulin. It is a sterile, cloudy, white, aqueous suspension of human insulin. One (1) IU of insulin is equivalent to human insulin 0.035 mg. It also contains m-cresol 0.16% w/v and phenol 0.065% w/v as preservatives, and water for injection. The cartridge also contains the following excipients: Zinc, glycerol, dibasic sodium phosphate, sodium hydroxide or hydrochloric acid (for pH adjustment), protamine sulfate. Insunova-N (NPH) is for SC use only and not for IV use.
Insunova-30/70 (Biphasic): Insunova-30/70 is a sterile, cloudy, white, aqueous suspension of human insulin. It is a mixture of biphasic isophane insulin injection containing 30% short-acting insulin solution and 70% immediate-acting isophane (NPH) insulin suspension. One (1) IU of insulin is equivalent to human insulin 0.035 mg. It also contains m-cresol 0.16% w/v and phenol 0.065% w/v as preservatives, and water for injection. The cartridge also contains the following excipients: Zinc, glycerol, dibasic sodium phosphate, sodium hydroxide or hydrochloric acid (for pH adjustment), protamine sulfate. Insunova-30/70 (Biphasic) is for SC use only and not for IV use.
Insunova-G: Each mL contains insulin glargine (rDNA) 100 IU and m-cresol 2.7 mg as preservative.
Each Insulin glargine is produced in Pichia pastoris by recombinant deoxyribonucleic acid (DNA) technology. It also contains the following excipients: Glycerol, metacresol, zinc chloride, hydrochloric acid, sodium hydroxide, water for injection, solution for injection 1000 IU (10 mL only).

Pharmacotherapeutic Group: Insunova-R: Insulins and analogues for injection, fast-acting, insulin (human). ATC Code: A10AB01.
Insunova-N: Insulins and analogues for injection, intermediate-acting, insulin (human). ATC Code: A10AC01.
Insunova-30/70: Insulins and analogues for injection, intermediate-acting combined with fast-acting, insulin (human). ATC Code: A10AD01.
Insunova-G: Drugs used in diabetes. Insulins and analogues for injection, long-acting.
Pharmacodynamics: Insulin, a hormone secreted by the β-cells of the pancreas, plays an essential role in controlling the metabolism and storage of carbohydrates, fat and protein. Insulin is secreted in response to a rise in blood glucose (sugar).
Mechanism of Action: The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and suppression of glucose output from the liver. Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action profile of an insulin preparation is determined solely by its absorption characteristics. This process is influenced by several factors (eg, insulin dosage, injection route and site), which is why considerable intra- and interpatient variability is seen.
Insunova-G: Insulin glargine is a human insulin analogue designed to have low solubility at a neutral pH. It is completely soluble at the acidic pH of the injection solution (pH 4). After injection into SC tissue, the acidic solution is neutralised leading to formation of microprecipitates from which small amounts of insulin glargine are continuously released, providing a smooth, peakless, predictable concentration/time profile with a prolonged duration of action.
Insulin Receptor Binding: Insulin glargine is very similar to human insulin with respect to insulin receptor binding kinetics and can therefore, be considered to mediate a similar effect via the insulin receptor.
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.
In clinical pharmacology studies, IV insulin glargine and human insulin have shown to be equipotent when given at the same doses. As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.
In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of SC insulin glargine was slower than neutral protamine hagedorn (NPH) human insulin. The efficacy profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH human insulin.
The longer duration of action (up to 24 hrs) of insulin glargine is directly related to its slower rate of absorption and supports once daily SC administration. The time course of action of insulins, including insulin glargine, may vary between individuals and/or within the same individual.
In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similar on administration of IV insulin glargine and human insulin both in healthy volunteers and in patients with type 1 diabetes.
In an another 5-year NPH-controlled study (NPH given twice daily) in 1024 type 2 diabetic patients, progression of retinopathy by ≥3 steps on the early treatment diabetic retinopathy study (ETDRS) scale was investigated by fundus photography. No significant difference was seen in the progression of diabetic retinopathy when insulin glargine was compared to NPH insulin.
Paediatric Population: In a randomised, controlled clinical study, paediatric patients (range 6-15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohaemoglobin and the incidence of symptomatic hypoglycaemia were observed in both treatment groups, however fasting plasma glucose decreased more from baseline in the insulin glargine group than in the NPH group. There was less severe hypoglycaemia in the insulin glargine group as well. One hundred and forty-three (143) patients treated with insulin glargine in this study continued treatment with insulin glargine in an uncontrolled extension study with mean duration of follow up of 2 years. No new safety signals were seen during this extended treatment with insulin glargine.
Clinical Studies: Efficacy of Biocon's insulin glargine was assessed in a phase 3 study conducted by Biocon limited to establish safety and non-inferiority (in comparison to reference product), with respect to decrease in glycosylated haemoglobin (HbA_1c) in patients with type 1 diabetes mellitus.
The results established non-inferiority of Biocon's insulin glargine compared to the reference product, with respect to change in HbA_1c. The changes in fasting plasma glucose (FPG), polypropylene glycol (PPG) and 7-point glucose were comparable between the 2 study arms. The proportion of patients who achieved target HbA_1c <7% was comparable between groups. Mean insulin dose was also comparable between the 2 arms. Compliance was good during the study, with average compliance >98% for both basal and pre-meal soluble insulin which was comparable for both study arms.
Overall the 2 study treatments were comparable with respect to efficacy.
Pharmacokinetics: Insulin is metabolized in the liver and kidney; small amounts are metabolized in muscle and fat. It binds to cell surface receptors, is taken into the cells and is then degraded by glutathione insulin transhydrogenase to the A and B chains and by specific intracellular proteases. When injected subcutaneously, the onset of action will occur within 30 min of injection for both Insunova-R and Insunova 30/70, and within 1-1.5 hrs for Insunova-N (NPH).
The maximum peak effect is attained between 2 and 4 hrs for Insunova-R, between 2 and 8 hrs for Insunova-30/70, and within 4-8 hrs for Insunova-N (NPH).
The duration of action is 4-6 hrs for Insunova-R, and up to 24 hrs for both Insunova-30/70 and Insunova-N (NPH).
Insunova-G: In healthy subjects and in diabetic patients, insulin serum concentrations indicated a slower and much more prolonged absorption and showed a lack of a peak after subcutaneous injection of insulin glargine in comparison to human NPH insulin, concentrations were thus, consistent with the time profile of the pharmacodynamic activity of insulin glargine. Insulin glargine injected once daily will reach steady-state levels in 2-4 days after the 1st dose. When given IV the elimination half-life (t_½) of insulin glargine and human insulin were comparable.
In man, insulin glargine is partly degraded in the SC tissue at the carboxyl terminus of the chain with formation of the active metabolites 21 A-Gly-insulin and 21 A-Gly-des-308-Thr-insulin.
Unchanged insulin glargine and degradation products are also present in plasma. In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safety and efficacy in insulin glargine-treated patients compared to the entire study population.
Paediatric Population: No specific pharmacokinetics study in children or adolescents was conducted.
Toxicology: Preclinical Safety Data: The nonclinical studies performed with the human recombinant insulin reveals no special hazard to humans. Human insulin was not mutagenic in a series of in vitro and in vivo genotoxicity assays.
Insunova-G: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Treatment of all types of diabetes mellitus.
Insunova-G: Once-daily SC administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus.

Dosage is individualized and determined by the physician in accordance with the needs of the patient. The average insulin requirement for diabetes therapy ranges between 0.3 and 1 IU/kg, depending on the individual metabolic status and glycaemic control.
In geriatric patients, the primary aim of treatment may be relief of symptoms and avoidance of hypoglycaemic events.
Insunova-R and Insunova-N are administered SC into the thigh or abdominal wall, preferably before meals. If convenient, the gluteal region or deltoid region may be used.
Subcutaneous injection of Insunova-R into the abdominal wall results in faster absorption than from other injection sites. Injection into a lifted skin fold minimises the risk of an IM injection.
Insunova-30/70 and Insunova-N cannot be given IV.
Injection sites should be rotated within anatomic region and also amongst various other sites in order to avoid lipodystrophy.
In patients with diabetes mellitus, optimised glucose control delays the onset and slows progression of late diabetic complications. Close blood glucose monitoring is therefore recommended.
The injection should ideally but not always, followed within 30 min by a meal or a snack containing carbohydrates.
Insunova-R (vial): May be taken 1-4 times daily, before meals and possible at bedtime. Regular (or rapid-acting) insulin should be administered 30-45 min before a meal. It can be mixed in the same syringe with immediate-acting insulins, but in such situations, the regular insulin is drawn first.
Insunova-R (cartridge): 1-4 times daily depending upon the requirement of the individual, preferably before meals. May also be used along with Insupen to administer Insunova-R cartridge IV but it should be an exception only in situations where vials are not available. In this case, Insunova-R cartridge should be drawn into an insulin syringe, provided air is avoided, or infused with an infusion system. This procedure should only be carried out by healthcare professionals.
Insunova-N (vial and cartridge): 1-2 times daily depending upon the requirement of the individual, preferably 30 min before meals.
Insunova-N (vial) can also be mixed in the same syringe with short-acting soluble insulins, and in such situations, the regular insulin is drawn first.
Insunova-30/70 (vial and cartridge): A premixed insulin is usually given 1-2 times daily, preferably just before meals when a rapid initial effect together with a more prolonged effect is desired.
Insunova-G: Insunova-G contains insulin glargine, an insulin analogue, and has a prolonged duration of action.
Insunova-G should be administered once daily at any time but at the same time each day.
The Insunova-G dose regimen (dose and timing should be individually adjusted. In patients with type 2 diabetes mellitus, Insunova-G can also be given together with orally active antidiabetic medicinal products.
Initiation of Insunova-G Therapy: The recommended starting dose of lnsunova-G in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, pre-meal insulin should be used to satisfy the remainder of the daily insulin requirements.
Based on published information the recommended starting dose on an average is 10 IU once daily and subsequently adjusted according to the patient's need to a total daily dose ranging from 2-100 IU, however doses needs to be individualized by the physician for a particular patient.
Transition From Other Insulins to Insunova-G: When changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Insunova-G, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins or fast-acting insulin analogues or the dose of oral antidiabetic medicinal products). To reduce the risk of nocturnal and early morning hypoglycaemia, patients who are changing their basal insulin regimen from twice daily NPH insulin to a once daily regimen with Insunova-G should reduce their daily dose of basal insulin by 20-30% during the 1st week of treatment. During the 1st week the reduction should, at least partially, be compensated by an increase in mealtime insulin, after this period the regimen should be adjusted individually. As with other insulin analogues, patients with high insulin doses may experience an improved insulin response with Insunova-G because of antibodies to human insulin. Close metabolic monitoring is recommended during transition and in the initial weeks thereafter. With improved metabolic control and resulting increase in insulin sensitivity a further adjustment in dose regimen may become necessary. Dose adjustment may also be required, for example, if the patient's weight or life-style changes, change of timing of insulin dose or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia (see Precautions).
Children: Safety and efficacy of insulin glargine have been established in adolescents and children of ≥6 years. In children, efficacy and safety of insulin glargine have only been demonstrated when given in the evening.
Due to limited experience on the efficacy and safety of insulin glargine in children <6 years, Insunova-G should only be used in this age group under careful medical supervision.
Elderly (≥65 years): In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.
Renal Impairment: In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism.
Hepatic Impairment: In patients with hepatic impairment, insulin requirements may be diminished due to capacity for gluconeogenesis and reduced insulin metabolism.
Administration: How to Inject the Insulin: Inject the insulin under the skin. Use the injection technique described in the InsuPen manual.
Keep the needle under the skin for at least 10 sec to make sure that the full dose has been delivered.
After each injection, be sure to remove and discard the needle appropriately. Store Insunova-R (Regular) cartridge in InsuPen without any needle attached, otherwise, the liquid may leak out which can cause inaccurate dosing.
Insunova-G: Insunova-G is administered SC and should not be given IV. The prolonged duration of action of Insunova-G is dependent on injection into SC tissue. Intravenous administration of the usual SC dose could result in severe hypoglycaemia.
There are no clinically relevant differences in serum insulin or glucose levels after abdominal, deltoid or thigh administration of Insunova-G. The prolonged duration of action of Insunova-G is dependent on injection into SC space. As with all insulins, injection sites within an injection area (abdomen, thigh, or deltoid) must be rotated from 1 injection to the next.
In published clinical studies, there was no relevant difference in insulin glargine absorption after abdominal, deltoid or thigh SC administration. As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables.
Insunova-G must not be mixed with any other insulin or diluted. Mixing or diluting can change its time or action profile and mixing can cause precipitation.

A specific overdose of insulin cannot be defined. However, hypoglycemia may develop over sequential stages:
Mild hypoglycemic episodes can be treated by oral administration of glucose or sugary products.
It is therefore recommended that the diabetic patient constantly carry some sugar lumps, sweets, biscuits or sugary fruit juice.
Severe hypoglycemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5-1 mg) given IM or SC by a person who has received appropriate instruction, or glucose given IV by a medical professional. Glucose must also be given IV if the patient does not respond to glucagon within 10-15 min.
Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent relapse.
Insunova G: Symptoms: Insulin overdose may lead to severe and sometimes long-term and life-threatening hypoglycaemia.
Treatment: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in dose of the medicinal product, meal patterns or physical activity may be needed.
More severe episodes with coma, seizure, or neurologic impairment may be treated with glucagon IM/SC or concentrated glucose IV. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

Hypersensitivity to human insulin or any of the excipients of Insunova; hypoglycemia.

The insulin vials have protective color-coded, tamper proof plastic caps, which must be removed before insulin can be withdrawn. The patient must be instructed to return the vial to the pharmacy if the plastic cap is loose or missing.
Inadequate dosage or discontinuation of treatment, especially in type 1 diabetes may lead to hyperglycemia and diabetic ketoacidosis. Usually the 1st symptoms of hyperglycemia set in gradually over a period of hrs or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odor of the breath.
Cartridges should only be used in combination with products that are compatible with them and allow the cartridge to function safely and effectively. Insunova-R (Regular) is a clear solution of human insulin. Never use Insulin-R (Regular) if the liquid appears white and cloudy or has some visible suspended particles.
Insunova-30/70 and Insunova-N contain a cloudy, white, aqueous suspension of human insulin. Never use Insunova-30/70 or Insunova-N (NPH) if the liquid is not white and uniformly cloudy after gentle rolling.
Insunova-R (Regular), Insunova-N (NPH) and Insunova-30/70 (Biphasic) contain m-cresol, which may cause Type IV (delayed hypersensitivity) allergic reactions.
Missed Dose: Timing of insulin doses is extremely important. The best approach is to measure blood glucose and add a dose of regular insulin if glucose levels are too high. Otherwise, wait for the next scheduled dose.
Stopping the Drug: Do not stop taking insulin injections unless ordered by the doctor. Patients with diabetes are often given general instructions for modifying their insulin doses based on home blood glucose measurements.
Switching Types of Insulin: Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (rapid-acting, immediate-acting, short-acting insulin, etc), species (animal, human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in the dose.
Patients switching to and from Insunova-R (Regular)/Insunova-N (NPH)/Insunova-30/70 (Biphasic) may require a change in their usual insulin dosage. If an adjustment is needed, it may occur within the first few days to few weeks. Patients whose blood glucose control has greatly improved eg, by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycemia and should be advised accordingly.
A few patients who have experienced hypoglycemic reactions after transfer from animal source insulin have reported that early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin.
Changes in the Dose Requirement: Adjustment of dosage may also be necessary if patients increase their physical activities or change their usual diet. Concomitant illnesses especially infection and other feverish conditions usually increase the patient's insulin requirement. Alcohol may intensify and prolong the hypoglycemic effect of insulin.
Prolonged Use: After many years with diabetes, some patients become insensitive to the symptoms of hypoglycemia and are at risk for serious brain complications of prolonged, unrecognized hypoglycemia.
Alcohol: Moderate alcohol intake, especially when taken with large meals, does not adversely affect control of diabetes or alter the dose of insulin. However, large amounts of alcohol increase the risk of hypoglycemia.
Insunova-G: lnsunova-G is not the insulin of choice for the treatment of diabetic ketoacidosis. Instead, regular insulin administered IV is recommended in such cases.
In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered.
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture may result in the need for a change in dose.
Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia (see Adverse Reactions).
Hypoglycaemia: The time of occurrence of hypoglycaemia depends on the action profile of the insulins used and may therefore, change when the treatment regimen is changed. Due to more sustained basal insulin supply with lnsunova-G, less nocturnal but early morning hypoglycaemia can be expected.
Particular caution should be exercised and intensified blood glucose monitoring is advisable in patients in whom hypoglycaemic episodes might be of particular clinical relevance eg, in patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia).
Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients: In whom glycaemic control is markedly improved, in whom hypoglycaemia develops gradually, who are elderly, who are transferred from animal insulin to human insulin, in whom an autonomic neuropathy is present, with a long history of diabetes, suffering from a psychiatric illness, receiving concurrent treatment with certain other medicinal products (see Interactions).
Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to the patient's awareness of hypoglycaemia. The prolonged effect of SC insulin glargine may delay recovery from hypoglycaemia. If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.
Adherence of the patient to the dose and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These include: Change in the injection area, improved insulin sensitivity (eg, by removal of stress factors), unaccustomed, increased or prolonged physical activity, intercurrent illness (eg, vomiting, diarrhoea), inadequate food intake, missed meals, alcohol consumption, certain uncompensated endocrine disorders, (eg, in hypothyroidism and in anterior pituitary or adrenocortical insufficiency), concomitant treatment with certain other medicinal products.
lnsunova-G contains metacresol, which may cause allergic reactions.
Intercurrent Illness: Intercurrent illnesses requires intensive metabolic monitoring. In many cases urine tests for ketones are indicated and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates on a regular basis, even if they are able to eat only little or no food or in conditions where they are vomiting and they must never omit insulin entirely.
Combination of Insunova-G with Pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and Insunova-G is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.
Effects on the Ability to Drive or Operate Machinery: The patient's ability to concentrate and react quickly may be impaired as a result of hypoglycemia or hyperglycemia or as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycemia whilst driving. It should be considered whether it is advisable to drive or operate machines in these circumstances.
Impairment of Fertility: Animal studies do not indicate direct harmful effects with respect to fertility.
Use in pregnancy & lactation: There are no restrictions on the treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier. In the treatment of pregnant women with diabetes, intensified control of blood sugar is recommended throughout pregnancy and the same type of control even when contemplating pregnancy. Strict metabolic control, using insulin injections in most women, must be maintained during pregnancy to reduce the risk of birth defects, fetal complications or death at the time of delivery.
Requirements of insulin usually fall in the 1st trimester and subsequently increase during the 2nd and 3rd trimester. When diabetes first develop during pregnancy (gestational diabetes), insulin requirements drop rapidly after delivery and most do not need to continue with insulin treatment.
Postpartum insulin requirements return rapidly to pre-conception levels. There are no restrictions in insulin treatment while treating a lactating diabetic mother, as it involves no risk to the baby. Insulin requirements tend to be lower during breastfeeding. Home glucose monitoring is important to avoid hypoglycemia. However, the insulin dosage may need to be reduced. Insulin is not present in breast milk.
Insunova-G: No clinical data on insulin glargine exposed during pregnancies from controlled clinical trials are available. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) exposed to marketed insulin glargine indicate no adverse effects on pregnancy and no malformative, nor feto- or neonatal-toxicity.
Animal data do not indicate reproductive toxicity.
Patients with diabetes should be advised to inform their health care professional if they are pregnant or are contemplating pregnancy.
The use of Insunova-G may be considered during pregnancy, if necessary.
It is essential for patients with preexisting or gestational diabetes to maintain good metabolic control throughout pregnancy. Insulin requirements may decrease during the 1st trimester and generally increase during the 2nd and 3rd trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.
It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingested insulin glargine on the breastfed newborn or infant are anticipated since insulin glargine as a peptide is digested into amino acids in the human gastrointestinal tract. Breastfeeding women may require adjustments in insulin dose and diet.
Use in children: Treatment with insulin in young patients is the same as that in older people with diabetes.
Use in the elderly: Patients >60 years: No special warnings. However, some older people may have vision problems that may make it difficult to draw up the correct dose of insulin.

There are no restrictions on the treatment of diabetes with insulin during pregnancy, as insulin does not pass the placental barrier. In the treatment of pregnant women with diabetes, intensified control of blood sugar is recommended throughout pregnancy and the same type of control even when contemplating pregnancy. Strict metabolic control, using insulin injections in most women, must be maintained during pregnancy to reduce the risk of birth defects, fetal complications or death at the time of delivery.
Requirements of insulin usually fall in the 1st trimester and subsequently increase during the 2nd and 3rd trimester. When diabetes first develop during pregnancy (gestational diabetes), insulin requirements drop rapidly after delivery and most do not need to continue with insulin treatment.
Postpartum insulin requirements return rapidly to pre-conception levels. There are no restrictions in insulin treatment while treating a lactating diabetic mother, as it involves no risk to the baby. Insulin requirements tend to be lower during breastfeeding. Home glucose monitoring is important to avoid hypoglycemia. However, the insulin dosage may need to be reduced. Insulin is not present in breast milk.
Insunova-G: No clinical data on insulin glargine exposed during pregnancies from controlled clinical trials are available. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) exposed to marketed insulin glargine indicate no adverse effects on pregnancy and no malformative, nor feto- or neonatal-toxicity.
Animal data do not indicate reproductive toxicity.
Patients with diabetes should be advised to inform their health care professional if they are pregnant or are contemplating pregnancy.
The use of Insunova-G may be considered during pregnancy, if necessary.
It is essential for patients with preexisting or gestational diabetes to maintain good metabolic control throughout pregnancy. Insulin requirements may decrease during the 1st trimester and generally increase during the 2nd and 3rd trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.
It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingested insulin glargine on the breastfed newborn or infant are anticipated since insulin glargine as a peptide is digested into amino acids in the human gastrointestinal tract.
Breastfeeding women may require adjustments in insulin dose and diet.

Serious: As for other insulin products, in general, hypoglycaemia is the most frequently occurring undesirable effect. It may occur if the insulin dose is too high in relation to the insulin requirement. Symptoms of hypoglycaemia can be caused by the release of adrenaline or by an inadequate supply of glucose to the brain. Mild nocturnal hypoglycaemia may cause restless sleep, nightmares, or a cold sweat that awakens patient at night. With severe hypoglycaemia, lack of sufficient glucose to the brain may cause slurred speech, impaired concentration, confusion, seizures, coma and irreversible brain damage and death.
Common: Symptoms resulting from release of an adrenaline are common manifestations of mild to moderate hypoglycaemia. They include cold sweats, anxiety, shakiness, hunger, rapid heartbeat, headache, and nervousness. Weight gain is common when taking insulin.
Less Common: Anaphylactic reactions and lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area. Oedema may occur upon initiation of insulin therapy. These symptoms are usually a transitory nature.
Insunova-G: Hypoglycaemia, in general the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.
The following related adverse reactions from clinical investigations are listed as follows by system organ class and in order of decreasing incidence: Very Commonly (≥1/10): Metabolism and Nutrition Disorders: Hypoglycaemia.
Commonly (≥1/100 to <1/10): Skin and Subcutaneous Tissue Disorders: Lipohypertrophy.
General Disorders and Administration Site Conditions: Injection site reactions.
Uncommonly (≥1/1000 to <1/100): Skin and Subcutaneous Tissue Disorders: Lipoatrophy.
Rarely (≥1/10,000 to <1/1000): Immune System Disorders: Allergic reactions.
Eye Disorders: Visual impairment, retinopathy.
General Disorders and Administration Site Conditions: Oedema.
Very Rarely (<1/10,000): Nervous System Disorders: Dysgeusia.
Musculoskeletal and Connective Tissue Disorders: Myalgia.
Metabolism and Nutrition Disorders: Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life threatening. In many patients, the signs and symptoms of neuroglycopaenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.
Immune System Disorders: Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalised skin reactions, angiooedema, bronchospasm, hypotension and shock and may be life threatening. Insulin administration may cause insulin antibodies to form. In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed with the same frequency in both NPH-insulin and insulin glargine treatment groups. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper-or hypoglycaemia.
Eye Disorders: A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens. Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensive insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient amaurosis.
Skin and Subcutaneous Tissue Disorders: As with any insulin therapy, lipodystrophy may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions.
General Disorders and Administration Site Conditions: Injection site reactions include redness, pain, itching, hives, swelling or inflammation. Most minor reactions to insulins at the injection site usually resolve in a few days to a few weeks. Rarely, insulin may cause sodium retention and oedema particularly if previously poor metabolic control is improved by intensified insulin therapy.
Paediatric Population: In general, the safety profile for children and adolescents (18 years) is similar to the safety profile for adults. The adverse reaction reports received from post-marketing surveillance included relatively more frequent injection site reactions (injection site pain, injection site reaction) and skin reactions (rash, urticaria) in children and adolescents (18 years) than in adults. No safety data from clinical studies are available in children <6 years. In a clinical study done by Biocon the adverse events were similar in nature, frequency and severity as compared to the reference product.
Hypoglycaemic events were the most common adverse events in both the treatment groups. Apart from hypoglycaemia, pyrexia was the next most common adverse event with 3 events in each study arm. Retinal adverse events reported in this study were comparable between the treatment groups. The abnormalities in the laboratory parameters were comparable between the 2 study arms and all of them were considered not clinically significant. Antibodies against Biocon's insulin glargine were observed with the same frequency as compared to the reference product.

A number of drugs with Insunova are known to interact with the glucose metabolism. Possible interactions must therefore be taken into account by the physician.
Some of the drugs leading to reduced insulin requirement: Oral hypoglycemic agents (OHA), octreotide, monoamine oxidase inhibitors (MAOIs), non-selective β-blocking agents, angiotensin-converting enzyme (ACE) inhibitors, salicylates, alcohol and anabolic steroids.
Some of the drugs leading to increased insulin requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones and sympathomimetics, danazol, etc. Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Alpha-lipoic acid, chromium, ephedra (Ma Huang), Ginkgo biloba, ginseng, etc, when co-prescribed may need a change in the insulin dosage and close monitoring of blood glucose levels.
Food Interactions: Insulin requirements are increased when larger amounts of calories are ingested, especially simple sugars and carbohydrates.
Disease Interactions: Insulin requirements are increased by infections, psychological stress or an uncontrolled overactive thyroid, and often at a time of surgery. Requirements may diminish with kidney disease or a less active adrenal or pituitary gland.
Incompatibilities: In general terms, insulin should only be added to compounds with which it is known to be compatible. Insulin suspensions should not be added in infusion fluids.
Insunova-R Cartridge: Drugs added to the insulin solution may cause degradation of the insulin eg, if the drugs contains thiols or sulphites.
Insunova-G: A number of substances affect glucose metabolism and may require dose adjustment of insulin glargine.
Substances that may enhance the blood glucose-lowering effect and increase susceptibility to hypoglycaemia include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.
Substances that may reduce the blood glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic medicinal products [eg, epinephrine (adrenaline), salbutamol, terbutaline], thyroid hormones, atypical antipsychotic medicinal products (eg, clozapine and olanzapine) and protease inhibitors.
Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycaemia.
In addition, under the influence of sympatholytic medicinal products eg, β-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.
Incompatibilities: lnsunova-G must not be mixed with other medicinal products. It is important to ensure that syringes do not contain traces of any other material.

Vial: Insunova-N (NPH)/Insunova-30/70 (Biphasic) is a cloudy, white, aqueous suspension of human insulin. Never use the vials if the liquid is not white and uniformly cloudy after gently rolling.
Before Injecting the Insulin: Disinfect the rubber stopper; roll the vial between the palms of the hands until the liquid is uniformly white and cloudy; draw into the syringe the same amount of air as the dose of insulin to be injected; inject the air into the vial; turn the vial and syringe upside down and draw the correct insulin dose into the syringe; withdraw the needle and expel the air from the syringe and check that the dose is correct; inject immediately. Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy and an injection should be followed within 30 min by a meal or a snack containing carbohydrates.
How to Inject the Insulin: Pinch the skin between 2 fingers, push the needle into the skin fold and inject the insulin under the skin SC; SC injection into the abdominal wall results in a faster absorption than from the other injection sites; injection into a lifted skin fold minimizes the risk of IM injection; keep the needle under the skin for at least 6 sec to make sure all the insulin has been injected; if blood appears after the needle has been withdrawn, press the injection site lightly with a finger.
Cartridge: Instructions to be given to the patient on how to handle Insunova-R (Regular), Insunova-N (NPH) and Insunova-30/70 (Biphasic) Cartridge:
The Insunova-R (Regular), Insunova-N (NPH) and Insunova-30/70 (Biphasic) cartridges are designed to be used with the InsuPen. (Detailed instructions accompanying the InsuPen must be followed.)
If a patient is using another type of insulin cartridge besides what is used, 2 different InsuPen should be used for the respective insulins.
The Insunova-R (Regular), Insunova-N (NPH) and Insunova-30/70 (Biphasic) cartridge is for single person use only and should not be refilled.
Before using Insunova-R (Regular), Insunova-N (NPH) and Insunova-30/70 (Biphasic) Cartridge: Check the label to make sure it is the right type of insulin.
Remove the cartridge from the blister pack by pushing through the foil side of the packaging.
Do check the cartridge, including the plunger stopper. Do not use it if damage is seen or if there is a gap between the plunger and the label band.
Appearance of air bubble is a normal phenomenon, vigorous shaking immediately before the dose is administered may also result in the formation of air bubbles which could cause dosage errors; in that case, tap the container gently with a finger. A small air bubble may remain in the cartridge after tapping; this small air bubble will not affect the dose.
Cartridges containing Insunova-R (Regular) do not require resuspension and should only be used if it is clear, colourless, with no visible solid particles and if it is of water-like appearance.
If the InsuPen with the cartridge inside is in cold storage, take it out 1-2 hrs before injecting to allow it to warm up. Cold insulin is more painful to inject. Detailed instruction accompanying the InsuPen must be followed.
Use a medicinal swab to disinfect the rubber membrane.
To prevent contamination always use a new pen needle for each injection.
Do not use Insunova-R (Regular), Insunova-N (NPH) and Insunova-30/70 (Biphasic) Cartridge: In insulin infusion pumps.
If the cartridge or the InsuPen containing the cartridge is dropped, damaged or crushed as there may be a risk of leakage of insulin.
If it has not been stored properly or if it has been frozen.
If the liquid in Insunova-R (Regular) appears white and cloudy or has some suspended particles or if Insunova-N (NPH) and Insunova-30/70 (Biphasic) is not uniformly white and cloudy when resuspended.
Before Inserting a 3-mL Cartridge of Insunova-N or Insunova-30/70 into the InsuPen for the First Time: Roll the cartridge between the palms 10 times.
These steps should be done with the 3-mL cartridge in a flat (horizontal) position.
Then turn the cartridge up and down so the glass bead moves from one end of the cartridge to the other. Do this at least 10 times.
Repeat the rolling and turnings steps until the insulin looks uniformly white and cloudy. Resuspending is easier when the insulin is at room temperature.
Complete the other stages of injection without delay.
Do not force the dose knob.
Check for the desired units of insulin left in the cartridge before resuspending. If there are less than desired units left, use a new cartridge.
Insunova-G: Before injecting this insulin, disinfect the rubber stopper with an alcohol swab; visually inspect the vial to ensure that there are no suspended impurities; draw air into the syringe, the same amount as the volume of insulin to be injected; inject the air into the vial: Push the needle through the rubber stopper and press the plunger; turn the vial and syringe upside down; draw the correct dose of insulin into the syringe; before the patient take the needle out of the insulin vial, check the syringe for air bubbles. Make sure that there is no air left in the syringe: Point the needle upwards and push the air out. Appearance of air bubble is a normal phenomenon, vigorous shaking immediately before the dose is administered may also result in the formation of air bubbles which could cause dosage errors; in that case tap the side of the syringe gently with the patient's finger. A small air bubble may remain after tapping; this small air bubble will not affect your dose; check you have the right dose; inject straight away.
Drawing and Self-Injecting Insulin: Get supplies. Wash hands. Wipe top of bottle. Pull plunger down to appropriate number of units as advised by the physician. Push needle into bottle. Push plunger down. Pull plunger down to appropriate number of units as advised by the physician. Pick injection site wipe with alcohol swab. Pinch up skin, push needle into skin, push plunger in. Pull needle in. Dispose syringe safely, check the town rules. Eat after appropriate interval.
Special Precautions for Disposal and Handling: Any unused product or waste material should be disposed of in accordance with local requirements.
Insunova-G: lnsunova-G must not be mixed with any other insulin or diluted. Mixing or diluting can change its time or action profile and mixing can cause precipitation.
Inspect the vial before use. It must only be used if the solution is clear, colourless, with no visible solid particles. Since Insunova-G is a solution; it does not require re-suspension before use.

Vial: Vials which are not in use should be stored in its carton at 2-8°C in a refrigerator (not too near the freezing compartment).
Vials that are in use can be kept at room temperature (up to 25°C) for up to 6 weeks.
Vials should never be exposed to heat or direct sunlight and should never be frozen.
Insulin products, which have frozen, must not be used.
Protect from light.
Cartridge: Store cartridge in a refrigerator at temperature between 2-8°C. It should not be allowed to freeze.
Insunova-N (NPH) and Insunova-30/70 (Biphasic) container should be gently shaken before a dose is withdrawn.
The solution or suspension can be kept at room temperature (below 25°C) for up to 42 days once the cartridge has been put to use.
Do not expose to excessive heat or direct sunlight.
Do not use frozen cartridge.
Shelf-Life: Insunova-G: 24 months when stored between 2-8°C.
28 days when used or stored at room temperature (below 25°C).

Insulin Preparations

A10AB01 - insulin (human) ; Belongs to the class of fast-acting insulins and analogues. Used in the treatment of diabetes.
A10AC01 - insulin (human) ; Belongs to the class of intermediate-acting insulins and analogues. Used in the treatment of diabetes.
A10AE04 - insulin glargine ; Belongs to the class of long-acting insulins and analogues for injection. Used in the treatment of diabetes.
A10AD01 - insulin (human) ; Belongs to the class of intermediate-acting combined with fast-acting insulins and analogues. Used in the treatment of diabetes.

POM

Insunova-R (Regular): Inj (vial) 100 IU/mL x 10 mL. Soln for inj (cartridge) 100 IU/mL x 3 mL x 5's.
Insunova-G: Soln for inj (vial) 100 IU/mL x 10 mL. Susp for inj (cartridge) 100 IU/mL x 3 mL x 5's.
Insunova-N (NPH): Inj (vial) 100 IU/mL x 10 mL. Susp for inj (cartridge) 100 IU/mL x 3 mL x 5's.
Insunova-30/70 (Biphasic): Inj (vial) 100 IU/mL x 10 mL. Susp for inj (cartridge) 100 IU/mL x 3 mL x 5's.