Each mL contains: Insulin Aspart 3.5 mg equivalent to 100 U/mL.
Excipients/Inactive Ingredients: Glycerine, m-Cresol, phenol, disodium hydrogen phosphate dihydrate, sodium chloride, zinc chloride, hydrochloric acid/sodium hydroxide (pH adjustment), and water for injection.
Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, fast-acting. ATC code: A10AB05.
Pharmacology: Pharmacodynamics: Mechanism of Action: SANSULIN Rapid produces a more rapid onset of action compared to soluble human insulin, together with a lower glucose concentration, as assessed within the first four hours after a meal. SANSULIN Rapid has a shorter duration of action compared to soluble human insulin after subcutaneous injection.
When SANSULIN Rapid is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after injection. The duration of action is 3 to 5 hours.
Insulin aspart is equipotent to soluble human insulin on a molar basis.
Adults: Clinical trial reports in patients with type 1 diabetes have demonstrated a lower postprandial blood glucose with innovator product compared to soluble human insulin. In two long-term open label trials in patients with type 1 diabetes comprising 1,070 and 884 patients, respectively, insulin aspart reduced glycated haemoglobin by 0.12 percentage points and by 0.15 percentage points compared to soluble human insulin; a difference of limited clinical significance.
Clinical trials in patients with type 1 diabetes have demonstrated a reduced risk of nocturnal hypoglycaemia with insulin aspart compared to soluble human insulin. The risk of daytime hypoglycaemia was not significantly increased.
Elderly: In a reported PK/PD trial, the relative differences in the PD properties between insulin aspart and soluble human insulin in the elderly patients with type 2 diabetes were similar to those seen in healthy subjects and younger patients with diabetes.
Children and adolescents: When given to children, insulin aspart showed similar long-term glucose control compared to soluble human insulin. In reported clinical trials for children and adolescents aged 2 to 17 the pharmacodynamics profile of insulin aspart in children was similar to that seen in adults.
Pregnancy: A clinical trial report comparing safety and efficacy of insulin aspart vs. soluble human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn.
In addition, the data from a clinical trial reported from innovator, including 27 women with gestational diabetes randomised to treatment with insulin aspart vs. soluble human insulin showed similar safety profiles between treatments as well as a significant improvement in postprandial glucose control in the insulin aspart treated group.
Pharmacokinetics: In reported data of innovator product substitution of amino acid proline with aspartic acid as position B28 reduces the tendency to form hexamers as observed with soluble human insulin. Insulin aspart is therefore more rapidly absorbed from the subcutaneous layer compared to soluble human insulin.
The time to maximum concentration is, on average, half of that for soluble human insulin. A mean maximum plasma concentration of 492 pmol/l was reached 40 minutes after a subcutaneous dose of 0.15 U/kg bodyweight in type 1 diabetic patients. The insulin concentrations returned to baseline about 4 to 6 hours after dose. The absorption rate was somewhat slower in type 2 diabetic patients, resulting in a lower Cmax (352 ± 240 pmol/l) and later tmax (60 minutes). The intra-individual variability in time to maximum concentration is significantly less for insulin aspart product than for soluble human insulin, whereas the intra-individual variability in Cmax for insulin aspart product is larger.
Children and adolescents: The pharmacokinetic and pharmacodynamic properties of insulin aspart product were investigated in children and adolescents with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, Cmax differed between the age groups, stressing the importance of the individual titration of insulin aspart.
Elderly: The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly patients with type 2 diabetes were similar to those observed in healthy subjects and in younger patients with diabetes. A decreased absorption rate was observed in elderly patients, resulting in a later tmax (82 minutes), whereas Cmax was similar to that observed in younger patients with type 2 diabetes and slightly lower than in patients with type 1 diabetes.
Hepatic impairment: In patients with hepatic impairment tmax was delayed to about 85 min. (50 min. in subjects with normal hepatic function) while AUC, Cmax and CL/F were similar.
Renal impairment: A single dose pharmacokinetic reported study of insulin aspart in 18 subjects with normal to severely impaired renal function was performed. No apparent effect of creatinine clearance values on AUC, Cmax, CL/F and tmax of insulin aspart was found. Data were limited in patients with moderate and severe renal impairment. Patients with renal failure necessitating dialysis treatment were not investigated.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction. In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.
Non-clinical data reveal no observable adverse reaction level of the insulin aspart injection on conventional studies of toxicity, toxicokinetic characteristic and immunogenicity test.
Clinical Study: A 24-week-long clinical study compared biosimilar product (insulin aspart injection fluid) to innovator product in patients with type 1 or type 2 diabetes using parameters of HbA1c, fasting blood glucose, and 2-hr post-meal blood glucose, which is venous blood glucose levels as determination criteria.
After 24 weeks of treatment, the biosimilar group and innovator group achieved an HbA1c target of < 7.0%, that were 52.61% and 51.01% for each group. The percentage difference between the two groups was 1.6%. The percentages of the two groups that achieved an HbA1c target of ≤ 6.5% were 34.24% and 30.87%, for a difference of 3.37%. The data were no statistically significant difference: Statistical results of the decrease in HbA1c until the 24th week.
The decrease in HbA1c until 24th week was -2.20 (biosimilar group) vs -2.32 (innovator group) for fasting state and -2.38 (biosimilar group) vs -2.40 (innovator group) for 2 hours after the start of a meal with p-value < 0.0001. The 95% confidence interval between the biosimilar group and innovator group was 0.04 (-0.17; 0.26) of fasting state and -0.10 (-0.29; 0.09) of 2 hours after the start of a meal.
Statistical results of change in fasting blood glucose levels between baseline and the 24th week.
Change in fasting blood glucose levels between baseline and the 24th week with a mean of -2.02 (biosimilar group) vs -1.70 (innovator group) in the fasting state and -2.21 (biosimilar group) vs -1.77 (innovator group) for 2 hours after the start of a meal with p-value < 0.001.
Statistical results of changes in blood glucose levels for 2 hours after the start of a meal between baseline and the 24th week.
Change in blood glucose levels for 2 hours after the start of a meal between baseline and the 24th week with a mean value of -6.14 (biosimilar group) vs -6.29 (innovator group) in the fasting state and -6.62 (biosimilar group) vs -6.48 (innovator group) for 2 hours after the start of a meal, with p-value < 0.001.
Aside from hypoglycemic events, the adverse reactions reported by the two groups were similar. The researchers determined that all trial drug-associated adverse reaction were less than 5%.
Treatment of diabetes mellitus.
SANSULIN Rapid is a rapid acting insulin analogue. SANSULIN Rapid dosage is individual and determined on the basic of the physician's advice in accordance with the needs of the patient. It should normally be used in combination with intermediate-acting or long-acting insulin given at least once a day. Blood glucose monitoring and insulin dose adjustment are recommended to achieve optimal glycaemic control.
The individual insulin requirement in adults and children is usually between 0.5 and 1.0 U/kg/day. In a basal-bolus treatment regimen, 50 - 70% of this requirement may be provided by SANSULIN Rapid and the remainder by intermediate-acting or long-acting insulin. Adjustment of dosage may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.
SANSULIN Rapid has a faster onset and a shorter duration of action than soluble human insulin.
Due to the faster onset of action, SANSULIN Rapid should generally be given immediately before a meal. When necessary SANSULIN Rapid can be given soon after a meal.
Due to the shorter duration, SANSULIN Rapid has a lower risk of causing nocturnal hypoglycaemic episodes. No studies have been performed in children under the age of 2 years.
Special Population: As with insulin products, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and the SANSULIN Rapid dosage adjusted on an individual basis.
Pediatric Population: SANSULIN Rapid can be used in children in preference to soluble human insulin when a rapid onset of action might be beneficial, for example, in the timing of the injections in relation to meals.
Transfer from Other Insulin Products: When transferring from other insulin products, adjustment of the SANSULIN Rapid dose and the dose of the basal insulin may be necessary.
Method of Administration: SANSULIN Rapid is administered subcutaneously by injection in the abdominal wall, the thigh, the upper arm, the deltoid region or the gluteal region. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see Precautions and Adverse Reactions). As with all insulin products, subcutaneous injection in the abdominal wall ensures a faster absorption than other injection sites.
The duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. However, the faster onset of action compared to soluble human insulin is maintained regardless of injection site.
Continuous Subcutaneous Insulin Infusion (CSII): SANSULIN Rapid may be used for Continuous Subcutaneous Insulin Infusion (CSII) in pump systems suitable for insulin infusion. CSII should be administered in the abdominal wall. Infusion sites should be rotated. When used with an insulin infusion pump, SANSULIN Rapid should not be mixed with any other insulin products.
Patients using CSII should be comprehensively instructed in the use of the pump system and use the correct reservoir and tubing for the pump. The infusion set (tubing and cannula) should be changed in accordance with the instructions in the product information supplied with the infusion set.
Patients administering SANSULIN Rapid by CSII must have alternative insulin delivery method available in case of pump system failure.
Intravenous use: If necessary, SANSULIN Rapid can be administered intravenously by physicians or other healthcare staff if applicable.
For intravenous use, infusion systems with SANSULIN Rapid 100 U/mL at concentrations from 0.05 U/mL to 1.0 U/mL insulin aspart in the infusion fluids 0.9% sodium chloride, 5% dextrose or 10% dextrose including 40 mmol/L potassium chloride using polypropylene infusion bags, are stable at room temperature for 24 hours.
Although stable over time, a certain amount of insulin will be initially adsorbed to the infusion bag. Monitoring of blood glucose is necessary during insulin infusion.
A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient's requirement are administered: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carries sugar containing products.
Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by physicians or other healthcare staff if applicable, or glucose must be given intravenously if the patient does not respond to glucagon within 10 to 15 minutes.
Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent a relapse.
During episode of hypoglycaemia. Hypersensitivity to the active substance or any of the excipients.
Special warning and precautions for use: Before travelling between different time zones, the patient should seek the doctor's advice since this may mean that the patient has to take the insulin and meals at the different times.
Hyperglycaemia: Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis.
Hypoglycaemia: Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia. Especially in children, care should be taken to match insulin doses (especially in basal-bolus regimens) with food intake, physical activities and current blood glucose level in order to minimize the risk of hypoglycaemia.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Patients whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia, and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.
A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared to soluble human insulin.
Since SANSULIN Rapid should be administered in immediately relation to a meal, the rapid onset of action should be considered in patients with concomitant disease or medication where a delayed absorption of food might be expected.
Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirements. Concomitant diseases of the kidney, liver or the affecting the adrenal, pituitary or thyroid gland, can require changes in the insulin dose.
When patients are transferred between different types of insulin products, the early warning symptoms of hypoglycaemia may become less pronounced than dose experienced with their previous insulin.
Transfer from other insulin products: Transferring a patient to another type or brand (e.g. as strength or manufacturer) of insulin should be done under strict medical supervision and may require a change in dosage or number of daily injections from that used with their usual insulin products. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.
Injection site reactions: As with any insulin therapy, injection site reactions may occur and include pain, redness, hives, inflammation, bruising, swelling, and itching. Continuous rotation of the injection site within a given area reduces the risk of developing of these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of SANSULIN Rapid.
Skin and subcutaneous tissue disorders: Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medications may be considered.
Combination of Thiazolidinediones and insulin medical products: Cases of congestive heart failure have been reported when Thiazolidinediones were used in combination with insulin, especially in patients with risk factors for development of congestive heart failure. This should be kept in mind if treatment with the combination of Thiazolidinediones and insulin medical products is considered. If the combination is used, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema. Thiazolidinediones should be discontinued if any deterioration in cardiac symptoms occurs.
Avoidance of accidental mix-ups/medication errors: Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between SANSULIN Rapid and other insulin products.
Insulin antibodies: 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.
Effect on ability to drive and use machines: The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia.
Use in Pregnancy: SANSULIN Rapid (insulin aspart) can be used in pregnancy. Reported data from two randomised controlled clinical trials do not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn when compared to soluble human insulin (see Pharmacology: Pharmacodynamics under Actions).
Intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
Use in Lactation: There are no restrictions on treatment with SANSULIN Rapid during breast-feeding. Insulin treatment of the nursing mother presents no risk to the baby. However, the SANSULIN Rapid dosage may need to be adjusted.
Pregnancy: SANSULIN Rapid (insulin aspart) can be used in pregnancy. Reported data from two randomised controlled clinical trials do not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn when compared to soluble human insulin (see Pharmacology: Pharmacodynamics under Actions).
Intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
Lactation: There are no restrictions on treatment with SANSULIN Rapid during breast-feeding. Insulin treatment of the nursing mother presents no risk to the baby. However, the SANSULIN Rapid dosage may need to be adjusted.
Summary of The Safety Profile: Adverse reactions observed in patients using insulin aspart injection are mainly due to the pharmacologic effect of insulin.
The most frequently reported adverse reaction during treatment is hypoglycaemia. The frequencies of hypoglycaemia vary with patient population, dose regimens and level of glycaemic control, see Description of Selected Adverse Reactions as follows.
At the beginning of the insulin treatment, refraction anomalies, oedema and injection site reactions (pain, redness, hives, inflammation, bruising, swelling, and itching at the injection site) may occur. These reactions are usually of transitory nature. Fast improvement in blood glucose control may be associated with acute painful neuropathy, which is usually reversible. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.
Tabulated List of Adverse Reactions: Adverse reactions listed as follows are based on clinical trial data and classified according to MedDRA System Organ Class. Frequency categories are defined according to the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10, 000); not known (cannot be estimated from the available data). (See Table.)
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In a clinical study of biosimilar product, the adverse reactions were similar in nature, frequency, and severity as compared to the innovator product. There were eye diseases 0.23%, immune system diseases 0.23%, systemic disease and administration site reactions 0.91%, metabolic and nutritional diseases (e.g. hypoglycaemia) 9.79%.
Description of Selected Adverse Reactions: Anaphylactic reactions: The occurrence of generalised hypersensitivity reactions (including generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure) is very rare but can potentially be life threatening.
Hypoglycaemia: The most frequently reported adverse reaction is hypoglycaemia. It may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation.
In reported clinical trials, the frequency of hypoglycaemia varied with patient population, dose regimens and level of glycaemic control. During the clinical trials, overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared to human insulin.
Skin and Subcutaneous Tissue Disorders: Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis 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 (see Precautions).
Interaction with other medicinal products and other forms of interaction: A number of medicinal products are known to interact with the glucose metabolism.
The following substances may reduce the patient's insulin requirement: Oral antidiabetic products, monoamine oxidase inhibitors (MAOIs), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.
The following substance may increase the patient's insulin requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia.
Octreotide/lanreotide may either increase or decrease the insulin requirements.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
Incompatibilities: Substances added to SANSULIN Rapid may cause degradation of insulin aspart.
This product must not be diluted or mixed with other products, except infusion fluids as described in DOSAGE & ADMINISTRATION.
Special precautions for disposal and other handling: SANSULIN Rapid must not be used if it does not appear clear and colourless or if it has been frozen.
SANSULIN Rapid may be used in an infusion pump system (CSII) as described in Method of Administration under Dosage & Administration. Tubings in which the inner surface material are made of polyethylene or polyolefin have been evaluated and found compatible with pump use.
Before opening, store between (2°- 8°C). Do not freeze.
Protect from light.
Once in use, the product may be used for up to 4 weeks.
Do not store above 30°C. During use, the product must not be stored in the freezer.
Shelf Life: 24 months.
A10AB05 - insulin aspart ; Belongs to the class of fast-acting insulins and analogues. Used in the treatment of diabetes.
Sansulin Rapid soln for inj 100 U/mL
(disposable pens) 3 mL x 5 × 1's (Rp820,000/boks)
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