Rinsulin® Mix 30/70 (insulin human)

Composition

1 mL of the medicinal product contains:

Active ingredient: human insulin 100 IU (equivalent to 3.47 mg)

Excipients: metacresol 1.6 mg, phenol 0.65 mg, glycerol 16.00 mg, protamine sulfate 0.244 mg, sodium hydrophosphate heptahydrate 3.78 mg (calculated as sodium hydrophosphate dihydrate: 2.51 mg), zinc oxide (Zn++ content up to 40 µg), 10 % hydrochloric acid solution or 10 % sodium hydroxide solution (pH up to 6.9–7.8), water for injection (up to 1 mL).

The medicinal product contains 30 % human insulin solution and 70 % human insulin protamine suspension.

Appearance:

White suspension. Sedimentation is possible in vertical position. The liquid above the precipitate is clear and colourless or almost colourless. The precipitation is easily resuspended by light shaking.

Pharmacotherapeutic group:

Hypoglycaemic agent, combination of rapid-acting and intermediate-acting insulins.

ATC code: A10AD01

Pharmacological properties

Pharmacodynamics

Rinsulin® Mix 30/70 is a combination of rapid-acting and intermediate-acting human insulin produced by using recombinant DNA technology with E. coli BL21/pF265 producer strain, which is characterised by a faster onset of action compared to human insulin and containing 30 % Rinsulin® R and 70 % Rinsulin® NPH. The main action of insulin is the regulation of glucose metabolism. Insulin also has anabolic and anticatabolic effect on various body tissues. Through this effect, content of glycogen, fatty acids, and glycerol increases in muscle tissue, while protein synthesis and amino acid consumption is boosted; at the same time, glycogenolysis, glyconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid release are inhibited. Individual differences in insulin activity have been shown to depend on factors such as dose, selected injection site, patient activity level, etc.

Pharmacokinetics

In pharmacokinetic studies in healthy male subjects, when human biphasic insulin was administered subcutaneously at a dose of 0.3 IU/kg, the onset of its pharmacological action began after approximately 50 minutes (ranging from 30 to 90 minutes), with maximal effect observed after 3.5 hours (ranging from 1.5 to 6.5 hours). The mean duration of action of human biphasic insulin was approximately 23 hours (ranging from 18 to 24 hours). The absorption rate of insulin varies by dose of insulin, injection site, patient activity level, etc. Absorption and degradation of insulin occurs primarily in the liver, kidneys, muscles, and adipocytes, with the liver being the main organ involved in insulin clearance.

Indications

• Diabetes mellitus in patients requiring insulin therapy to maintain normal blood glucose concentrations.

Contraindications

• Hypersensitivity to insulin and/or to any of the product excipients.

• Hypoglycaemia.

• Intravenous administration of the medicinal product (according to the “Posology and method of administration” section).

• Age under 18 years (due to the lack of data on the efficacy and safety of the medicinal product in this patient population).

With caution

• Patients at risk of hypokalemia.

• Concomitant use with thiazolidinedione in patients with cardiovascular disease, especially with the risk of chronic heart failure.

Use during pregnancy and lactation

Despite the lack of adequate controlled clinical trials of recombinant biphasic human insulin in pregnant women, the literature suggests that careful glycaemic control in female diabetic patients significantly reduces the risk of congenital malformations and foetal death. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. During labour and immediately afterwards, insulin needs may dramatically decrease. Female patients with diabetes mellitus are advised to notify their doctors about pregnancy or plans of conceiving a baby.

There is no information on the excretion of recombinant biphasic human insulin in human milk. Oral insulin breaks down in the gastrointestinal tract. To date, no reports of adverse reactions in breastfed infants associated with the administration of insulin to a nursing mother have been reported. Patients with diabetes mellitus who are breastfeeding may require adjustments in insulin dose, diet or both. Adequate glycaemic control is a supporting factor for breastfeeding in diabetic patients.

Trade name: Rinsulin^® Mix 30/70

International nonproprietary name: biphasic insulin [recombinant human insulin]

Pharmaceutical form: suspension for subcutaneous injection

Composition

1 mL of the medicinal product contains:

Active ingredient: human insulin 100 IU (equivalent to 3.47 mg)

Excipients: metacresol 1.6 mg, phenol 0.65 mg, glycerol 16.00 mg, protamine sulfate 0.244 mg, sodium hydrophosphate heptahydrate 3.78 mg (calculated as sodium hydrophosphate dihydrate: 2.51 mg), zinc oxide (Zn++ content up to 40 µg), 10 % hydrochloric acid solution or 10 % sodium hydroxide solution (pH up to 6.9–7.8), water for injection (up to 1 mL).

The medicinal product contains 30 % human insulin solution and 70 % human insulin protamine suspension.

Appearance:

White suspension. Sedimentation is possible in vertical position. The liquid above the precipitate is clear and colourless or almost colourless. The precipitation is easily resuspended by light shaking.

Pharmacotherapeutic group:

Hypoglycaemic agent, combination of rapid-acting and intermediate-acting insulins.

ATC code: A10AD01

Pharmacological properties

Pharmacodynamics

Rinsulin^® Mix 30/70 is a combination of rapid-acting and intermediate-acting human insulin produced by using recombinant DNA technology with E. coli BL21/pF265 producer strain, which is characterised by a faster onset of action compared to human insulin and containing 30 % Rinsulin^® R and 70 % Rinsulin^® NPH. The main action of insulin is the regulation of glucose metabolism. Insulin also has anabolic and anticatabolic effect on various body tissues. Through this effect, content of glycogen, fatty acids, and glycerol increases in muscle tissue, while protein synthesis and amino acid consumption is boosted; at the same time, glycogenolysis, glyconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid release are inhibited. Individual differences in insulin activity have been shown to depend on factors such as dose, selected injection site, patient activity level, etc.

Pharmacokinetics

In pharmacokinetic studies in healthy male subjects, when human biphasic insulin was administered subcutaneously at a dose of 0.3 IU/kg, the onset of its pharmacological action began after approximately 50 minutes (ranging from 30 to 90 minutes), with maximal effect observed after 3.5 hours (ranging from 1.5 to 6.5 hours). The mean duration of action of human biphasic insulin was approximately 23 hours (ranging from 18 to 24 hours). The absorption rate of insulin varies by dose of insulin, injection site, patient activity level, etc. Absorption and degradation of insulin occurs primarily in the liver, kidneys, muscles, and adipocytes, with the liver being the main organ involved in insulin clearance.

Indications

• Diabetes mellitus in patients requiring insulin therapy to maintain normal blood glucose concentrations.

Contraindications

• Hypersensitivity to insulin and/or to any of the product excipients.

• Hypoglycaemia.

• Intravenous administration of the medicinal product (according to the “Posology and method of administration” section).

• Age under 18 years (due to the lack of data on the efficacy and safety of the medicinal product in this patient population).

With caution

• Patients at risk of hypokalemia.

• Concomitant use with thiazolidinedione in patients with cardiovascular disease, especially with the risk of chronic heart failure.

Use during pregnancy and lactation

Despite the lack of adequate controlled clinical trials of recombinant biphasic human insulin in pregnant women, the literature suggests that careful glycaemic control in female diabetic patients significantly reduces the risk of congenital malformations and foetal death. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. During labour and immediately afterwards, insulin needs may dramatically decrease. Female patients with diabetes mellitus are advised to notify their doctors about pregnancy or plans of conceiving a baby.

There is no information on the excretion of recombinant biphasic human insulin in human milk. Oral insulin breaks down in the gastrointestinal tract. To date, no reports of adverse reactions in breastfed infants associated with the administration of insulin to a nursing mother have been reported. Patients with diabetes mellitus who are breastfeeding may require adjustments in insulin dose, diet or both. Adequate glycaemic control is a supporting factor for breastfeeding in diabetic patients.

Posology and method of administration

The dose of Rinsulin^® Mix 30/70 is determined by a physician individually, depending on the concentration of glucose in the blood. The medicinal product should be administered subcutaneously.

Intravenous administration of Rinsulin^® Mix 30/70 is contraindicated.

The temperature of the injected product should be ambient.

The product should be injected subcutaneously into the thigh, anterior abdominal wall, buttocks or deltoid muscle of the upper arm. Use of injection sites should be rotated so that the same site is not used more than approximately once a month. When insulin is administered subcutaneously, care should be taken when injecting the product to ensure that a blood vessel has not been entered.

After injection, the site of injection should not be massaged. Patients must be educated to proper use of the insulin pen injector.

Rinsulin^® Mix 30/70 is a ready mixed product with a certain content of Rinsulin^® R and Rinsulin^® NPH. Rinsulin^® Mix 30/70 is specially designed to avoid the need for patients to mix insulins.

The insulin dosing regimen is individualised.

Use in specific clinical groups of patients

Children and adolescents under 18 years of age

The efficacy and safety of Rinsulin^® Mix 30/70 in patients under 18 years of age have not been established.

Elderly patients

The effect of age on the pharmacokinetics and pharmacodynamics of Rinsulin^® Mix 30/70 has not been studied. Elderly patients using any insulin products are at increased risk of hypoglycaemia due to concomitant pathologies and polypharmacy.

Patients with renal failure

The pharmacokinetics and pharmacodynamics of Rinsulin^® Mix 30/70 in patients with renal failure have not been studied. Patients with renal failure are at increased risk of hypoglycaemia and may require more frequent dose adjustment and more frequent monitoring of blood glucose concentrations.

Preparation for insulin administration

For Rinsulin^® Mix 30/70 in vials

Vials containing Rinsulin^® Mix 30/70 should be rotated several times in the palms of the hands immediately before use to completely resuspend the insulin, until it appears uniformly cloudy or milky. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.

Do not use the insulin if it contains clumps after mixing. Do not use the insulin if solid white particles stick to the bottom or wall of the vial, giving it a frosted appearance.

Use an insulin syringe marked for the strength of insulin being administered.

For Rinsulin^® Mix 30/70 in cartridges

Cartridges containing Rinsulin^® Mix 30/70 should be rotated in the palms of the hands ten times and shaken by inverting 180° ten times immediately before use to completely resuspend the insulin, until it appears uniformly cloudy or milky. Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose. Each cartridge contains a small glass bead to facilitate mixing of the insulin.

Do not use the insulin if it contains clumps after mixing.

Cartridges are not designed to allow their contents to be mixed with any other insulins in the cartridge. Cartridges are not designed to be refilled.

Before the insulin injection, the manufacturer’s instructions on the use of the insulin pen injector must be read.

For Rinsulin^® Mix 30/70 in Rinastra^® II pen injector

Before the insulin injection, the user’s manual for Rinastra^® II pen injector must be read.

Use of Rinsulin^® Mix 30/70 cartridges with reusable pen injectors

Rinsulin^® Mix 30/70 cartridges may be used with reusable pen injectors:

• RinsaPen^® I individual insulin pen-injector with accessories (Ypsomed AG, Switzerland)

• RinsaPen^® II individual insulin pen-injector with accessories (Ypsomed AG, Switzerland)

• HumaPen^® Savvio insulin pen-injector (Eli Lilly and Company, USA)

• Autopen Classic 3 mL 1 Unit (1–21 units) AN3810

• Autopen Classic 3 mL 2 Unit (2–42 units) AN3800 by Owen Mumford Ltd, UK

These cartridges should not be used with other reusable pen injectors; dose accuracy has been validated when used with above pen injectors only. Before using the selected pen injector, please read the manufacturer’s manual for use of reusable pen injectors supplied with each pen injector.

When in use, the medicinal product must not be stored at room temperature (15–25 °C) for more than 28 days. Keep away from direct sunlight and heat.

Side effects

Hypoglycaemia is the most common adverse reaction that occurs when administering insulin products, including Rinsulin^® Mix 30/70. Severe hypoglycaemia may result in loss of consciousness and, in extreme cases, in death.

Local allergic reactions are common (≥ 1/100 to 1/10) and are manifested as hyperaemia, swelling or itching at the injection site. These reactions typically resolve within a few days to a few weeks. In some cases, such reactions can be caused by any reasons not related to insulin (for example, skin irritation with a cleansing agent or inappropriate injections).

General allergic reactions are very rare (< 1/10000), but are more serious as they represent a generalised allergic reaction to insulin. They can manifest as generalised itching, respiratory difficulty, shortness of breath, decreased blood pressure, increased heart rate or increased sweating.

Severe cases of systemic allergic reactions can be life threatening. In rare cases of severe allergic reaction to Rinsulin^® Mix 30/70, immediate treatment is required. A change of insulin or desensitisation may be required.

Lipodystrophy at the injection site is uncommon (≥ 1/1000 to < 1/100).

Cases of lipohypertrophy have been reported in some patients using Rinsulin^® Mix 30/70.

Cases of oedema have been reported, which developed mainly during rapid blood glucose normalisation in the settings of intensive insulin therapy with poor baseline glycaemic control (see the “Special precautions” section).

As is the case with any other insulin products, body weight gain may occur with Rinsulin^® Mix 30/70 due to its anabolic action.

Insulin antibodies

Insulin administration may cause insulin antibodies to form. In rare cases, such insulin antibodies may necessitate insulin dose adjustment to correct a tendency to hyper-or hypoglycaemia.

Overdose

An overdose of insulin causes hypoglycaemia accompanied by the following symptoms: listlessness, increased sweating, tachycardia, skin pallor, headache, shivering, vomiting, and confusion. Under certain conditions, such as long duration or intensive control of diabetes mellitus, the warning symptoms of hypoglycaemia may change.

Diabetic patients should always carry sugary foods with them.

Episodes of mild hypoglycaemia are controlled by intake of dextrose (glucose) or products containing sugar. Adjustments of insulin dose, diet, or physical activity may be required. Moderate hypoglycaemia can be managed by intramuscular or subcutaneous injection of glucagon, followed by oral intake of carbohydrates once the patient’s condition is stabilised. If glucagon has no effect, the patient should be given intravenous dextrose (glucose) solution.

Severe hypoglycaemia accompanied by coma, seizures or neurological disorders is corrected by intramuscular/subcutaneous injection of glucagon or intravenous injection of 40 % dextrose (glucose) concentrated solution. After the recovery of consciousness, the patient should take a carbohydrate-rich meal to prevent recurrent hypoglycaemia.

Further carbohydrate intake and follow-up of the patient may be required, as recurrent hypoglycaemia may occur.

Interaction with other medicinal products

If other medicinal products in addition to insulin are required, the physician should be consulted (see the “Special precautions” section).

The physician should consider possible drug interactions and should always ask patients about the medications they take.

Insulin requirements may be increased by substances with hypoglycaemic activity, such as glucocorticosteroids, thyroid hormones, growth hormone, danazol, beta 2-adrenomimetics (e. g. ritodrine, salbutamol, terbutaline), thiazides, oral contraceptives, isoniazid, niacin, estrogens, phenothiazine derivatives, protease inhibitors, and atypical antipsychotics.

Insulin requirements may be reduced by substances with hypoglycaemic activity, such as oral hypoglycaemics, sulfonamide antibiotics, salicylates (e. g. acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-adrenoblockers, fluoxetine, disopyramide, fibrates, propoxyphene, and pentoxifylline.

Somatostatin analogues (octreotide, lanreotide), salicylic acid derivatives, lithium salts, clonidine, and alcohol can both decrease and increase the need for insulin.

Beta-adrenoblockers, clonidine, guanethidine and reserpine, when used together with insulin, may mask or attenuate the warning symptoms of hypoglycaemia.

Special precautions

Transferring a patient to another type or brand of insulin should be done under strict medical supervision.

Changes in type (regular, NPH, etc.), strength, manufacturer of insulin, species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for dose adjustment.

Some patients may require dose adjustments when switching from animal-source insulin to human insulin. This can occur as early as the first administration of human insulin or gradually over a period of weeks or months after the switching.

Warning symptoms of hypoglycaemia during treatment with human insulin in some patients may be less pronounced or different from those experienced with their previous animal insulin. When blood glucose level is normalised, e. g. as a result of intensive insulin therapy, all or some of the warning symptoms of hypoglycaemia may resolve, and patients should be informed about this. The warning symptoms of hypoglycaemia may be changed or be less pronounced in the long-term course of diabetes mellitus, diabetic neuropathy or under the influence of medicinal products such as beta-adrenoblockers.

If not managed properly, hypoglycaemia and hyperglycaemia reactions can lead to unconsciousness, coma or death.

The use of inadequate doses or discontinuation of treatment, especially in patients with type 1 diabetes mellitus, may lead to hyperglycaemia and diabetic ketoacidosis (potentially life-threatening conditions for the patient).

Treatment with human insulin may cause formation of antibodies, but titres of antibodies in such cases are lower than those to purified animal insulin.

Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment.

Insulin requirements may be increased with certain diseases or emotional disturbances. Adjustment of insulin dosage may also be necessary if patients increase their level of physical activity or change their usual diet.

The use of insulin products in combination with thiazolidinediones increases the risk of oedema and chronic heart failure, especially in patients with cardiovascular diseases and risk factors for chronic heart failure. With the combined application of these products, the patient’s condition should be monitored for symptoms and signs of heart failure, weight gain and oedema.

To prevent possible transmission of infectious diseases, each cartridge/pen injector should only be used by a single patient, even if the needle is changed.

Effects on ability to drive or operate machinery

The patient’s ability to concentrate and psychomotor performance may be impaired during 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 whilst driving. This is particularly important in those who have diminished or absent warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. In such cases, the physician should consider whether it is advisable for the patient to drive or operate machinery.

Dosage form

Suspension for subcutaneous injection, 100 IU/mL.

1) 10 mL of the medicinal product in clear neutral glass vials hermetically sealed with a flip-off aluminium and plastic caps with rubber discs.

Self-adhesive labels are applied to each vial.

Each vial along with a package leaflet is placed into a carton.

2) 5 mL of the medicinal product in clear neutral glass vials hermetically sealed with a flip-off aluminium and plastic caps with rubber discs. Self-adhesive labels are applied to each vial.

Each vial along with a package leaflet is placed into a carton.

3) 3 mL of the medicinal product in clear neutral glass cartridges with rubber plungers, sealed with flip-off aluminium caps with rubber discs. Each cartridge has a polished glass bead. A label made of transparent film is applied to each cartridge.

3.1) 5 cartridges in blisters of polyvinylchloride or polyethylene terephthalate film and printed lacquered aluminium foil. 1 blister with a package leaflet into a carton.

3.2) The cartridge is installed in a plastic multidose disposable pen injector for multiple injections Rinastra^® II. A label is applied to the body of each pen injector.

5 pre-filled multidose disposable pen injectors for multiple injections Rinastra^® II with a package leaflet and a user’s manual into a carton.

Shelf life

2 years.

Do not use after the expiration date indicated on the package.

Storage conditions

In a place protected from light at 2 to 8 °C. Do not freeze.

Keep away from children.

Prescription status

Prescription only.

Legal entity for which marketing authorisation has been issued

ООО “GEROPHARM”, Russia

9, ul. Zvenigorodskaya, Saint Petersburg, 191119.

Phone: (812) 703-79-75 (multiline), fax: (812) 703-79-76

Manufacturer

ООО “GEROPHARM”, Russia

Manufacturing site address:

1. Unit 82, bldg. 4, “Kvartal A” area, Obolensk work settlement, Serpukhov city district, Moscow region

2. Unit 1, bldg. 5; bldg. 5, “Kvartal A” area, Obolensk work settlement, Serpukhov city district, Moscow region.

Organisation accepting customer complaints

ООО “GEROPHARM”

11B Degtyarny per., Saint Petersburg 191144, Russian Federation

Phone: (812) 703-79-75 (multiline), fax: (812) 703-79-76

Hotline number: 8-800-333-4376 (free throughout Russia)

www.geropharm.ru

Please, send all information on adverse reactions to the email address farmakonadzor@geropharm.com or contact details of ООО “GEROPHARM” specified above.

Solutions relating the package should provide safety and control when using insulin.

The package has several types of informational indications.
The informational indications are visual (colorful, numeral) and tactile – for patients with poor eyesight.

Color indication
Color indication of Rinsulin type is given in accordance with IDF color chart (International Diabetes Federation).
For Rinsuin NPH this is a light-green strip on the package and on the cartridge. If the cartridge is already mounted into RinAstra NPH pen, the button for dose administration of such pen is light-green with two light-green strips at the label of the pen case.
For Rinsuin R this is a yellow strip on the package and on the cartridge. If the cartridge is already mounted into RinAstra R pen, the button for dose administration of such pen is yellow with two yellow strips at the label of the pen case.

Numeral indication
Numeral indication of Rinsulin type is given as QR code. QR (Quick Response) is a barcode giving information for fast recognition thereof with the help of the mobile phone’s camera. QR code scanned this way directs a doctor or a patient to the website of GEROPHARM to the page about Rinsulin®.

Tactile indication
Tactile indication of Rinsulin type is given as a convex indication (Braille). So the package is suitable for people with poor eyesight.

Safety
Patient safety when using different types and packages of Rinsulin can be of several levels:
• control of the first opening of the package in the form of a valve;
• free edge of the foil for easy removal of the cartridge of Rinsulin;
• all the surfaces of a blister with Rinsulin cartridges are rounded without sharp edges. This is significant for patients with diabetes mellitus who can have reduced sensitivity and they can damage their skin without noticing and feeling pain.