RinLis^® Mix 25 (Suspension) Instructions for Use

Marketing Authorization Holder

Geropharm, LLC (Russia)

ATC Code

A10AD04 (Insulin lispro)

Active Substance

Insulin lispro – biphasic (Rec.INN registered by WHO)

Dosage Form

RinLis® Mix 25

Suspension for subcutaneous injection 100 IU/ml: 3 ml cartridges, 5 pcs.; 3 ml cartridges installed in multi-dose disposable pen injectors, 5 pcs.

Dosage Form, Packaging, and Composition

Suspension for subcutaneous injection white in color, which separates to form a white sediment and a clear colorless or almost colorless supernatant liquid; the sediment is easily resuspended with gentle shaking.

Excipients: metacresol, crystalline phenol, glycerol, protamine sulfate, sodium hydrogen phosphate heptahydrate, zinc oxide, diluted hydrochloric acid 10% (for pH adjustment) and/or sodium hydroxide solution 10% (for pH adjustment), water for injection.

3 ml – cartridges of colorless glass (5) – blister packs (1) – cardboard boxes.
3 ml – cartridges of colorless glass, installed in multi-dose disposable pen injectors for multiple injections Rinastra^® II or Rinastra^® III (5) – cardboard boxes.

Clinical-Pharmacological Group

Intermediate-acting human insulin with rapid onset of action

Pharmacotherapeutic Group

Hypoglycemic agent – combination of short- and intermediate-acting insulin analogs

Pharmacological Action

Hypoglycemic agent. It is a mixture of insulin lispro solution (a short-acting human insulin analog) and insulin lispro protamine suspension (an intermediate-acting human insulin analog) in various ratios, depending on the dosage form used.

The main action of biphasic insulin lispro is the regulation of glucose metabolism.

In addition, it has anabolic and anticatabolic effects on various body tissues. In muscle tissue, there is an increase in the content of glycogen, fatty acids, glycerol, an enhancement of protein synthesis, and an increase in amino acid uptake; however, there is a decrease in glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid release.

Onset of action is approximately 15 minutes.

The completeness of absorption and onset of insulin action depend on the injection site (abdomen, thigh, buttocks), dose (volume of insulin injected), blood supply, body temperature, and physical activity.

After subcutaneous injection of this agent, a rapid onset of action and an early peak of insulin lispro activity are observed.

Pharmacokinetics

The pharmacokinetics of biphasic insulin lispro is determined by the individual pharmacokinetic properties of the two components of this agent.

Indications

Diabetes mellitus when insulin therapy is necessary.

ICD codes

Dosage Regimen

Administer subcutaneously into the shoulder, thigh, buttock, or abdominal area.

Treatment with insulin preparations should be carried out strictly in accordance with the instructions for medical use of the specific medicinal product.

Correction of the insulin dose may be required when the patient’s physical activity, dietary regimen (e.g., diet or meal times), kidney or liver function changes during an acute illness.

Adverse Reactions

Most frequently hypoglycemia. Severe hypoglycemia can lead to loss of consciousness and, in exceptional cases, death. Since the occurrence of hypoglycemia depends both on the insulin dose used and on other factors, such as the patient’s diet and physical activity, it is impossible to precisely determine the frequency of hypoglycemia occurrence.

Immune system disorders local allergic reactions – redness, swelling, or itching at the injection site (these reactions usually resolve within a few days or weeks; in some cases, these reactions may be caused by reasons unrelated to insulin, such as contact with irritating substances in a skin cleansing agent or improper injection technique); systemic allergic reactions – generalized itching, difficulty breathing, shortness of breath, decreased blood pressure, tachycardia, increased sweating. Severe cases of systemic allergic reactions can be life-threatening.

Skin and subcutaneous tissue disorders lipodystrophy and cutaneous amyloidosis may develop at the injection site, which can lead to delayed insulin absorption; lipoatrophy (skin dimpling) or lipohypertrophy (tissue thickening) are possible. Cases of hyperglycemia have been reported with repeated insulin injections in areas of localized cutaneous amyloidosis and cases of hypoglycemia with a sudden change of the injection site to an area unaffected by cutaneous amyloidosis. Cases of edema have been identified, mainly during rapid normalization of blood glucose concentration against the background of intensive insulin therapy with initially unsatisfactory glycemic control.

Metabolism and nutrition disorders hypokalemia, weight gain (due to the anabolic effects of insulin and reduced glucosuria) are possible.

Immunogenicity: insulin administration can cause the formation of anti-insulin antibodies. The frequency of antibody formation upon administration of preparations containing this combination is unknown.

Contraindications

Hypersensitivity to insulin lispro, hypoglycemia, children and adolescents under 18 years of age.

Use in Pregnancy and Lactation

Numerous data on the use of insulin lispro during pregnancy indicate the absence of adverse effects of insulin lispro on the course of pregnancy or the condition of the fetus and newborn.

During pregnancy, the main goal is to maintain good glycemic control in patients with diabetes mellitus receiving insulin therapy. The need for insulin usually decreases during the first trimester and increases during the second and third trimesters. Patients with diabetes should inform their attending physician if pregnancy is diagnosed or planned. During pregnancy, careful glycemic control and monitoring of general health are important for patients with diabetes.

In patients with diabetes during breastfeeding, adjustment of the insulin dose and/or diet may be required.

Use in Hepatic Impairment

The glycemic response to insulin lispro is independent of liver function.

Use in Renal Impairment

The glycemic response to insulin lispro is independent of kidney function.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Switching a patient to another type or brand of insulin with a different trade name should occur under strict medical supervision with more frequent monitoring of blood glucose concentration. Changes in activity, brand (manufacturer), type (soluble insulin, isophane insulin, etc.), species (animal insulin, human insulin, human insulin analog) and/or method of production (DNA-recombinant insulin or animal insulin) may require adjustment of the insulin dose.

The warning symptoms of hypoglycemia may change and be less pronounced in long-standing diabetes, intensive insulin therapy, diabetic neuropathy, or treatment with drugs such as beta-blockers.

In the absence of adequate correction, hypoglycemia and hyperglycemia can lead to loss of consciousness, coma, or death.
The use of inadequate doses or discontinuation of treatment, especially in insulin-dependent patients, can lead to hyperglycemia and diabetic ketoacidosis – conditions that are potentially life-threatening.

Hypoglycemia is the most common adverse reaction accompanying all types of insulin therapy.
Hypoglycemia can occur suddenly, and symptoms may vary among different patients and change over time in the same patient. Recognition of hypoglycemia symptoms may be less pronounced in patients with long-standing diabetes, in patients with diabetic nerve damage, in patients taking medications that block the sympathetic nervous system (e.g., beta-blockers), or in patients who suffer from recurrent hypoglycemia.

The risk of developing hypoglycemia depends on the duration of insulin action, which, in turn, depends on many conditions (including the injection area, blood supply, and temperature at the injection site) and can vary in the same person. Other factors that increase the risk of hypoglycemia include changes in diet or meal times, the patient’s physical activity, or concomitant use of other medications, impaired kidney and/or liver function. Patients and caregivers should be informed about the symptoms of hypoglycemia and how to manage it. Self-monitoring of blood glucose concentration plays an important role in the prevention and treatment of hypoglycemia. Patients with unexpressed warning symptoms of hypoglycemia should be advised to increase the frequency of blood glucose monitoring.

Patients should be informed about the need to rotate injection sites to reduce the risk of lipodystrophy and cutaneous amyloidosis. When injecting insulin into areas with lipodystrophy and cutaneous amyloidosis, there is a potential risk of delayed insulin absorption and worsening glycemic control. Cases of hypoglycemia have been reported with a sudden change of the injection site from an area with lipodystrophy or cutaneous amyloidosis to an unaffected area. It is recommended to monitor blood glucose after changing the injection site; adjustment of the dose of hypoglycemic drugs may also be required.

The need for insulin may increase during certain illnesses or emotional stress.
Adjustment of the insulin dose may be required with increased physical activity or changes in the usual diet. Physical exercise immediately after a meal may lead to an increased risk of hypoglycemia.

Potassium concentration should be monitored in patients at risk of hypokalemia (e.g., patients taking drugs that lower blood potassium levels or drugs sensitive to blood potassium concentration).

Effect on ability to drive vehicles and operate machinery

During hypoglycemia, the patient’s concentration and speed of psychomotor reactions may decrease. This can be dangerous in situations where these abilities are particularly necessary (e.g., driving vehicles or operating machinery).

Patients are advised to take precautions to prevent hypoglycemic reactions while driving vehicles and operating machinery. This is especially important for patients with mild or absent warning symptoms of hypoglycemia or with frequent episodes of hypoglycemia. In such cases, the advisability of driving vehicles and operating machinery should be assessed.

Drug Interactions

The need for insulin may increase when used concomitantly with the following medicinal products: estrogens, progestogens, oral contraceptives, glucocorticoids, iodine-containing thyroid hormones, danazol, beta₂-adrenergic agonists (e.g., ritodrine, salbutamol, albuterol, terbutaline), epinephrine, atypical antipsychotics (e.g., olanzapine and clozapine), diuretics, glucagon, isoniazid, niacin, phenothiazines, protease inhibitors, somatropin.

The need for insulin may decrease when used concomitantly with the following medicinal products: beta-blockers, ethanol and ethanol-containing preparations, oral hypoglycemic drugs, salicylates (e.g., acetylsalicylic acid), sulfonamide antibiotics, somatostatin analogs (e.g., octreotide), pentoxifylline, pramlintide, some antidepressants (MAO inhibitors, SSRIs), ACE inhibitors (captopril, enalapril), angiotensin II receptor antagonists.

Alcohol, beta-blockers, clonidine, and lithium salts can either decrease or increase the need for insulin. Pentamidine can cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Symptoms of hypoglycemia may be masked or attenuated when used concomitantly with beta-blockers, clonidine, guanethidine, and reserpine.

When insulin preparations are used in combination with pioglitazone, the risk of heart failure increases, especially in patients with risk factors for heart failure. During combination therapy, patients should be monitored for the development of signs and symptoms of heart failure, weight gain, and edema. Pioglitazone therapy should be discontinued if any worsening of cardiac activity occurs.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.