CinnoVex (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Cia International AFS, LLC (Russia)

Manufactured By

Cinnagen Co. (Iran)

Primary Packaging

CASPIAN TAMIN PHARMACEUTICALS, Co. (Iran)

Secondary Packaging

CINNAGEN, Co. (Iran)

ATC Code

L03AB07 (Interferon beta-1a)

Active Substance

Interferon beta-1a

Interferon beta-1a (USAN)

Dosage Form

CinnoVex

Lyophilizate for the preparation of solution for intramuscular administration 30 mcg: fl. 4 pcs. incl. with solvent

Dosage Form, Packaging, and Composition

Solvent water for injections – 1 ml.

Glass vials with a volume of 3 ml (1) in a kit with a solvent (1 ml in ampoules – 1 pc.), a disposable syringe and 2 needles – plastic trays (4) in a kit with 8 alcohol wipes – cardboard packs.

Clinical-Pharmacological Group

Interferon. A drug used for multiple sclerosis

Pharmacotherapeutic Group

MIBP-cytokine

Pharmacological Action

CinnoVex is a recombinant interferon beta-1a produced using recombinant DNA technology on Chinese hamster ovary cells with an integrated human interferon beta genome. It is a glycosylated polypeptide containing 166 amino acids with a molecular weight of 22,500.

The amino acid sequence corresponds to natural human interferon beta.

Interferons are natural proteins produced by eukaryotic cells in response to viral infection and exposure to other biological factors. Interferons are cytokines that are mediators of the body’s antiviral, antiproliferative and immunomodulatory systems.

Beta-interferon is synthesized by various cell types, including fibroblasts and macrophages. Natural beta-interferon and the drug CinnoVex (interferon beta-1a) exist in a glycosylated form and contain a single complex carbohydrate fragment linked to an N atom. Glycosylation of proteins affects their stability, activity, biodistribution and T_1/2.

The biological properties of CinnoVex are determined by its ability to bind to specific receptors on the surface of human cells and trigger a complex cascade of intercellular interactions leading to interferon-induced expression of numerous gene products and markers, such as the major histocompatibility complex class I, Mx protein, 2’/5′-oligoadenylate synthetase, b2-microglobulin and neopterin. The presence of some of these compounds has been detected in the serum and cellular fractions of the blood of patients treated with CinnoVex. After a single intramuscular administration of the drug, the levels of these compounds in the serum remained elevated for at least 4-7 days.

It is unknown whether the mechanism of action of CinnoVex in the treatment of multiple sclerosis is associated with the initiation of the biological interactions described above, since the pathophysiology of multiple sclerosis is not yet fully understood. The effect of CinnoVex in the treatment of multiple sclerosis was demonstrated in a double-blind study conducted in patients with relapsing-remitting multiple sclerosis (for CinnoVex n=41, for the comparator drug Avonex n=43). According to the study design, patients were observed for different periods of time. 60 study participants took CinnoVex under observation for 2 years. It was shown that the total number of patients who experienced progression of disability (determined by the Kaplan-Meier table) by the end of the second year was 34% when Avonex was prescribed and 32% when CinnoVex was used.

Progression of disability was measured as an increase in the disability score (on the EDSS scale) by 1 point, persisting for at least 6 months. It was also found that the use of CinnoVex led to a reduction in the frequency of relapses per year by one third. These data were obtained after treatment lasting more than one year.

Pharmacokinetics

The pharmacokinetics of interferon beta-1a were studied based on the measurement of interferon antiviral activity. After a single intramuscular administration of CinnoVex, peak levels of antiviral activity in plasma were reached between 5 and 15 hours; T_1/2 was about 10 hours. After applying an appropriate correction for the absorption rate from the injection site, the estimated bioavailability of the drug is approximately 40%.

Indications

• Relapsing multiple (disseminated) sclerosis (RMS), characterized by at least two relapses over the previous three-year period in the absence of signs of disease progression between relapses. CinnoVex slows the progression of disability and increases the interval between relapses over a period of more than two years;
• Treatment of patients who have experienced a case of demyelination due to an active inflammatory process that required intravenous administration of corticosteroids, provided that a diagnosis other than multiple sclerosis is excluded.

ICD codes

Dosage Regimen

The use of the drug should be started under the guidance and supervision of a physician experienced in the treatment of multiple sclerosis (MS).

Adults: the recommended dose of CinnoVex (interferon beta-1a) for RMS is 30 mcg (6 million IU), i.e., 1 ml of the reconstituted drug in a vial, and is administered intramuscularly once a week.

Treatment can be started either with the full dose of 30 mcg or with a half dose once a week, gradually increasing it to the full dose of 30 mcg so that the body can get used to the drug. To achieve sufficient effectiveness after the initial treatment period, it is necessary to increase the dose to 30 mcg once a week and then adhere to this dose.

Prescribing a higher dose (60 mcg) once a week does not provide additional benefit.

Children and adolescents the safety profile when prescribing CinnoVex 30 mcg intramuscularly once a week to adolescents aged 12-16 years is similar to the safety profile for adults. There is no information on the use of the drug in the treatment of children under 12 years of age, therefore CinnoVex should not be used in this patient population.

Elderly patients clinical studies did not include a sufficient number of patients over 65 years of age to establish a possible difference in response to treatment in this age group compared to younger patients. However, based on the clearance of the active substance, there is no theoretical basis for adjusting the dose of this drug for elderly patients.

Injections of the drug should, if possible, be given at the same time and on the same day of the week. The intramuscular injection site should be changed every week.

The duration of the course of therapy is determined individually. After two years of treatment, the patient should undergo a clinical examination and, on an individual basis, the attending physician may recommend continuing the course of therapy. Treatment should be discontinued if the patient develops chronic progressive MS.

It is possible for the patient to perform the injections themselves with the permission of the attending physician and after training in the method of intramuscular injection. The following instructions are intended for those who self-administer the injection

• Each package contains 4 trays with single doses of the drug each and 8 antiseptic wipes impregnated with alcohol, in separate hermetically sealed bags. Each tray contains a vial with CinnoVex lyophilized powder, an ampoule with 1 ml of water for injections, a syringe with a needle for solution preparation and a needle for injection.
• Remove the drug from the refrigerator and leave it at room temperature 15-30°C (-22°F) for about 30 minutes. Do not use external heat sources, such as hot water, to heat the ampoule with the solvent.
• After washing your hands, place two antiseptic wipes and a tray with a dose on a clean surface. Carefully open the tray package and remove the contents. It is advisable to additionally prepare sterile medical cotton wool, a disinfectant solution (for example, 70% ethyl alcohol) and a bactericidal adhesive plaster.
• Open the syringe and needle packages. Without removing the protective cap from the needle, attach the needle to the syringe by turning it half a turn.
• Using an alcohol wipe, open the ampoule with water for injections by breaking the ampoule along the red line on the neck. Remove the needle sheath without rotating the needle and draw the water for injections into the syringe. Leave the protective cap for further use. If air bubbles get into the syringe, carefully get rid of them by holding the syringe vertically with the needle up and gently pressing the plunger. Put the protective cap on the needle.
• Remove the cap from the drug vial. Wipe the top of the drug vial with an alcohol wipe.
• Remove the protective cap from the needle, pierce the rubber stopper of the drug vial with the needle. Direct the needle towards the side wall of the vial and slowly inject the solvent (the entire contents of the syringe).
• Leaving the needle and syringe in place, gently rotate the contents of the vial until all the powder has dissolved. Do not shake the vial vigorously as this will cause foaming. If the solution is cloudy or discolored or solid particles are visible in the solution, the vial should not be used. A light yellow color of the solution is acceptable.
• Before drawing the solution, fully immerse the plunger into the syringe to remove air. Then place the vial on the work surface at a slight angle. The entire needle should be in the vial, and the end of the needle should be constantly immersed in the solution. Slowly draw the solution into the syringe up to the 1 ml mark on the side of the syringe. Remove the syringe with the needle from the vial. Put the protective cap on the needle. Disconnect the needle from the syringe by rotating. Do not touch the syringe outlet.
• The second needle is intended for the administration of the CinnoVex solution. It is a standard needle for intramuscular injections. As described above, attach the needle to the syringe with a turn. Remove the plastic protective cap from the needle and set it aside. To remove air, turn the syringe with the needle up and gently tap it so that the bubbles collect at the top. Gently press the plunger to remove the air, allowing only a small drop of solution to come out. Replace the protective sheath and set the syringe aside while preparing the injection site.
• Clean the selected injection site with a new alcohol wipe. Remove the plastic protective sheath from the needle and insert the needle through the skin into the muscle tissue. Perform the injection slowly, then remove the needle with the syringe. Wipe the injection site with an alcohol wipe and, if necessary, cover the injection site with a plaster.
• The next injection should be given in a different location on the body.
• If circumstances arise that prevent the injection from being given when the solution has already been prepared, it can be placed in the refrigerator at a temperature of 2-8°C (17.6°F) for no more than 5.5-6 hours, after first bringing the temperature of the solution to room temperature, and then the injection can be given according to the above scheme.

The prepared solution stored for more than 6 hours in the refrigerator or left at room temperature for more than 30 minutes is not suitable for further use.

Adverse Reactions

The most common manifestation of the side effects of interferons is flu-like syndrome. It manifests as weakness, feeling tired, muscle pain, fever, chills, headache, nausea. These symptoms are usually more pronounced at the beginning of treatment, and their frequency decreases as treatment continues. To alleviate these symptoms, an antipyretic-analgesic can be prescribed, which should be taken before the administration of CinnoVex and then every 6 hours, for a total of 24 hours after each injection. Consultation with a doctor is necessary before taking any drug simultaneously with CinnoVex treatment. If the doctor recommends taking an antipyretic-analgesic, the recommendation must be carefully followed; the dose of the antipyretic-analgesic should not be increased beyond the recommended one.

At any time during treatment, neurological symptoms similar to an exacerbation of multiple sclerosis may occur: transient episodes of muscle hypertonia and/or muscle weakness that limit the ability to perform voluntary movements. These episodes, limited in duration, are temporally related to the injections and may recur with subsequent administrations. In some cases, these symptoms are accompanied by flu-like symptoms.

In each specific category, side effects are presented in descending order of severity

Very common (>1/10 patient-years);

Common (from 1/100 to 1/10 patient-years);

Uncommon (1/1000 to 1/100 patient-years);

Rare (from 1/10,000 to 1/1,000 patient-years);

Very rare (< 1/10,000 patient-years);

Unknown (cannot be estimated from the available data).

Where patient-years represents the sum of the individual units of time during which a study patient received the drug until an adverse reaction developed.

Investigations : common – lymphocytopenia, leukopenia, neutropenia, decreased hematocrit, increased blood potassium, increased blood urea nitrogen; uncommon – thrombocytopenia; unknown – weight loss, weight gain, abnormal liver function test parameters.

Cardiovascular system common – facial flushing; unknown – cardiomyopathy, congestive heart failure, palpitations, arrhythmia, tachycardia, vasodilation.

Endocrine system: unknown – pancytopenia, thrombocytopenia, hypothyroidism, hyperthyroidism.

Nervous system: very common – headache²; common – muscle spasms, hypesthesia; unknown – neurological symptoms, syncope³, hypertension, dizziness, paresthesia, seizures, migraine.

Respiratory system: common – rhinorrhea; rare – dyspnea.

Digestive system: common – anorexia, vomiting, diarrhea, nausea²; unknown – hepatic failure, hepatitis, autoimmune hepatitis.

Skin and subcutaneous tissues: common – rash, increased sweating, bruising; uncommon – alopecia; unknown – angioedema, pruritus, vesicular rash, urticaria, exacerbation of psoriasis.

Musculoskeletal system: common – muscle spasms, neck pain, myalgia², arthralgia, limb pain, back pain, muscle stiffness, musculoskeletal rigidity; unknown – systemic lupus erythematosus, muscle weakness, arthritis.

General disorders and administration site conditions very common – flu-like syndromes, fever², chills², sweating²; common – injection site pain, injection site erythema, injection site hematoma, asthenia², pain, fatigue², malaise, night sweats; uncommon – injection site burning; unknown – injection site abscess¹, injection site cellulitis, injection site inflammation, injection site necrosis, injection site hemorrhage, chest pain.

Immune system: unknown – anaphylactic reaction, anaphylactic shock, hypersensitivity reaction (angioedema, shortness of breath, urticaria, rash, itchy rash).

Reproductive system uncommon – metrorrhagia, menorrhagia.

Central nervous system common – depression, insomnia; unknown – suicide, psychosis, anxiety, confusion, emotional lability.

¹ The described injection site reactions include pain, inflammation and very rare cases of abscess or cellulitis, which may have required surgical intervention.

² The frequency of these side effects is higher at the beginning of treatment.

³ Fainting may occur after an injection of CinnoVex; as a rule, such fainting is a single episode at the beginning of treatment and does not recur with subsequent injections.

Contraindications

• Pregnancy;
• Lactation period;
• Severe depressive state;
• Severe depression and the appearance of suicidal thoughts;
• Patients with epilepsy with seizures that are poorly controlled by therapeutic agents;
• Age under 12 years due to lack of clinical data on the use of the drug in this group;
• Hypersensitivity to natural or recombinant interferon beta, human serum albumin or any other component of the drug.

Use in Pregnancy and Lactation

Due to the potential risk of developing side effects, the use of CinnoVex during pregnancy is contraindicated. There is evidence suggesting the possibility of spontaneous abortion.

Due to the potential risk of developing side effects in the breastfed infant, CinnoVex is contraindicated for use during lactation.

Women of childbearing potential should use effective methods of contraception. In case of pregnancy or planning pregnancy during treatment with CinnoVex, the patient should be informed about the potential danger and the advisability of discontinuing treatment should be considered. In patients with a high frequency of relapses before starting treatment, the risk of severe relapses due to discontinuation of CinnoVex in case of pregnancy should be weighed against the possible increased risk of spontaneous abortion due to its use during pregnancy.

Use in Hepatic Impairment

Caution should be exercised when prescribing, as well as careful monitoring of patients suffering from severe hepatic insufficiency.

The use of interferon beta has been associated with the occurrence of signs of impaired liver function, such as increased levels of liver enzymes in the blood serum, the development of hepatitis, including autoimmune hepatitis, and liver failure. However, it is unknown whether this is a consequence of taking interferon beta-1a or due to taking other drugs that are usually prescribed to such patients. Patients should be carefully monitored for the development of signs of impaired liver function, especially if interferon is used in combination with other hepatotoxic drugs.

Use in Renal Impairment

Caution should be exercised when prescribing, and careful monitoring should be conducted for patients suffering from severe renal insufficiency.

Pediatric Use

Children and adolescents The safety profile when prescribing CinnoVex 30 mcg IM once/week to adolescents 12-16 years old is similar to the safety profile for adults. Information on the use of the drug in the treatment of children under 12 years of age is not available; therefore, CinnoVex should not be used for this patient population.

Geriatric Use

Elderly patients Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. However, based on the clearance of the active substance, there is no theoretical reason for dose adjustment of this drug for elderly patients.

Special Precautions

CinnoVex, like other interferons, should be used with caution in the treatment of patients suffering from depression or depressive disorders. It is known that the use of interferons can cause depression and suicidal thoughts, and the frequency of such events increases in the group of individuals suffering from multiple sclerosis. The occurrence of depressive states is possible at any time during treatment with CinnoVex. If any signs of depression or suicidal thoughts appear, patients should immediately contact their doctor. Such patients should be carefully monitored during treatment and appropriate therapeutic measures should be applied urgently if necessary. In some cases, it may be necessary to discontinue the drug.

Caution is required when prescribing CinnoVex to patients with a history of seizures. This applies to cases where patients who have not previously suffered from epileptic seizures are taking antiepileptic drugs, particularly if the treatment of epilepsy and the use of antiepileptic drugs is not controlled or is inadequately controlled.

Caution should be exercised when prescribing, and careful monitoring should be conducted for patients suffering from severe renal and hepatic insufficiency, as well as with bone marrow suppression.

The use of interferon beta has been associated with signs of liver dysfunction, such as increased levels of liver enzymes in the blood serum, development of hepatitis, including autoimmune hepatitis, and liver failure. However, it is not known whether this is a consequence of taking interferon beta-1a or due to taking other drugs that are usually prescribed to such patients. Patients should be carefully monitored for the development of signs of liver dysfunction, especially if interferon is used in combination with other hepatotoxic drugs.

When using CinnoVex, the condition of patients with cardiovascular diseases should be carefully monitored: angina pectoris, history of myocardial infarction, decompensated heart failure, arrhythmia. Manifestations of the flu-like syndrome caused by the drug may have a stressful effect on such patients.

The use of interferons causes deviations in laboratory parameters; therefore, in addition to the usual laboratory tests performed on patients with MS, it is recommended to perform a blood cell count (including platelets), determination of the leukocyte formula, and a biochemical blood test (including liver enzymes) during treatment. Those patients who have signs of bone marrow suppression may require a more thorough blood test with determination of cellular elements by fractions and platelets.

When using CinnoVex, interferon-neutralizing antibodies may appear in the blood serum, which can reduce the activity of interferon beta-1a, and consequently, the clinical efficacy of the drug. Available data indicate that after 12 months of treatment, approximately 8% of patients develop antibodies to interferon beta-1a in their serum.

Effect on the ability to drive vehicles and operate machinery

In case of side effects from the central nervous system, the ability of sensitive patients to drive a car and use machinery may be minimally reduced.

Overdose

Due to the method of administration and dosage form, overdose is unlikely. Nevertheless, overdose of CinnoVex, like any other drug, should be avoided. In case of overdose, the patient should be hospitalized for medical observation and appropriate therapy.

Drug Interactions

Specific studies on the interaction of CinnoVex (interferon beta-1a) with other drugs, including corticosteroids or ACTH, have not been conducted in humans. However, clinical trial experience shows that patients with multiple sclerosis can take CinnoVex concomitantly with corticosteroids or ACTH during exacerbations of the disease. It is known that interferons can reduce the activity of enzymes associated with hepatic cytochrome P450. In this regard, caution should be exercised when prescribing CinnoVex concomitantly with drugs whose clearance is largely dependent on the cytochrome P450 system, for example, antiepileptic drugs and antidepressants.

Storage Conditions

Store the drug in a place protected from light at a temperature of 2-8°C (35.6-46.4°F). Keep out of reach of children.

Shelf Life

The shelf life of the lyophilizate is 2 years, the shelf life of the solvent is 3 years.

Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.