Instruction for use: Rebif

Dosage form: Solution for subcutaneous administration

Active substance: Interferonum beta-1a

ATX

L03AB07 Interferon beta-1a

Pharmacological groups:

Cytokines [Antiviral (except HIV) agents]

Cytokines [Interferons]

The nosological classification (ICD-10)

G35 Multiple Sclerosis: Disseminated Sclerosis; Multiple sclerosis; Recurrent multiple sclerosis; Secondary-progressive multiple sclerosis; Exacerbation of multiple sclerosis; Mixed forms of multiple sclerosis

Composition

Solution for subcutaneous injection / syringe 0.5 ml

active substance: Interferon beta-1a 22 mkg (6 million IU); 44 mkg (12 million IU)

Auxiliary substances: benzyl alcohol - 2.5 mg; Mannitol - 22.5 mg; Methionine - 0.06 mg; Poloxamer 188 - 0.25 mg; 0.01 M sodium acetate buffer solution (sodium acetate, acetic acid, sodium hydroxide to adjust pH, water for injection) - q.s. Up to 0.5 ml

Solution for subcutaneous injection / cartridge 1.5 ml

active substance: Interferon beta-1a 66 mkg (18 million IU); 132 mkg (36 million IU)

Auxiliary substances: benzyl alcohol - 7.5 mg; Mannitol - 67.5 mg; Methionine - 0.18 mg; Poloxamer 188 - 0.75 mg; 0.01 M sodium acetate buffer solution (sodium acetate, acetic acid, sodium hydroxide to adjust pH, water for injection) - q.s. Up to 1.5 ml

Description of dosage form

Solution: slightly opalescent, light yellow.

Pharmachologic effect

Mode of action - antiviral, immunomodulating, antitumor.

Pharmacodynamics

The drug Rebif® has immunomodulatory, antiviral and antiproliferative properties. The protein structure of the drug Rebif® (interferon beta-1a recombinant human) is a natural amino acid sequence of human interferon beta, obtained by genetic engineering using the Chinese hamster ovary cell culture.

The mechanism of action of the drug Rebif® in patients with multiple sclerosis is not fully understood. It is shown that the drug contributes to limiting the damage to the central nervous system underlying the disease. At the recommended dosage, Rebif® showed a reduction in incidence (30% for 2 years) and severity of exacerbations in patients with two or more exacerbations over the past 2 years and an assessment of 0 to 5 in the extended disability assessment scale (EDSS) before treatment . The proportion of patients with confirmed disability progression decreased from 39% (placebo) to 30 and 27% (Rebif®, 22 μg and Rebif®, 44 μg, respectively). After 4 years, the mean reduction in the number of exacerbations was 22% and 29% in patients treated with Rebif®, 22 μg and Rebif®, 44 μg, respectively, compared to the placebo group treated for 2 years and then Rebif®, 22 μg And Rebif®, 44 μg.

In a three-year study in patients with secondary progressive multiple sclerosis (3-6.5 EDSS scores) with a significant progression of disability during the previous 2 years and no exacerbations during the previous 8 weeks, Rebif® did not significantly affect disability, however The frequency of exacerbations decreased by 30%. In the two groups of patients (who had or had not had an exacerbation of the disease in the last 2 years), the effect of the drug on the progression of disability was not found in the "without exacerbations" group, whereas in the "exacerbated" group the proportion of patients with progression at the end of the study decreased from 70 % (Placebo) to 57% (Rebif®, 22 mcg and Rebif®, 44 mcg). The effect of the drug on primary progressive MS has not been studied.

Pharmacokinetics

When SC or IM introduction of interferon beta, the latter is determined in the blood serum for 12-24 hours, regardless of the mode of administration. After a single dose injection, 60 μg of Cmax, determined by immunological methods, is detected after 3 hours and is 6-10 IU / ml. With a 4-fold infusion of the same dose every 48 hours, a moderate cumulation of the drug occurs. After a single administration, the intracellular and serum activity of 2-5A synthetase and the serum concentration of beta 2 microglobulin and neopterin (biological response markers) increase within 24 hours, and then decrease within 2 days. Interferon beta is metabolized and excreted by the liver and kidneys. The total ground clearance is about 33-55 l / h.

Indication of the Rebif

Treatment of remitting multiple sclerosis. Efficacy was not demonstrated in patients with secondary-progressive multiple sclerosis in the absence of exacerbations.

Contraindications

Increased sensitivity to natural or recombinant interferon beta, to other components of the drug;

Pregnancy and lactation;

Severe depressive disorders and / or suicidal ideation;

Epilepsy in the absence of effect from the application of appropriate therapy;

Age up to 12 years.

Application in pregnancy and breastfeeding

Rebif® is contraindicated during pregnancy and lactation. Women of childbearing age should use effective means of contraception. Given the potential danger to the fetus, patients planning pregnancy or becoming pregnant while on treatment should inform their physician about this in order to resolve the issue of cancellation of therapy.

Data on the excretion of the drug Rebif® in breast milk are not available. Given the likelihood of developing serious adverse reactions in newborns, a choice should be made between abolishing Rebif® and stopping breastfeeding.

Side effects

To indicate the frequency of adverse events, the following classification is used: very often (≥1 / 10 cases); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000).

Adverse reactions noted in clinical trials

Below are summarized data obtained in clinical studies in patients with multiple sclerosis during the first 6 months of treatment compared with placebo. Adverse reactions are listed according to their frequency and system-organ class.

Infections and infestations: infrequently - postinjection abscess.

From the blood and lymphatic system: very often - neutropenia, lymphopenia, leukopenia, thrombocytopenia, anemia.

From the endocrine system: infrequently - hypo- or hyperthyroidism.

Mental disorders: often - depression, insomnia.

From the nervous system: very often - a headache.

From the skin and subcutaneous tissues; Often - itching, rash (in particular erythematous and maculopapular).

From the musculoskeletal and connective tissue: often - myalgia, arthralgia.

General disorders and disorders at the injection site: very often - inflammation at the injection site, reactions at the injection site (eg bruising, swelling, redness), flu-like symptoms. Flu-like symptoms (headache, fever, chills, muscle and joint pain, nausea) are observed in approximately 70% of patients during the first 6 months of treatment and decrease with continued therapy.

Reactions at the injection site are observed in approximately 30% of patients, usually less pronounced and reversible: often - pain at the injection site, fatigue, chills, fever; Infrequently, necrosis at the injection site.

Laboratory and instrumental data: very often - an asymptomatic increase in the concentration of transaminases in the blood; Often - significant (more than 5 times higher than UGN) increase in the concentration of transaminases in the blood.

Adverse reactions observed during post-registration follow-up (the frequency is unknown, most likely from "infrequently" to "very rare").

Infections and infestations: infection at the injection site, incl. Inflammation of the subcutaneous tissue.

On the part of the blood and lymphatic system: thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome.

From the side of the nervous system: convulsions, transient neurological symptoms (hypoesthesia, muscle spasms, paresthesia, difficulty walking, rigidity of the muscles), which can mimic the aggravation of multiple sclerosis.

From the vessels: thromboembolic disorders.

On the part of the respiratory system: dyspnea.

Mental disorders: attempted suicide.

From the side of the organ of vision: damage to the vessels of the retina (ie, retinopathy, cotton spots on the retina, artery obstruction or retinal vein).

From the skin and subcutaneous tissues: Quincke's edema, urticaria, erythema multiforme and similar skin reactions, Stevens-Johnson syndrome, alopecia.

From the immune system: anaphylactic reactions.

From the immune system: anaphylactic reactions.

From the liver and biliary tract: liver failure, hepatitis (with jaundice or without it).

It is necessary to inform the doctor of any of the above-listed adverse reactions, as well as those not listed in this manual. If side effects are maintained for a long time or if serious adverse reactions develop, at the discretion of the doctor, a temporary reduction in the dose of the drug or interruption of treatment is allowed. Do not discontinue treatment or change the dose without the indication of the attending physician.

Interaction

Special clinical studies to evaluate the interaction of the drug Rebif® with other drugs have not been conducted. It is known that in humans and animals, interferons decrease the activity of cytochrome P450-dependent liver enzymes. Therefore, care should be taken when prescribing Rebif® concomitantly with drugs that have a narrow therapeutic index, the clearance of which depends to a large extent on the cytochrome P450 system in the liver, for example antiepileptic drugs, some antidepressants. A systematic study of the interaction of the drug Rebif® with corticosteroids or ACTH was not performed. Data from clinical studies indicate the possibility of obtaining patients with multiple sclerosis with Rebif® and corticosteroids or ACTH during exacerbations of the disease.

Dosing and Administration

SC.

Treatment should be started under the supervision of a doctor who has experience in the treatment of this disease. Adults and adolescents over 16 years of age usually receive a recommended dose of 44 μg 3 times a week. At a dose of 22 mcg 3 times a week, Rebif® is prescribed to those patients who, according to the attending physician, do not tolerate the high dose well enough. Adolescents from 12 years to 16 years of age usually receive a dose of 22 mcg 3 times a week. The drug should be used at the same time (preferably in the evening), on certain days of the week, with an interval of at least 48 hours. Rebif® can be used only if the solution of the drug is clear or slightly opalescent and if it contains no foreign particles . During the first 2 weeks of therapy, the Rebif® preparation should be administered at a dose of 8.8 μg (0.2 ml of the drug with a dosage of 22 μg or 0.1 ml of the drug at a dosage of 44 μg), during the 3rd and 4th weeks - In a dose of 22 μg (0.5 ml of the drug with a dosage of 22 μg or 0.25 ml of the drug at a dosage of 44 μg). For the introduction of the initial dose of the drug during the first 4 weeks of treatment, syringes or cartridges should be used. Syringe-pens are not designed for this purpose. With the appointment of the drug Rebif® at a dose of 44 mcg, starting with the 5th week, 0.5 ml of the drug is administered in this dosage. If necessary, to reduce influenza-like symptoms associated with the appointment of the drug Rebif®, it is recommended to prescribe an antipyretic analgesic before the injection and within 24 hours after each injection. At present, there are no clear recommendations on how long the treatment should be carried out. It is recommended to assess the condition of patients at least every second year during the first 4 years of treatment with Rebif®, the decision about longer-term therapy should be taken by the attending physician individually for each patient.

Information for the patient when self-administered

To use Rebif® was effective and safe, you should:

Read the instructions carefully and follow its instructions to prevent necrosis at the injection site.

If a reaction occurs at the injection site, consult a physician.

Do not change the dose without consulting the doctor.

Do not discontinue treatment without consulting a doctor.

Warn doctor if the patient has intolerance to any medications.

During treatment, tell your doctor about any health problems.

The preparation of Rebif® is administered subcutaneously. The Rebif® preparation should be a clear or slightly opalescent solution, with no visible foreign matter. If foreign matter is found in the solution or if there is any doubt as to the quality of the drug, it should not be used, it is necessary to contact the attending physician or nurse.

Subcutaneous self-administration

Choose a site for injection on the advice of a doctor (comfortable areas are located at the top of the thigh or in the lower part of the abdomen). It is recommended to alternate injection sites, avoiding frequent injections in the same place. Do not administer the drug to places where there is swelling, hard nodules or pain; Tell the doctor or nurse about the presence of such sites.

Filled Syringes

The first injection of the drug is recommended to be performed under the supervision of a qualified medical professional. Before performing the Rebif® injection, the following instructions should be carefully read:

- Wash hands thoroughly with soap and water;

- get a syringe with Rebif® from the package;

- Wipe the skin at the injection site with an alcoholic napkin. Allow the skin to dry. If alcohol partially remains on the skin, a burning sensation is possible. Gently squeeze the skin around the selected place so that it is slightly raised;

- pressing your wrist against the skin near the site, insert the needle at a right angle into the skin with a quick and firm movement. Hold the syringe like a pencil or a dart. Introduce the drug slowly with constant pressure (press on the piston until the syringe is empty). For convenience, the appropriate syringe (graduation) is plotted on the syringe.

- remove the needle from the skin. Clamp the injection site with a swab;

- lightly massage the injection site with a dry cotton ball or gauze.

- discard the used syringe. The drug remaining in the syringe is not subject to further use.

Cartridges for 3 doses

Cartridges with the preparation Rebif® are designed for reusable use together with an autoinjector.

The first injection should be carried out under the supervision of a doctor or other specialist with the appropriate qualifications. After the appropriate instruction is given, the patient will be able to use Rebif® cartridges with an automatic injector at home.

How to install the Rebif® cartridge:

- Wash hands thoroughly with soap and water;

- Immediately after removing the cartridge from the refrigerator, it is necessary to make sure that the solution in the cartridge in the package or in the autoinjector is not accidentally frozen;

- remove the Rebif® cartridge from the blister pack by removing the plastic cover from it;

- To install the cartridge in the injector, follow the instructions in the manual for the autoinjector.

How to administer Rebif® in cartridges

- The doctor should instruct the patient on how to set the prescribed dose (22 or 44 μg) in the autoinjector, which is also reflected in the instructions to the device. Before the injection, it is necessary to make sure that the dose of the drug displayed on the screen corresponds to the prescribed by the doctor.

- Wipe the skin at the injection site with an alcoholic napkin. Allow the skin to dry. If alcohol partially remains on the skin, a burning sensation is possible;

- place the auto-injector on the skin at a right angle (90 °) to the selected injection site;

- Press the button to start the injection;

- Wait until the end of the injection;

- remove from the injection site;

- remove and dispose of the used needle in accordance with the instructions to the autoinjector;

- lightly massage the injection site with a dry cotton ball or gauze.

Detailed instructions for working with the autoinjector are contained in the manual that accompanies it.

Syringe handles

Syringe pens are for single use only. Carefully read the instructions below before using the syringe pen.

For the injection, you will need:

- the syringe-pen;

- Ensure the integrity of the syringe-pen package;

- alcohol wipes;

- Wash hands thoroughly with soap and water;

- remove the syringe handle from the container.

- check the appearance of the preparation Rebif® through the transparent control zone of the syringe-pen;

- check the expiration date on the label of the syringe pen.

How to inject Rebif® with a syringe pen

- Wipe the skin at the injection site with an alcoholic napkin. Allow the skin to dry. If alcohol partially remains on the skin, a burning sensation is possible;

- remove the lid immediately before injection (holding the syringe-pen in one hand by the body, the other to remove the lid);

- place the syringe handle at a right angle (90 °) to the skin at the intended injection site, press the syringe handle onto the skin until resistance is felt. In this case, the limiter is retracted into the body of the syringe pen and the button on the syringe handle is unlocked;

- keeping sufficient pressure of the syringe pen on the injection area, press the button with your thumb. You will hear a click indicating the start of the injection and the start of the plunger movement. Keep the syringe-pen on the skin for at least 10 seconds to ensure that the injection is fully completed. After the injection, the button can be released;

After the injection, raise the syringe pen. At the same time, the limiter automatically extends and locks around the needle, providing protection against possible needle damage;

- check the transparent control zone to make sure that the piston has moved down.

- make sure that there is no drug left in the syringe pen. If the solution remains in the syringe pen after the injection, the Rebif® preparation has not been completely injected, and the patient should seek advice from the treating physician;

- lightly massage the injection site with a dry cotton ball or swab.

In case of any difficulties with the use of the syringe pen, you should seek help from a doctor or nurse.

What to do with used syringes

Syringe-pens are intended only for a one-time dose of 0.5 ml and should never be reused;

Never put a lid on the used syringe pen;

Immediately after the injection, discard the used syringe pen;

To avoid injury, never put your fingers in the hole of the safety stop that covers the needle.

What to do if an overdose of Rebif®

No cases of overdose have been described to date. However, if the dose is exceeded (an increase in the single-dose volume or frequency of admission per week), the doctor should be informed immediately.

What to do if a dose is missed

If a dose is missed, it is necessary to continue injections, starting from the next on schedule. Do not administer a double dose.

What to do if the patient decides to stop taking Rebif®

The effect of the Rebif® preparation may not be immediately noticeable. To achieve the desired result, you must continue taking Rebif® regularly. You can not stop treatment without consulting your doctor.

Overdose

If a patient injects more than prescribed doses, immediately inform the attending physician. If necessary, in case of an overdose, the patient should be hospitalized for follow-up and maintenance therapy.

Special instructions

Caution should be exercised when administering interferon to patients with depression. Patients should be warned that they should immediately report any symptoms of depression and / or suicidal ideation to the treating doctor. Treatment of patients with depression with interferon beta-1a should be under close monitoring and providing them with the necessary care. In some cases, there may be a question about discontinuing interferon beta treatment. Caution should also be exercised in prescribing interferon beta-1a to patients who have previously experienced seizures, patients receiving antiepileptic drugs, especially if they are not effective enough. If Rebif® cramps occur during treatment with patients who did not previously suffer from such disorders, it is necessary to establish their etiology and prescribe anticonvulsant therapy before resuming treatment. At the first stages of interferon beta-1a treatment, strict observation of patients suffering from cardiovascular diseases such as angina pectoris, congestive heart failure and rhythm disturbances is necessary. This observation should be aimed at the timely detection of possible deterioration of the condition. In heart diseases, influenza-like symptoms associated with interferon beta-1a therapy can be a serious burden for patients. There are isolated reports of necrosis at the injection site. To minimize the risk of necrosis, strict adherence to the rules of asepsis during the injection and a change in the injection site after each injection is necessary. If there is damage to the skin with swelling and discharge of fluid at the injection site, you should see a doctor before proceeding with the drug. For multiple skin lesions, the drug should be discontinued before healing. With a single lesion, it is possible to continue therapy with Rebif®, provided that the lesion is moderately expressed. In clinical trials, increased activity of hepatic transaminases, especially ALT, has been demonstrated. In the absence of clinical symptoms, it is necessary to monitor the concentration of ALT in the plasma prior to the use of the preparation Rebif®, in the 1 st, 3 rd and 6 th months from its onset, and periodically during further treatment. It is necessary to reduce the dose of the drug if the ALT level exceeds 5 times the IVH, and gradually increase the dose after its normalization. Caution should be exercised when assigning interferon beta-1a to patients with severe hepatic insufficiency in history, with signs of liver disease, signs of alcohol abuse, ALT levels 2.5 times higher than ULN. Therapy with Rebif® should be discontinued if jaundice or other clinical signs of liver dysfunction occur. Rebif®, like other interferons beta, can potentially cause severe liver damage, including. Acute hepatic insufficiency. The mechanism of these conditions is unknown, specific risk factors have not been identified. In addition to laboratory tests that are always performed for patients with multiple sclerosis, it is recommended in the 1 st, 3 rd and 6 th months after initiation of Rebif ® therapy, and periodically, in the absence of clinical symptoms, during further treatment, determine A general clinical analysis of blood with a leukocyte formula, the content of platelets, as well as a biochemical blood test, including functional tests of the liver. Patients receiving Rebif® sometimes develop or exacerbate existing pathological changes in the thyroid gland. It is recommended to perform a thyroid function test right before the beginning of treatment and, if violations are detected, every 6-12 months from the moment of its onset. If the function of the thyroid gland is normal before the start of treatment, then periodic studies of its function are not required, but they are necessary when there are clinical signs of thyroid dysfunction. In patients receiving interferons beta, the formation of neutralizing antibodies is possible. Their clinical value is not established. If the patient does not have a good response to Rebif® therapy, and this is due to the persistent presence of neutralizing antibodies, the physician should evaluate the feasibility of continuing interferon therapy. Caution should also be observed when prescribing the drug to patients with severe renal failure and myelosuppression.

Use in children. The safety profile of adolescents aged 12 to 16 years receiving Rebif® at a dose of 22 μg SC 3 times a week is similar to the profile of adult patients.

Impact on the ability to drive and technical means. Adverse reactions from the CNS to the therapy with interferons (see section "Side effect") can affect the ability to drive and technique.

Release form

A solution for subcutaneous administration was 22 mkg / 0.5 ml, 44 mkg / 0.5 ml. For 0.5 ml (dose) of the drug in syringes of transparent colorless borosilicate glass type I (HeF./F.USA) with a nominal capacity of 1 ml, equipped with a stainless steel injection needle with a two-layer protective cap. 1 syringe is placed in a plastic container and sealed with a film with a paper coating. By 3 or 12 plastic containers are placed in a cardboard box.

For 0.5 ml (dose) of the preparation in syringes of transparent colorless borosilicate glass type I (HeF./F.S.) with a nominal capacity of 1 ml, equipped with a stainless steel injection needle with a two-layer protective cap and placed in a plastic device representing A non-separable disposable syringe pen. 1 syringe-pen is placed in a plastic container and sealed with a transparent film. By 3 or 12 plastic containers are placed in a cardboard box.

For 1.5 ml (3 doses) of the preparation in cartridges of transparent colorless borosilicate glass type I (Hebrew F./F. USA) with a nominal capacity of 3 ml, sealed with a siliconized rubber rod-piston on one side and an aluminum cap with a rubber gasket with other. One cartridge is placed in a plastic container and sealed with a transparent film. Four plastic containers are placed in a cardboard box.

Manufacturer

Merck Serono SpA Via delle Maniolie 15 (District Industrial Zone) 70026 Modogno (BA), Italy.

Name and address of the legal entity in whose name the registration certificate was issued: Merck Serono SpA Via Casilina 125, 00176 Rome, Italy.

Claims from consumers and information about undesirable phenomena should be sent to the address of the representative office of Ares Trading SA. In the Russian Federation: Moscow

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Rebif

At a temperature of 2-8 ° C (do not freeze).

Keep out of the reach of children.

Shelf life of the drug Rebif

2 years.

Do not use after the expiry date printed on the package.