Rebif - instructions for use, dose, side effects, contraindications

active substance: interferon beta-1a 22 μg (6 million ME) or 44 μg (12 million ME) and excipients: petrol alcohol 2.5 mg, mannitol 22.5 mg, methionine 0.06 mg, poloxamer 188 0.25 mg, 0.01 M sodium acetate buffer solution * qs up to 0.5 ml.

One filled cartridge in 1.5 ml of the preparation contains:

active substance: interferon beta-1a 66 μg (18 million IU) or 132 μg (36 million IU) and

excipients: petrol alcohol 7.5 mg, mannitol 67.5 mg, methionine 0.18 mg, poloxamer 188 0.75 mg, 0.01 M sodium acetate buffer solution * q.s. up to 1.5 ml.

* Ingredients: sodium acetate, acetic acid, sodium hydroxide to adjust pH, water for injection.

Description:Lightly opalescent light yellow solution.

Pharmacotherapeutic group:Cytokines.

ATX: & nbsp

L.03.A.B.07 Interferon beta-1a

Pharmacodynamics:

A drug Rebif® has immunomodulatory, antiviral and antiproliferative properties.The protein structure of the preparation 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 and, Consequently, is glycosylated, like a natural protein. The glycosylation of interferon beta 1a gives the molecule a dipole character, which causes its good solubility in water, temperature stability and tolerability.

The mechanism of action of the drug Rebif® in patients with multiple sclerosis is not fully understood. It is shown that the drug helps limit damage to the central nervous system (demyelination), underlying the disease.

The first episode of demyelination

In a biennial controlled clinical trial preparation Rebif® has been shown to be effective in treating patients with the first episode of demyelination, presumably as a result of multiple sclerosis. Patients included in the study had at least 2 asymptomatic focuses on T2-weighted MRI images with a size of at least 3 mm, and at least one of the foci was oval, periventricular or

infrastructorial.Other diseases that could better explain the patient's symptoms than the diagnosis of multiple sclerosis were excluded. It was found that Rebif® 44 μg when taken 3 times a week delayed the progression of multiple sclerosis in patients with the first episode of demyelination. The reduction in the risk of progression of the disease was 52% compared with placebo. Data on the effectiveness of the Rebif® preparation when taken 44 μg 3 times a week are given below:

Options	Therapy		Comparison of Rebif 44 and placebo therapy
	Placebo (n=171)	ht, ba 44 (p-171)	Risk reduction	Propor. relates. risk Cox (95% CI)	R- the value of e
Transition to Multiple Sclerosis by the McDonald Criterion (2005)
Number of cases	144	106	51%	0,49 (0,38; 0,64)	<0,001
Evaluation km	85,8%	62,5%
Transition to Clinical Reliable Multiple Sclerosis
Number of cases	60	33	52%	0,48 (0,31; 0,73)	<0,001
Evaluation km	37,5%	20,6%
Mean age-related lesions detected during scanning during a double-blind study
Minimal error	2,58 (0,30)	0,50 (0,06)	81%	0,19 (0,14; 0,26)	<0,001

Remittent Multiple Sclerosis

The safety and efficacy of the Rebif® preparation were evaluated in patients with remitting multiple sclerosis at doses in the range of 11-44 μg (3-12 million IU) administered subcutaneously three times a week.Rebif® was shown to reduce the frequency (30% for 2 years) and the severity of exacerbations in patients with two or more exacerbations during the last 2 years and a score of 0 to 5 on the extended scale of the degree of invalidization (at a dosage of 44 μg); EDSS) before starting treatment. Proportion of patients with confirmed progression invalidization 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 points on the EDSS scale) with a significant progression of disability in the previous 2 years and no exacerbations during the previous 8 weeks, Rebif® did not have a significant effect on disability,

However, the frequency of exacerbations decreased by 30%. When the two groups of patients (who had or had not had an exacerbation of the disease in the last 2 years) in the "without exacerbations" group, the effect of the drug on the progression of disability was not found, whereas in the group "with

exacerbations ", the proportion of patients with progression at the end of the study decreased from 70% (placebo) to 57% (Rebif® 22 μg and Rebif® 44 μg.) The effect of the drug with primary-

progressive multiple sclerosis has not been studied.

Pharmacokinetics:

Suction

After intravenous administration of healthy volunteers concentration of interferon beta-1a undergoes a sharp exponential decrease, and the serum levels of the drug are proportional to the dose. With subcutaneous or intramuscular injection, the Rebif® drug behaves similar to beta-interferon.

Distribution

After repeated subcutaneous injections of Rebif® at a dose of 22 μg and 44 μg, the maximum concentrations of interferon beta-1a are observed after 8 hours, but the values vary greatly. Excretion

After repeated subcutaneous injections of the Rebif® preparation to healthy volunteers, the main pharmacokinetic parameters (area under the pharmacokinetic curve (AUC) and maximum concentration (Cmax)) increase in proportion to the dose increase from 22 μg to 44 μg. The half-life is between 50 and 60 hours, which correlates with the cumulation process observed after repeated administration.

Metabolism

Interferon beta-1a is metabolized and excreted by the liver and kidneys.

Indications:

Rebif® is prescribed for treatment:

- patients with the first episode of demyelination, which is based on an acute inflammatory process, if other diagnoses have been excluded, and if there is a high risk of developing clinically

reliable multiple sclerosis;

- Patients with remittant multiple sclerosis, in whom the disease is characterized by two or more exacerbations in the previous two years.

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

Contraindications:

- Hypersensitivity to natural or recombinant interferon beta, to other

components of the drug.

- Initiation of therapy during pregnancy.

- Severe depressive disorders and / or suicidal ideation.

- Age before 12 years.

Pregnancy and lactation:

Women with childbearing potential

Women of childbearing age should use effective means of contraception. Given the potential danger to the fetus, patients planning pregnancy or who become pregnant during the treatment should inform the treating doctor about this decision for the decision to cancel the drug. For patients withhigh frequency of relapses before the start of treatment, it is necessary to compare the risk of a severe relapse in the event of discontinuation of the drug due to pregnancy with a possible increase in the likelihood of spontaneous abortion.

Pregnancy

Begin the treatment with the drug Rebif® during pregnancy is contraindicated. The available data indicate a possible increase in the risk of spontaneous abortion.

Breastfeeding period

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.

Dosing and Administration:The drug is administered subcutaneously. Treatment should be started under the supervision of a specialist doctor who has experience in the treatment of this disease. Treatment with Rebif® for the development of tachyphylaxis and reduction of undesirable reactions is recommended to begin with a dose of 8.8 μg and then for 4 weeks the dose should be increased to the recommended dosage according to the scheme below

Timing	Recommended	Dose titration
introduction of	no	preparation
	titration	Rebif® 44 μg
	(% of the final	3 times a week
	dosages)
Weeks	20%	8.8 μg 3 p / week
1 and 2
Weeks	50%	22 mcg 3 p / week
3 and 4
Week 5	100%	44 mcg 3 p / week
and beyond

To introduce an initial dose of the drug in During the first 4 weeks of treatment, syringes or cartridges should be used, since syringes are not designed for this purpose.

When prescribing Rebif® in a dose 44 mcg, starting from the 5th week, 0.5 ml drug in this dosage. To reduce influenza-like symptoms associated with with the appointment of Rebif® Before administration and within 24 hours after each injection, it is recommended to prescribe an antipyretic agent (antipyretic).

The first episode of demyelination

The dosage of Rebif® for patients with the first episode of demyelination is 44 mcg 3 times a week, subcutaneously.

Remittent Multiple Sclerosis

Adults and adolescents over 16 years of age the recommended dose of the drug is usually 44 μg 3 times a week. In a dose of 22 μg 3 times a week, Rebif® is assigned to those patients who, according to the attending physician, do not tolerate a high dose well enough.

The safety and effectiveness of the use of Rebif® in adolescents aged 12-16 years has not yet been established.The safety data given in the "Side effect" section does not give an opportunity to give recommendations on the dosing regimen for this group of patients. Nevertheless, the published data suggest that the safety profile of Rebif® in adolescents aged 12 to 16 years receiving subcutaneous injections of the drug at a dose of 22 μg 3 times a week is similar to that in adults. The safety and efficacy of Rebif® in children under 12 years of age is not established, only limited information is available, so Rebif® should not be used in this age group. 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 . There are currently no clear recommendations on how long the treatment should be carried out. It is recommended to assess the condition of patients at least every two years during the first 4 years of treatment with Rebif®, a decision about longer therapy It should be taken individually by the attending physician for each patient.

Side effects:

The most frequent adverse reactions observed with Rebif® treatment are associated with the onset of an influenza-like syndrome. Grippopodobnye symptoms are particularly pronounced at the beginning of treatment and weaken in frequency as the treatment continues. Approximately 70% of patients taking Rebif® can expect the appearance of a typical flu-like syndrome in the first six months after initiation of treatment. Approximately 30% of patients develop reactions at the injection site, mostly mild irritation or erythema.

Asymptomatic an increase in laboratory parameters of hepatic function and a decrease in the number of leukocytes are also frequent. Below are the undesirable reactions that were observed in both clinical trials and post-registration periods (marked *) in patients with multiple sclerosis. Undesirable reactions are listed according to their frequency and system-organ class. To denote the frequency of undesired reactions, a generally accepted classification is used:

Often (> 1/10 cases)

Often (>1/100, <1/10)

Infrequently (> 1/1,000, < 1/100)

Rarely (> 1/10,000, < 1/1,000)

Very rarely (<1 / 10,000)

The frequency is unknown (can not be established based on the received data)

Violations from the blood and lymphatic system:

Very often: neutropenia, lymphopenia, leukopenia, thrombocytopenia, anemia.

Rarely: thrombotic microangiopathy, including thrombotic thrombocytopenic purpura / hemolytic-uremic syndrome *, pancytopenia *.

Immune system disorders:

Rarely: anaphylactic reactions *.

Disorders from the endocrine system:

Infrequent: a dysfunction of the thyroid gland, most often manifested in the form of hypo- or hyperthyroidism.

Disorders from the liver and bile ducts:

Very often: an asymptomatic increase activity of transaminases in the blood.

Often: significant increase in activity transaminase in the blood.

Infrequently: hepatitis (with or without jaundice) *.

Rarely: hepatic insufficiency *, autoimmune hepatitis *.

Mental disorders:

Often: depression, insomnia.

Impaired nervous system:

Very often: headache.

Infrequently: convulsions *.

Frequency unknown: transitory neurological symptoms (hypoesthesia, muscle spasms, paresthesia, difficulty walking, muscle rigidity) that can mimic the aggravation of multiple sclerosis *.

Disturbances on the part of the organ of sight:

Infrequent: retinal vascular lesions (ie, retinopathy, "cotton spots" on the retina, arterial obstruction or retinal veins) *.

Disorders from the vascular system:

Infrequently: thromboembolism *.

Disturbances from respiratory system, chest organs and mediastinum:

Infrequently: dyspnea *

Disorders from the gastrointestinal tract:

Often: diarrhea, vomiting, nausea.

Disturbances from the skin and subcutaneous fabrics:

Often: itching, rash, erythematous rash, maculopapular rash, alopecia.

Infrequently: urticaria.

Rarely: Quincke's edema, erythema multiforme *, skin reaction resembling multiform erythema, Stevens-Johnson syndrome *.

Disturbances from the musculoskeletal and connective tissue:

Often: myalgia, arthralgia.

Rarely: drug lupus erythematosus *.

General disorders and disorders at the site of administration:

Very often: inflammation at the injection site, reactions at the injection site (eg, bruising, swelling at the injection site, swelling, redness), flu-like symptoms.

Often: pain at the injection site, fatigue, chills, fever.

Infrequent: necrosis at the injection site, abscess at the injection site, infection of the injection site *, increased sweating *.

Rarely: cellulite at the injection site *.

Children

Individual clinical or pharmacokinetic studies for children and adolescents were not conducted. However, the published data on the use of Rebif ® in adolescents aged 12 to 16 who received the drug at a dose of 22 μg 3 times per week subcutaneously suggest that the safety profile of the Rebif ® preparation in this group is similar to that of adult patients.

Class Effects

The use of interferons is associated with loss of appetite, dizziness, anxiety, arrhythmia, enlargement of blood vessels and rapid heart rate, menorrhagia and metrorrhagia.

In the course of treatment with interferon beta, enhanced antibody formation may occur.

It is necessary to inform the doctor about any of the above unwanted reactions, as well as those that are not indicated in the of this manual. If you save unwanted reactions during long time or in case of development severe adverse reactions to discretion of the doctor is temporary reduced dose of the drug or interruption treatment.

Do not stop treatment or change dose without the indication of the attending physician.

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.

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 reduce the activity of cytochrome P-450-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 P-450 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 carried out. Data from clinical studies indicate the possibility of obtaining patients with multiple sclerosis with Rebif® and corticosteroids or ACTH during exacerbations of the disease.

Special instructions:

Patients should be informed of the most common side effects associated with taking interferon beta, including influenza-like symptoms (see below).Section "Side effect"), which are especially pronounced at the beginning of treatment and decrease in frequency and severity as treatment continues.

Thrombotic microangiopathy (TMA)

There is information about cases of thrombotic microangiopathy, which manifested itself as thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome, including fatal cases. Such cases were recorded at different time periods, from several weeks to several years after initiation of treatment with Rebif®. It is recommended to monitor early symptoms such as thrombocytopenia, newly occurring cases of hypertension, fever, central nervous system disorders (eg confused consciousness, paresis) and decreased renal function. Laboratory data for a presumptive diagnosis of TMA include a decrease in the number of platelets, an increase in serum lactate dehydrogenase (LDH) activity, caused by hemolysis and schizocytes (fragments of erythrocytes) in the blood smear. If clinical signs of TMA are observed, it is recommended that the content platelets, serum LDH, take a blood smear and evaluate the kidney function. If the diagnosis of TMA is confirmed, immediate treatment is required (plasma transfusion may be required) and discontinuation of treatment with Rebif®.

Depression and suicidal ideation

Rebif® should be administered with caution to patients who are or have been depressed. Depressive and suicidal conditions with increased frequency are observed in the group of patients suffering from diffuse sclerosis and taking interferon.

Patients should be warned that they should immediately report any symptoms of depression and / or suicidal ideation to the treating physician.

Treatment of patients with depression, Rebif® preparation should take place in a close monitoring and providing them with the necessary assistance. In a number of cases, the issue of discontinuing treatment with Rebif® can arise.

Convulsive Syndrome

Required be careful when prescribing Rebif® to patients with epileptic seizures in an anamnesis, especially if the course of this disease is not fully controlled by antiepileptic drugs

Cardiovascular diseases

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 timely detection of possible deterioration of the condition. With heart disease, flu-like symptoms,

related to interferon beta-1a therapy, can be a serious burden for patients.

Necrosis at the injection site

There are isolated reports of necrosis at the injection site. To minimize the risk of developing necrosis, strict adherence to the rules of asepsis during the injection and changing the injection site after each injection is necessary. It is necessary to regularly evaluate the technique of self-administration of the drug by patients, especially when reactions occur at the injection site. If there is damage to the skin with swelling and discharge of fluid at the injection site, you should see a doctor before continuing with the introduction preparation. When

multiple skin lesions should be discontinued before they are healed.With a single lesion, further treatment with Rebif® may be possible, provided that the lesion is moderately expressed.

Dysfunction of the liver

In clinical trials, an asymptomatic increase in hepatic transaminase activity was demonstrated, especially alanine aminotransferase (ALT), and in 1-3% of patients the liver transaminase content exceeded the upper limits of the norm (IVF) by more than 5 times. In the absence of clinical symptomatology is necessary monitor the activity of ALT in plasma before the use of the drug Rebif®, in the 1 st, 3 rd and 6 th months of its onset, and also periodically during further treatment. It is necessary to lower the dose of the drug if ALT activity exceeds the upper limit by 5 times, and gradually increase the dose after its normalization. Care should be taken when assigning interferon beta-1a to patients with severe hepatic insufficiency in history, with signs of liver disease, signs of alcohol abuse, ALT activity 2.5 times higher than the upper limit of the norm. 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 liver failure. Severe dysfunction of the liver mainly occurs in the first 6 months of therapy. The mechanism of these conditions is unknown, specific risk factors have not been identified.

Impaired renal and urinary system

Nephrotic syndrome

During treatment with Rebif® and other interferons beta, there may be cases of nephrotic syndrome with various nephropathies, including focal segmental glomerulosclerosis

(OSGS), membranoproliferative glomerulonephritis and membrane glomerulopathy. Cases have occurred both in the process of treatment, and a few years after its completion. It is recommended that periodic monitoring of early signs or symptoms (eg, swelling, proteinuria, or renal dysfunction) be monitored in particular in patients at high risk of developing kidney disease. Nephrotic syndrome requires immediate treatment and discontinuation of Rebif®.

Violation of laboratory indicators

In addition to laboratory analyzes that are always performed in patients with multiple sclerosis,is recommended in the 1 st, 3 rd and 6 th months after the initiation of Rebif® therapy, and periodically, in the absence of clinical symptoms, during further treatment, determine the overall clinical blood count with the leukocyte formula,

the content of platelets, as well as a biochemical blood test, including

functional tests of the liver.

Thyroid gland diseases

Patients receiving Rebif® sometimes develop or exacerbate existing

pathological changes in the thyroid gland. It is recommended to carry out thyroid function tests immediately before the 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 their conduct is necessary when there are clinical signs of thyroid dysfunction.

Severe renal and hepatic impairment and expressed myelosuppression

Care should be taken when prescribing the drug to patients with severe renal disease

insufficiency and myelosuppression.

Neutralizing antibodies

In patients receiving interferons beta, the formation of neutralizing antibodies is possible. Clinical data allow us to suggest that after 24-48 months of treatment with the drug

Rebif® 44 μg at approximately 13-14% (24% for 22 μg) of patients in the serum appear neutralizing antibodies to interferon beta-1 a. The presence of antibodies is associated with a decrease

effectiveness of treatment, as confirmed by MRI study and clinical indicators.

The overall clinical significance of the production of neutralizing antibodies has not been sufficiently studied.

The formation of neutralizing antibodies is associated with the reaction to the presence of various forms

interferon beta. 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 advisability of continuing interferon therapy.

The use of various methods for detecting antibodies in serum and determining their characteristics limits the possibility of comparing the immunogenicity of various drugs.

Other forms of multiple sclerosis

For non-ambulatory patients with multiple sclerosis, only some data on the safety and efficacy of the drug are available.The use of Rebif® in patients with primary progressive multiple sclerosis has not been studied to date, so the drug should not be used in this disease.

Effect on the ability to drive transp. cf. and fur:

Adverse reactions from the central nervous system to interferon therapy (see section "Side effect") can affect the ability to drive and technique.

Form release / dosage:

The solution for subcutaneous administration is 22 μg / 0.5 ml, 44 μg / 0.5 ml.

Packaging:

For 0.5 ml (dose) of the drug in syringes of transparent colorless borosilicate glass type I (Hebrew F. / 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. For 3 or 12 plastic containers, along with the instructions for use are placed in a cardboard box.

0.5 ml (dose) of the preparation into syringes of transparent colorless borosilicate glass type I (Hebrew F. / F. USA) 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. For 3 or 12 plastic containers, along with the instructions for use 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 piston rod on one side and an aluminum cap with a rubber gasket with other.

1 cartridge is placed in a plastic container and sealed with a transparent film. 4 plastic containers together with instructions for use are placed in a cardboard box.

Storage conditions:Store and transport at a temperature of 2 to 8 ° C. Do not freeze. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014563 / 01

Date of registration:27.03.2008

The owner of the registration certificate:Merck Serono S.A.Merck Serono S.A. Switzerland

Manufacturer: & nbsp

MERCK SERONO, S.A. Switzerland

Representation: & nbspARES TRADING SAARES TRADING SARussia

Information update date: & nbsp14.12.2015

Illustrated instructions

Instructions

Rebif® (Rebif®)