Rebif利比

Rebif

interferon beta-1a

Manufacturer:

Merck

Distributor:

The Glory Medicina
/
DKSH
Full Prescribing Info
Contents
Recombinant human interferon β-1a.
Description
Each 0.5-mL pre-filled syringe contains 22 mcg (6 MIU) or 44 mcg (12 MIU) of interferon β-1a.
Action
Pharmacology: Pharmacodynamics: Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and antiproliferative properties.
Rebif is composed of the native amino acid sequence of natural human interferon β. It is produced in mammalian cells (Chinese hamster ovary) and is therefore glycosylated like the natural protein.
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple sclerosis at doses ranging from 11-44 mcg (3-12 MIU), administered SC 3 times/week. At licensed posology, Rebif 22 and 44 mcg has been demonstrated to decrease the incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with at least 2 exacerbations in the previous 2 years and with an expanded disability status scale (EDSS) of 0-5 at entry. The proportion of patients with disability progression, as defined by at least 1 point increase in EDSS confirmed 3 months later, was reduced from 39% (placebo) to 30% (Rebif 22 mcg) and 27% (Rebif 44 mcg). Over 4 years, the reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 mcg and 29% in patients treated with Rebif 44 mcg group compared with a group of patients treated with placebo for 2 years and then either Rebif 22 or 44 mcg for 2 years.
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence of clinical progression in the preceding 2 years and who had not experienced relapses in the preceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate was reduced by approximately 30%. If the patient population was divided into 2 subgroups (those with and those without relapses in the 2-year period prior to study entry), there was no effect on disability in patients without relapses, but in patients with relapses, the proportion with progression in disability at the end of the study was reduced from 70% (placebo) to 57% (Rebif 22 mcg and 44 mcg combined). These results obtained in a subgroup of patients a posteriori should be interpreted cautiously.
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis and should not be used in such patients.
Pharmacokinetics: In healthy volunteers after IV administration, interferon β-1a exhibits a sharp multi-exponential decline, with serum levels proportional to the dose. The initial half-life is in the order of minutes and the terminal half-life is several hours, with the possible presence of a deep compartment. When administered by the SC or IM routes, serum levels of interferon β remain low, but are still measurable up to 12-24 hrs post-dose. SC and IM administrations of Rebif produce equivalent exposure to interferon β. Following a single 60-mcg dose, the maximum peak concentration, as measured by immunoassay, is around 6-10 IU/mL, occurring on average around 3 hrs after the dose. After SC administration at the same dose repeated every 48 hrs for 4 doses, a moderate accumulation occurs (about 2.5 times for AUC).
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the administration of Rebif. After a single dose, intracellular and serum activity of 2-5A synthetase and serum concentrations of β-2 microglobulin and neopterin increase within 24 hrs, and start to decline within 2 days. IM and SC administrations produce fully superimposable responses. After repeated SC administration every 48 hrs for 4 doses, these biological responses remain elevated, with no signs of tolerance development.
Interferon β-1a is mainly metabolised and excreted by the liver and the kidneys.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and genotoxicity.
Rebif has not been investigated for carcinogenicity.
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. Based on observations with other α and β interferons, an increased risk of abortions cannot be excluded. No information is available on the effects of the interferon β-1a on male fertility.
Indications/Uses
Treatment of relapsing multiple sclerosis.
In clinical trials, this was characterised by ≥2 acute exacerbations in the previous 2 years (see Pharmacology under Actions).
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity (see Pharmacology under Actions).
Patient with single demyelinating event with an active inflammatory process, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis.
Dosage/Direction for Use
Recommended Dose: 44 mcg given 3 times weekly by SC injection.
Rebif 22 mcg, also given 3 times weekly by SC injection, is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.
Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.
When first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducing adverse reactions, it is recommended that 8.8 mcg (0.1 mL of Rebif 44 mcg or 0.2 mL of Rebif 22 mcg) be administered during the initial 2 weeks of therapy, 22 mcg (0.25 mL of Rebif 44 mcg or the total of Rebif 22 mcg) be administered in weeks 3 and 4, and the total of Rebif 44 mcg be administered from the 5th week onwards.
Children and Adolescents: No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents 12-16 years receiving Rebif 22 mcg SC 3 times weekly is similar to that seen in adults. There is very limited information on the use of Rebif in children <12 years and therefore, Rebif should not be used in this population.
Prior to injection and for an additional 24 hrs after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with Rebif administration.
At the present time, it is not known for how long patients should be treated. Safety and efficacy with Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients should be evaluated at least every 2nd year in the 4-year period after initiation of treatment with Rebif and a decision for longer-term treatment should then be made on an individual basis by the treating physician.
Overdosage
In case of overdose, patients should be hospitalised for observation and appropriate supportive treatment should be given.
Contraindications
Patients with a history of hypersensitivity to natural or recombinant interferon β or to any excipients of Rebif.
Initiation of treatment in pregnancy (see also Use in pregnancy under Precautions).
Patients with current severe depression and/or suicidal ideation (see Precautions and Adverse Reactions).
Special Precautions
Patients should be informed of the most common adverse reactions associated with interferon β administration, including symptoms of flu-like syndrome (see Adverse Reactions). These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.
Rebif should be administered with caution to patients with previous or current depressive disorders in particular to those with antecedents of suicidal ideation (see Contraindications). Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Rebif should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with Rebif and treated appropriately. Cessation of therapy with Rebif should be considered (see Contraindications and Adverse Reactions).
Rebif should be administered with caution to patients with a history of seizures, to those receiving treatment with antiepileptics, particularly if their epilepsy is not adequately controlled with antiepileptics (see Interactions and Adverse Reactions).
Patients with cardiac disease eg, angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during initiation of therapy with interferon β-1a. Symptoms of the flu-like syndrome associated with interferon β-1a therapy may prove stressful to patients with cardiac conditions.
Injection site necrosis (ISN) has been reported in patients using Rebif (see Adverse Reactions). To minimise the risk of injection site necrosis patients should be advised to use an aseptic injection technique and rotate the injection sites with each dose.
The procedure for self-administration by the patient should be reviewed periodically, especially if injection site reactions have occurred.
If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with their physician before continuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until healing has occurred. Patients with single lesions may continue provided that necrosis is not too extensive.
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine aminotransferase (ALT) were common and 1-3% of patients developed elevations of hepatic transaminases >5 times the upper limit of normal (ULN). In the absence of clinical symptoms, serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on-therapy, and periodically thereafter. Dose reduction of Rebif should be considered if ALT rises >5 x ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated with caution in patients with a history of significant liver disease, clinical evidence of active liver disease, alcohol abuse or increased serum ALT (>2.5 x ULN). Treatment with Rebif should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see Adverse Reactions).
Rebif, like other interferons β, has a potential for causing severe liver injury (see Adverse Reactions) including acute hepatic failure. The mechanism for the rare symptomatic hepatic dysfunction is not known. No specific risk factors have been identified.
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring and complete and differential blood cell and platelet counts are recommended at regular intervals (1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the absence of clinical symptoms. These should be more frequent when initiating Rebif 44 mcg.
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following initiation of therapy. If tests are normal at baseline, routine testing is not needed but should be performed, if clinical findings of thyroid dysfunction appear (see Adverse Reactions).
Caution should be used, and close monitoring considered when administering interferon β-1a to patients with severe renal and hepatic failure, and to patients with severe myelosuppression.
Serum neutralising antibodies against interferon β-1a may develop. The precise incidence of antibodies is as yet uncertain. Clinical data suggest that after 24-48 months of treatment with Rebif 22 mcg and 44 mcg, approximately 24% and 13-14%, respectively, of patients develop persistent serum antibodies to interferon β-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic response to interferon β-1a (β-2 microglobulin and neopterin). Although the clinical significance of the induction of antibodies has not been fully elucidated, the development of neutralising antibodies is associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to therapy with Rebif, and has neutralising antibodies, the treating physician should re-assess the benefit/risk ratio of continued Rebif therapy.
The use of various assays to detect serum antibodies and differing definitions of antibody positivity limits the ability to compare antigenicity among different products.
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple sclerosis.
Effects on the Ability to Drive or Operate Machinery: Less commonly reported central nervous system-related adverse events associated with the use of interferon β might influence the patient's ability to drive or use machines (see Adverse Reactions).
Use in pregnancy: There is limited information on the use of Rebif in pregnancy. Available data indicates that there may be an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy (see Contraindications).
Women of Childbearing Potential: Women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Rebif, the patient should be informed of the potential hazards and discontinuation of therapy should be considered (see Toxicology under Actions). In patients with a high relapse rate before treatment started, the risk of a severe relapse following discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion.
Use in lactation: It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or Rebif therapy.
Use In Pregnancy & Lactation
Use in pregnancy: There is limited information on the use of Rebif in pregnancy. Available data indicates that there may be an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy (see Contraindications).
Women of Childbearing Potential: Women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Rebif, the patient should be informed of the potential hazards and discontinuation of therapy should be considered (see Toxicology under Actions). In patients with a high relapse rate before treatment started, the risk of a severe relapse following discontinuation of Rebif in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion.
Use in lactation: It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or Rebif therapy.
Adverse Reactions
General: The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like syndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment. Approximately 70% of patients treated with Rebif can expect to experience the typical interferon flu-like syndrome within the first 6 months after starting treatment. Approximately 30% of patients will also experience reactions at the injection site, predominantly mild inflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function and decreases in WBC are also common.
The majority of adverse reactions observed with interferon β-1a are usually mild and reversible, and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of Rebif may be temporarily lowered or interrupted, at the discretion of the physician.
Adverse Reactions by Frequency: The adverse reactions reported as follows are classified according to frequency of occurrence as follows: Very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse Reactions Identified in Clinical Studies: The data presented is obtained from pooled clinical studies in multiple sclerosis (placebo=824 patients; Rebif 22 mcg 3 times weekly = 398 patients; Rebif 44 mcg 3 times weekly = 727 patients) and shows the frequency of adverse reactions observed at 6-month (excess over placebo). Adverse reactions are listed as follows by frequency of occurrence and by MedDRA system organ class.
Infections and Infestations: Uncommon: Injection site abscess.
Blood and Lymphatic System Disorders: Very Common: Neutropenia, lymphopenia, leucopenia, thrombocytopenia, anemia.
Endocrine Disorders: Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism or hyperthyroidism.
Psychiatric Disorders: Common: Depression, insomnia.
Nervous System Disorders: Very Common: Headache.
Gastrointestinal Disorders: Common: Diarrhoea, vomiting, nausea.
Skin and Subcutaneous Tissue Disorders: Common: Pruritus, rash, erythematous rash, maculopapular rash.
Musculoskeletal and Connective Tissue Disorders: Common: Myalgia, arthralgia.
General Disorders and Administration Site Conditions: Very Common: Injection site inflammation, injection site reaction, influenza-like symptoms. Common: Injection site pain, fatigue, rigors, fever. Uncommon: Injection site necrosis, injection site reaction mass.
Investigations: Very Common: Asymptomatic increased transaminase.
Adverse Reactions Identified During Post-Marketing Surveillance (Frequency Unknown): Infections and Infestations: Injection site infections, including cellulitis.
Immune System Disorders: Anaphylactic reactions.
Psychiatric Disorders: Suicide attempt.
Nervous System Disorders: Seizures.
Vascular Disorders: Thromboembolic events.
Hepatobiliary Disorders: Hepatitis with or without icterus.
Skin and Subcutaneous Tissue Disorders: Angioedema, urticaria, erythema multiforme, erythema multiforme-like skin reactions, hair loss.
Information Characterising Individual Serious and/or Frequently Occurring Adverse Reactions: Rebif, like other interferon β, has a potential for causing severe liver injury. The mechanism for the rare symptomatic hepatic dysfunction is not known. The majority of the cases of severe liver injury occurred within the first 6 months of treatment. No specific risk factors have been identified. Treatment with Rebif should be stopped if icterus or other clinical symptoms of liver dysfunction appear (see Precautions).
Adverse Reactions that Apply to the Pharmacological Class: The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, vasodilation and palpitation, menorrhagia and metrorrhagia.
An increased formation of autoantibodies may occur during treatment with interferon β.
Drug Interactions
No interaction studies have been performed with Rebif (interferon β-1a) in humans. Interferons have been reported to reduce the activity of hepatic cytochrome P-450-dependent enzymes in humans and animals. Caution should be exercised when administering Rebif in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P-450 system for clearance eg, antiepileptics and some classes of antidepressants.
The interaction of Rebif with corticosteroids or ACTH has not been studied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and corticosteroids or ACTH during relapses. Incompatibilities: Not applicable.
Caution For Usage
Special Precautions for Handling and Disposal: The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a suitable auto-injector.
Any unused product or waste material should be disposed of in accordance with local requirements. For single-use only. Only clear to opalescent solution without particles should be used and without visible signs of deterioration.
Storage
Store at 2-8°C in a refrigerator. Do not freeze. Store in the original package in order to protect from light.
ATC Classification
L03AB07 - interferon beta-1a ; Belongs to the class of interferons. Used as immunostimulants.
Presentation/Packing
Cartridge 66 mcg x 4's. 132 mcg x 4's.
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