INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo BETAFERON
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

BETAFERON
DILUENT FOR BETAFERON

COMPOSITION
Betaferon:                        One 3 mL vial contains interferon beta-1b 9,6 million IU (0,3 mg) per vial as a lyophilised cake. (This includes an overfill of 20%, so that after reconstitution with 1,2 mL of sodium chloride solution (10,8 mg per 2 mL), the dose of 0,25 mg interferon beta-1b can be extracted in 1 mL.)
Diluent for Betaferon: One pre-filled syringe contains 1,2 mL sterile sodium chloride solution 0,54% w/v (6,48 mg sodium chloride per 1,2 mL).
1 mL of the reconstituted solution for injection contains 8 million IU (0,25 mg) of interferon beta-1b.

PHARMACOLOGICAL CLASSIFICATION
A. 34 Others.

PHARMACOLOGICAL ACTION
The activities of interferon beta-1b are species-restricted and therefore, the most pertinent pharmacological information on interferon beta-1b is derived from studies of human cells in culture or human in vivo studies.
Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis are not clearly understood. However, it is known that the biologic response-modifying properties of interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces the expression of a number of gene products that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b.
Pharmacokinetics
Serum concentrations after subcutaneous administration of 0,25 mg (8 million units) cannot be detected or are low and maximum serum levels of about 40 IU/mL were found 1 to 8 hours after subcutaneous injection of 0,5 mg (16 million IU) interferon beta-1b. From various studies mean clearance rates and half-lives of disposition phases from serum were estimated to be at most 30 mL/min/kg or 5 hours, respectively. Every other day drug injections do not lead to drug accumulation and pharmacokinetics do not seem to change during therapy.
The absolute bioavailability of subcutaneously administered interferon beta-1b at a dose of 16 million units was approximately 50%.

INDICATIONS
Interferon beta-1b is indicated for use in:
1 Ambulatory patients with relapsing-remitting multiple sclerosis characterised by at least two attacks of neurologic dysfunction over a two year period followed by complete or incomplete recovery.
2 Secondary progressive multiple sclerosis.

CONTRA-INDICATIONS
Betaferon is contra-indicated in the following conditions:
During pregnancy.
In patients with a history of hypersensitivity to natural or recombinant interferon beta or human albumin.
Patients with decompensated liver disease.
Patients with epilepsy not adequately controlled by treatment.
Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria).
Patients with a history of severe depressive disorders and/or suicidal ideation.

WARNINGS
One suicide and four attempted suicides were observed among 372 study patients during a 3 year period. All five patients received Betaferon (three in the 0,05 mg (1,6 million IU) group and two in the 0,25 mg (8 million IU) group). There were no attempted suicides in patients on study who did not receive Betaferon. Depression and suicide have been reported to occur in patients receiving interferon alpha, a related compound. Patients to be treated with Betaferon should be informed that depression and suicidal ideation may be a side effect of the treatment and should report these symptoms immediately to the prescribing physician. Patients exhibiting depression should be monitored closely and cessation of therapy should be considered.

DOSAGE AND DIRECTIONS FOR USE
Treatment with Betaferon should be initiated under the supervision of a physician experienced in the treatment of the disease.
The recommended dose of Betaferon is 8 million IU (0,25 mg), contained in 1 mL of the reconstituted solution to be injected subcutaneously every other day.
To reconstitute lyophilised interferon beta-1b for injection use the pre-filled syringe and a needle to inject the 1,2 mL Diluent for Betaferon (sodium chloride solution, 0,54% w/v) into the Betaferon vial. Dissolve the drug completely without shaking. Inspect the reconstituted product visually before use. Discard the product before use if it contains particulate matter or is discoloured. The reconstituted solution contains 8 million IU (0,25 mg) of interferon beta-1b per mL.
Treatment should start as soon as the definite diagnosis of relapsing-remitting multiple sclerosis has been made and the patient has had at least two exacerbations : the treating physician should inform the patient of the possible risk and benefit of a treatment with Betaferon and decide with him/her whether he/she would be willing to accept possible side effects and inconveniences that might be related to the treatment with Betaferon.
At the present time it is not known how long the patient should be treated.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Although acute toxicity studies have not been carried out, the aspects of an acute toxicity study have been covered in systemic tolerance studies in primates using multiples of the intended human dose (50 to 100 times) and daily administration. The results from these studies show that there is no acute toxicity risk from the use of interferon beta-1b.
Experimental systemic tolerance studies following daily intravenous or subcutaneous administration indicated a pyrogenic potential as well as a potential for induction of haematological changes, whereby a transient decrease in segmented neutrophils and thrombocytes as well as a transient increase in lymphocytes were observed. No long term toxicity studies have been conducted.
Investigations into the influence on male and female fertility have not been conducted. Based on experiments using other interferons, a potential risk of impaired male and female fertility cannot be ruled out.
While the investigation of interferon beta-1b in embryotoxicity studies on monkeys revealed an abortive potential from the dose of 13,3 million IU/kg/day onwards, there was however no indication that malformations were induced in the surviving animals.
In the single study into genotoxic effects (Ames test) no mutagenic effect was observed.
In vivo studies for elucidation of a tumorigenic potential have not been performed. An in vitro cell transformation assay gave no indication of a tumorigenic potential.
Undesirable clinical effects
In the multiple sclerosis studies, 45% of the patients developed serum interferon beta-1b neutralising activity on at least one occasion. One third had neutralising activity confirmed by at least two consecutive positive titres. This development of neutralising activity is associated with a reduction in clinical efficacy, becoming evident at 19 to 24 months.
New adverse events have not been associated with the development of neutralising activity. However, the possibility of cross reactivity with endogenous interferon beta has not been investigated.
There are sparse and inconclusive data in patients who have developed neutralising activity and have completed Betaferon therapy.
Injection site reactions occurred frequently after administration of Betaferon. Redness, swelling, discolouration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associated with 0,25 mg (8 million IU) Betaferon treatment. The incidence rate of injection site reactions usually decreased over time. Injection site necrosis may occur.
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 Betaferon.
Flu-like symptom complex (fever, chills, myalgia, malaise, or sweating) has been seen frequently. The incidence rate of the symptoms decreased over time.
Menstrual disorders such as intermenstrual bleeding, spotting, early or delayed menses, decreased days of menstrual flow and clotting and spotting during menstruation may occur in premenopausal females.
Central nervous system related adverse events including depression, anxiety, emotional lability, depersonalisation, convulsions, suicide attempts and confusion have been observed.
Less frequently, nausea and vomiting may occur.
Alopecia has been reported in less frequent cases.
Muscular hypertonia (spasticity) has been reported to increase with treatment.
Less frequent cases of cardiomyopathy have been reported. See “Special warnings and special precautions for use”.
Less frequent cases of thyroid dysfunction (hyper- as well as hypothyroidism) associated with the use of Betaferon have been reported.
Other adverse reactions and laboratory events were : hypertension, tachycardia, palpitations, peripheral vascular disorders, gastro-intestinal disorders, somnolence, dyspnoea, laryngitis, cystitis, breast pain, pelvic pain, absolute neutrophil count <1500/mm³, white blood cell count <3000/mm³, ALT > five times baseline value and total bilirubin >2,5 times baseline value.
At the recommended dose, elevations in AST, ALT and gamma-GT may occur and there are reports of possible drug-induced hepatitis.
Leukopenia (lymphopenia, neutropenia) and anaemia have been reported. There have been reports of thrombocytopenia with profound decreases in platelet count in rare cases.

Adverse reactions and laboratory abnormalities reported in multicentre trials
(United States and Canada)
Adverse reaction Placebo
N=123		 0,25 mg
(8 mIU)
N=124
Body as a whole 
        Injection site reaction*         37%         85%
        Headache         77%         84%
        Fever*         41%         59%
        Flu-like symptom complex*         56%         76%
        Pain         48%         52%
        Asthenia*         35%         49%
        Chills*         19%         46%
        Abdominal pain         24%         32%
        Malaise*         3%         15%
        Generalised oedema         6%         8%
        Pelvic pain         3%         6%
        Injection site necrosis*         0%         5%
        Cyst         2%         4%
        Necrosis         0%         2%
        Suicide attempt         0%         2%
Cardiovascular system 
        Migraine         7%         12%
        Palpitation*         2%         8%
        Hypertension         2%         7%
        Tachycardia         3%         6%
        Peripheral vascular disorder         2%         5%
        Haemorrhage         1%         3%
Digestive system 
        Diarrhoea         29%         35%
        Constipation         18%         24%
        Vomiting         19%         21%
        Gastrointestinal disorder         3%         6%
Endocrine system 
        Goitre         0%         2%
Hemic and lymphatic system 
        Lymphocytes <1500/mm³         67%         82%
        ANC <1500/mm³*         6%         18%
        WBC <3000/mm³*         5%         16%
        Lymphadenopathy         11%         14%
Metabolic and nutritional disorders 
        ALT >5 times baseline*         6%         19%
        Glucose <55 mg/dL         13%         15%
        Total bilirubin > 2,5 times baseline         2%         6%
        Urine protein > 1+         3%         5%
        AST > 5 times baseline*         0%         4%
        Weight gain         0%         4%
        Weight loss         2%         4%
Musculoskeletal system 
        Myalgia*         28%         44%
        Myaesthenia         10%         13%
Nervous system 
        Dizziness         28%         35%
        Hypertonia         24%         26%
        Anxiety         13%         15%
        Nervousness         5%         8%
        Somnolence         3%         6%
        Confusion         2%         4%
        Speech disorder         1%         3%
        Convulsion         0%         2%
        Hyperkinesia         0%         2%
        Amnesia         0%         2%
Respiratory system 
        Sinusitis         26%         36%
        Dyspnoea*         2%         8%
        Laryngitis         2%         6%
Skin and appendages 
        Sweating*         11%         23%
        Alopecia         2%         4%
Special senses 
        Conjunctivitis         10%         12%
        Abnormal vision         4%         7%
Urogenital system 
        Dysmenorrhoea         11%         18%
        Menstrual disorder*         8%         17%
        Metrorrhagia         8%         15%
        Cystitis         4%         8%
        Breast pain         3%         7%
        Menorrhagia         3%         6%
        Urinary urgency         2%         4%
        Fibrocystic breast         1%         3%
        Breast neoplasm         0%         2%
*        Significantly associated with interferon beta-1b treatment.
Special warnings and special precautions for use
Patients to be treated with Betaferon should be informed that depression and suicidal ideation may be a side effect of the treatment and should report these symptoms immediately to the prescribing physician. In rare cases these symptoms may result in a suicide attempt. Patients exhibiting depression and suicidal ideation should be monitored closely and cessation of therapy should be considered.
Betaferon should be administered with caution to patients with a history of seizures and of depression and to patients who suffer from pre-existing cardiac disorders.
Caution should be exercised when administering Betaferon to patients with myelosuppression, anaemia or thrombocytopenia; patients who develop neutropenia should be monitored closely for the development of fever or infection.
Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxis and urticaria) may occur. If reactions are severe, Betaferon should be discontinued and appropriate medical intervention instituted. Other moderate to severe adverse experiences may require modifications of the Betaferon dosage regimen or even discontinuation of the agent.
A full blood count and differential WBC, AST, ALT and gamma-GT levels should be obtained prior to initiation of Betaferon therapy and regularly during therapy. The occurrence of elevations in serum transaminases should lead to close monitoring and investigation with withdrawal of Betaferon if the levels become significantly increased or if there are associated symptoms suggesting the development of hepatitis. In the absence of clinical evidence for liver damage and after normalisation of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.
There are no data on patients with renal impairment. Renal function should be monitored carefully when such patients receive Betaferon therapy.
It has been demonstrated in vitro that the neutralising antibodies against recombinant interferon beta-1b also interact with natural interferon beta albeit to a lesser extent. However, this has not been investigated in vivo and its clinical significance is uncertain.
Injection site necrosis has been reported in patients using Betaferon. It can be extensive and may involve muscle fascia as well as fat and therefore can result in scar formation. Occasionally debridement and, less often, skin grafting are required and healing may take up to 6 months.
If the patient has multiple lesions Betaferon should be discontinued until healing has occurred. Patients with single lesions may continue on Betaferon provided the necrosis is not too extensive, as some patients have experienced healing of injection site necrosis whilst on Betaferon.
To minimise the risk of injection site necrosis patients should be advised to:
- use an aseptic injection technique
- rotate the injection sites with each dose
The procedure for the self-administration by the patient should be reviewed periodically especially if injection site reactions have occurred.
Rare cases of cardiomyopathy have been reported: if this occurs and a relationship to Betaferon is suspected, treatment should be discontinued.
In very rare cases, the administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of systemic capillary leak syndrome with shock-like symptoms and fatal outcome.
Interactions
The effect of alternate-day administration of 8 million IU of Betaferon on drug metabolism in multiple sclerosis patients is unknown. Corticosteroid or ACTH treatment of relapses for periods of up to 28 days has been well tolerated in patients receiving Betaferon. However, in the clinical trials, patients receiving Betaferon had a significantly reduced steroid usage compared with placebo patients.
Due to lack of clinical experience in multiple sclerosis patients use of Betaferon together with immunomodulators other than corticoids or ACTH is not recommended.
Interferons have been reported to cause a down regulation of hepatic cytochrome P450 in humans and animals. Caution should be exercised when interferon beta-1b is administered in combination with drugs that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance.
Caution should be exercised with any co-medication which has an effect on the hematopoetic system.
Influence on laboratory tests/findings
At the recommended dose, elevations in AST, ALT and gamma-GT may occur and there are reports of possible drug-induced hepatitis.
Leukopenia (lymphopenia, neutropenia) and anaemia have been reported. There have been reports of thrombocytopenia with profound decreases in platelet count in rare cases.
Low calcium and high uric acid have appeared to be associated with Betaferon administration.
Pregnancy and lactation
It is not known whether Betaferon can cause foetal harm when administered to a pregnant woman, or can affect human reproductive capacity. Spontaneous abortions have been reported in subjects with multiple sclerosis using Betaferon in controlled clinical trials. Therefore, Betaferon is contra-indicated during pregnancy and women of childbearing potential should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Betaferon, she should be informed of the potential hazards and it should be recommended that therapy be discontinued.
It is not known whether interferon beta-1b is excreted in human milk. Because of the potential for serious adverse reactions to Betaferon in nursing infants a decision should be made whether nursing or the drug should be discontinued.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Interferon beta-1b has been given without serious adverse events compromising vital functions to adult cancer patients at individual doses as high as 176 million IU intravenously three times a week.

IDENTIFICATION
Betaferon - One 3 mL clear glass vial containing a white lyophilised cake.
Diluent for Betaferon - One pre-filled glass syringe containing a clear colourless solution.

PRESENTATION
One pack contains 15 vials of Betaferon and 15 pre-filled syringes of Diluent for Betaferon.

STORAGE INSTRUCTIONS
Store below 25°C.
After reconstitution store at 2 to 8°C for up to 3 hours.
Keep out of reach of children.

REGISTRATION NUMBERS
Betaferon - 30/34/0185
Diluent for Betaferon - 30/34/0186

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
Randjespark
Midrand        1685
P O Box 5278
Halfway House        1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
15 October 1999

SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Subsidiary of
Schering AG        Germany

Updated on this site: January 2005
Source: Pharmaceutical Industry

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