BETAFERON® and Product Details

Interferon beta-1b 250mcg (8MU) (BETAFERON®)
Name Of The Medicinal Product	Betaferon 250 microgram/ml, powder and solvent for solution for injection
Qualitative And Quantitative Composition	Betaferon contains 300 microgram (9.6 million IU) of recombinant interferon beta-1b per vial. Recombinant interferon beta-1b* 250 microgram (8.0 million IU) per ml when reconstituted. * produced by genetic engineering from a strain of Escherichia coli.
Therapeutic indications	1.       A single clinical event suggestive of multiple sclerosis(MS) (‘Clinically Isolated Syndrome’) o  Indicated to delay progression to definite multiples sclerosis 2.       Relapsing forms of Multiple sclerosis o  Indicated for the reduction of frequency and degree of severity of clinical relapses in ambulatory patients 3.       Secondary progressive multiple sclerosis with active disease, evidenced by relapses or pronounced neurological deterioration within the last two years o  Indicated for the reduction of frequency and degree of severity of clinical relapses and slowing the progression of disease
Age limitation	12 years old and above
Dosage and administration	Adults / Children And Adolescent ≥ 12 years old The recommended dose is 250 microgram (8.0 million IU), contained in 1 ml of the reconstituted solution, to be injected subcutaneously every other day (EOD) Dose titration recommended at the start of the treatment Initial: 0.0625 mg (2 million units [0.25 mL]) every other day; gradually increase dose by 0.0625 mg every 2 weeks to a target dose of 0.25 mg (8 million units [1 mL]) every other day. The titration period may be adjusted according to individual tolerability. No randomised controlled trials have been conducted in < 18 years old. However, data from observational studies suggested that the safety profile in adolescents ≥ 12 years old receiving 250 mcg Betaferon SC EOD is similar to that seen in adults. Only limited information available on Betaferon use for those below 12. Therefore, Betaferon should NOT be given to this age group. Remark: If a dose is missed, administer as soon as remembered; do not administer on 2 consecutive days. Time subsequent doses every 48 hours.
Reconstitution	To reconstitute lyophilised interferon beta-1b for injection: ·          Connect the vial adapter with the attached needle on the vial. ·          Connect the pre-filled syringe with solvent to the vial adapter and inject the 1.2 ml of the solvent (sodium chloride solution, 5.4 mg/ml (0.54% w/v) into the Betaferon vial. ·          Dissolve the powder completely without shaking. ·          After reconstitution, draw the required volume of medicine from the vial into the syringe ·          Remove the vial with the vial adapter from the pre-filled syringe before injection. Kindly refer to Pg 58-61 in the following link for graphic and more details: https://www.ema.europa.eu/en/documents/product-information/betaferon-epar-product-information_en.pdf Kindly refer to the following Youtube video link: https://youtu.be/fRuS6wG__-w
Method Of Administration	For subcutaneous injection ·          Site for injection: o    Outer surface of the arms o    Abdomen (except 2-inch area around the navel) o    Buttocks o    Thighs ·          For very thin patient, ONLY use the thigh or outer surface of the arms. ·          Rotate injection site. ·          Do not inject into area where skin is bruised, infected or broken. ·          Patient should be well hydrated Kindly refer to Pg 58-61 in the following link for graphic and more details: https://www.ema.europa.eu/en/documents/product-information/betaferon-epar-product-information_en.pdf Kindly refer to the following Youtube video link: https://youtu.be/fRuS6wG__-w
Adverse reactions (based on physical product leaflet)	Very common ≥ 1 in 10 users Common ≥ 1 in 100 users Uncommon ≥ 1 in 1000 users Unknown frequency ž Lymphocytopenia ž Neutropenia ž Headache ž Insomnia ž Incoordination ž Abdominal pain ž Raised ALT > 5X baseline ž Rash / Skin disorder ž Myalgia / Hypertonia ž Urinary urgency ž Injection site reaction ž Flu-like symptoms ž Pain ž Fever / Chills ž Peripheral oodema ž Asthenia (physical weakness) ž Lymphadenopathy ž Hypertension ž Dyspneoa ž Raised  AST > 5x baseline ž Impotence ž Menorrhagia ž Injection site necrosis ž Chest pain ž Malaise ž Nephrotic syndrome ž Glomerulo-sclerosis ž Anaemia ž Thrombocytopenia ž Leukopenia ž Thrombotic microangiopathy ž Anaphylaxis ž Capillary leak syndrome ž Thyroid disorder ž Blood triglyceride increase ž Weight increase / decrease ž Anorexia ž Bronchospasm ž Tachycardia ž Palpitation ž Vasodilatation ž Pulmonary arterial hypertension ž Raised GGT ž Blood bilirubin increased ž Psychiatric adverse events ž Confusion / Anxiety ž Emotional liability ž Arthralgia ž Menstrual disorder ž Menorrhagia ž Sweating
Special warnings / Precautions for use	Anaphylaxis / hypersensitivity Discontinue use Drug-induced lupus erythematosus Discontinue use Flu-like symptoms ·    Analgesics and/or antipyretics on treatment days. ·    Improvement in symptoms occurs over time. Hepatotoxicity ·    Use with caution in patients with concurrent exposure to other hepatotoxic drugs. Monitor liver function tests as clinically necessary. Consider discontinuation if serum transaminase levels increase significantly or are associated with clinical symptoms (eg, jaundice). Injection site reactions ·    Reversible / Irreversible necrosis may occur with continued therapy; reactions generally arise within the first 4 months of therapy, but have occurred ≥1 year after initiation ·    Tend to improve over time. ·    Patient and/or caregiver competency in injection technique should be confirmed and periodically re-evaluated. ·    Do not inject into affected area until completely healed ·    If multiple lesions occur, discontinue use until they are fully healed. Leukopenia ·    Recommend routine monitoring of complete blood counts with differentials. ·    Dose reduction may be required. (Severe) Psychiatric adverse events ·    e.g. psychosis, mania, depression, suicidal behavior/ideation ·    Avoid use in severe psychiatric disorders ·    Use with caution in patients with a history of depression ·    Those exhibiting symptoms of depression should be closely monitored and discontinuation of therapy should be considered. Thrombotic microangiopathy ·    e.g. Thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) (some fatal; some occur few years after therapy) ·    Monitor for new onset hypertension / thrombocytopenia / impaired renal function ·    Consider discontinuation of therapy and prompt treatment if confirmed TTP/HUS. Cardiovascular disease ·    Use with caution in patients with preexisting cardiovascular disease. ·    Rare cases of new-onset cardiomyopathy and/or HF have been reported. ·    If HF worsens in the absence of another etiology, consider discontinuation of therapy. ·    American Heart Association 2016: Interferon may cause reversible direct myocardial toxicity or exacerbate underlying myocardial dysfunction (strength:  moderate/major) Thyroid dysfunction ·    Thyroid abnormalities may develop with use ·    May worsen pre-existing thyroid conditions. ·    Monitor thyroid function tests every 6 months or as clinically necessary.             Others:  Bone marrow suppression, pancreatitis, nephritic syndrome, seizure disorder
Contraindications	·          Patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin or to any of the excipients ·         Canadian labeling: Additional contraindication (not in US labeling): Pregnancy, decompensated liver disease (Betaseron, Extavia); current severe depression and/or suicidal ideation (Extavia)
Monitoring	·          Baseline: Thyroid function test, thyroglubulin, anti-thyroglobulin antibody, TSH receptor antibody, thyroid peroxidise antibody ·          Baseline: GAD antibody, anti-islet cell antibody, fasting C-peptide level, fasting plasma glucose ·          Liver function tests ·          Full blood count with differentials ·          Adverse drug reactions / Side effects: v Neuropsychiatric side effects v Nephrotic syndrome: early signs or symptoms, e.g. oedema, proteinuria and impaired renal function v Thrombotic microangiopathy: new onset hypertension, thrombocytopenia, or impaired renal function v Others: Flu-like symptoms, allergic or anaphylactic reactions, injection-site reactions, worsening of cardiac symptoms (in HF patients); and for sign/symptoms of depression
Drug interactions	·            No interaction studies have been performed ·            Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when Betaferon is administered in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance
Pregnancy	Contraindicated. ·          No long-term studies have been conducted. ·          Data from pregnancy registries and post-marketing experience (mostly during 1st trimester) suggest that frequencies of miscarriages and congenital abnormalities in their children were comparable to estimated background risk in the general population. ·          Spontaneous abortions have been reported in MS subjects in controlled clinical trials, with incidence rates not exceeding those in general population. ·          Reproduction studies with rhesus monkeys revealed maternal toxicity and an increased rate of abortion, resulting in prenatal mortality. No malformations have been observed in the surviving animals.
Women of Child-bearing Potential	Consultation recommended regarding the need for appropriate contraception measures.
Lactation	Betaferon can be used during breast-feeding. ·          Unknown if excreted into breastmilk. ·          Limited information available on the transfer of interferon beta-1b into breast milk, together with the chemical / physiological characteristics of interferon beta, suggests that levels of interferon beta-1b excreted in human milk are negligible. ·          No harmful effects on the breastfed newborn/infant are anticipated.
Pharmaceutical Particulars	Vial (with powder for solution for injection): Human albumin, Mannitol Solvent (sodium chloride solution 5.4 mg/ml (0.54% w/v): Sodium chloride, Water for injection
Compatibility	This medicinal product must NOT be mixed with other medicinal products except for the supplied solvent
Shelf life	As packaged for sale 2 years, starting from the date of sterile filtration of the bulk solution After reconstitution, immediate use is recommended. However, the in-use stability has been demonstrated for 3 hours at 2-8 °C. Special precaution Do not store above 25°C. Do not freeze.

P/S: Dosing for COVID-19 in adults [based on most available literature]: 250 mcg EOD x 14 days ( total 7 doses )

References

1.        Product leaflet: Betaferon 25 mcg/ml Injection (Updated 18 July 2018)

2.        EPAR Product information : Betaferon [online]

https://www.ema.europa.eu/en/documents/product-information/betaferon-epar-product-information_en.pdf   [Accessed 27 Mac 2020]

3.        https://youtu.be/fRuS6wG__-w [Accessed 28 Mac 2020]

4.        UpToDate [online]: Drug information: Interferon beta-1b [Accessed 27 Mac 2020]

5.        Hoo G, et al. Interferon beta-1b (Betaferon) use for COVID-19 (Interim Guide v3.0). Tan Tock Seng Hospital, 13 Feb 2020.

6.        Hospital Kuala Lumpur: COVID-19 Drug Summary [Updated 20 Mac 2020]

7.        Sarawak General Hospital: COVID-19 Treatment & Drug Doses [Updated 23 Mac 2020]

Prepared by Mohd Zulhelmy ; Edited by JCK Ho [30.03.2020]