ReliFeron 5000000 TV injekcinis tirpalas 0.5ml N1

For the use of Registered Medical Practitioner or a Hospital or a Laboratory only

Interferon Alpha 2b Injection I.P.

ReliFeron

Prescribing Information

DESCRIPTION

ReliFeron® is a purified sterile human recombinant interferon product classified as an alpha interferon. It has 165 amino acids, with a molecular weight of 19 kDa and is water soluble. It is obtained from bacterial fermentation using Escherichia coli bearing a genetically engineered plasmid containing an interferon alpha 2b gene from human leukocytes. It is meant for use as intramuscular / subcutaneous injection.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single use vial contains

PHARMACOLOGY

Pharmacodynamics

Interferon alpha 2b in general has several effects in common with other interferons like antiviral, anti-oncogenic properties, macrophage and natural killer lymphocyte activation and enhancement of major histocompatibility complex glycoprotein classes I and II, and thus presentation of foreign (microbial) peptides to T cells.

In a majority of cases, the production of interferon alpha 2b is induced in response to microbes such as viruses and bacteria and their products.

Mechanism of action

Interferon alpha 2b after secretion by a cell binds to specific cell receptors which then initiates a cascade of intracellular events resulting in synthesis of various proteins. These proteins possess antiviral, antiproliferative and immunomodulatory actions. While there is evidence to suggest that other signaling mechanisms exist, the JAK-STAT (Janus kinases and Signal Transducers and Activators of Transcription) signaling pathway is the best-characterised and commonly accepted IFN signaling pathway. This pathway plays a central role in cell fate decisions, regulating the processes of cell proliferation, differentiation and apoptosis.

Pharmacokinetics

Absorption after subcutaneous injection of interferon alpha 2b is over 80%. Plasma levels are dose related, the peak plasma levels reaching between 4-8 hrs after drug administration and reaching to baseline within a span of 18-36 hrs. Elimination from the blood is related to the distribution of interferon in the tissues, cellular uptake and metabolism primarily in the kidneys and liver. Negligible amounts are excreted in the urine.

ANIMAL TOXICOLOGY OR PHARMACOLOGY

Pre-clinical safety pharmacology, teratogenicity and carcinogenicity studies with ReliFeron® were not conducted. Results of acute, high single dose (2000 µg/kg) and subacute dose (100 µg/kg for 28 days) toxicity studies of ReliFeron® on Swiss Albino mice and Sprague Dawley rats, involving intramuscular and subcutaneous routes showed no local intolerance or systemic toxicity. It did not produce any mutagenic changes in test bacterium.

INDICATIONS

Interferon Alpha 2b has been approved for the use of treatment of -

• Chronic Hepatitis B
• Chronic Hepatitis C
• Hairy Cell Leukemia
• Malignant Melanoma
• Follicular Lymphoma
• Condylomata Acuminata
• AIDS related Kaposi's sarcoma

It is also recommended for use in Non-Hodgkin's lymphoma, genital herpes, renal carcinoma and bladder carcinoma.

CONTRAINDICATIONS

Interferon alpha 2b should not be used in patients with known hypersensitivity to interferon alpha 2b or any other ingredient of the preparation. Its use is contraindicated in patients with pre-existing cardiac, renal or hepatic disease, or in patients with compromised central nervous system.

WARNINGS AND PRECAUTIONS

• Some patients may require dose adjustment   soon after interferon therapy is initiated.
• In patients with chronic hepatitis with highly decompensated hepatic function or cirrhosis, the benefits should be weighed against the risks involved. Patients should be monitored properly.
• Exacerbation of pre-existing skin lesions may occur. In these patients, interferon should be used with caution.
• Patients may experience depression and other psychiatric events like psychosis, mania etc.Careful neuropsychiatric monitoring is required in such patients.
• In myelosuppressive patients, interferon may cause further suppressive effects on bone marrow. Blood counts in such patients should be constantly monitored.

USE IN SPECIAL POPULATION

Pregnancy Category C

Interferon alpha has been shown to have HYPERLINK "https://www.rxlist.com/script/main/art.asp?articlekey=10912" abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). There are no adequate and well-controlled studies in HYPERLINK "https://www.rxlist.com/pregnancy/article.htm" pregnant women. Interferon alpha therapy should be used during HYPERLINK "https://www.rxlist.com/pregnancy_planning_preparing_for_pregna ncy/article.htm" pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category X

Applies to combination treatment with interferon alpha and ribavirin. See Ribavirin prescribing information for additional information.

Significant   HYPERLINK   "https://www.rxlist.com/script/main/ art.asp?articlekey=22266" teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant.

Nursing  Mothers It is not known whether this drug is excreted in human milk. However, studies in mice have shown that mouse interferons are excreted into the milk. Because of the potential for serious adverse reactions from the drug in HYPERLINK "https://www.rxlist.com/breastfeeding/ article.htm" nursing infants, a decision should be made whether to discontinue nursing or to discontinue Interferon alpha therapy, taking into account the importance of the drug to the mother.

Pediatric Use General

Safety and effectiveness in pediatric patients have not been established for indications other than chronic hepatitis B and chronic

HYPERLINK   "https://www.rxlist.com/hepatitis_c_quiz/quiz.htm" hepatitis C. Chronic Hepatitis B Safety and effectiveness in pediatric patients ranging in age from 1 to 17 years have been established based upon one controlled innovator clinical trial.

Chronic Hepatitis C

Safety and effectiveness in pediatric patients ranging in age from 3 to 16 years have been established based upon innovator clinical studies. See Ribavirin prescribing information for additional information. Long-term data in a limited number of patients suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients.

Geriatric Use

In a database consisting of innovator clinical study and postmarketing reports for various indications, cardiovascular adverse   events   and   HYPERLINK"   https://www.rxlist.com/ confusion/symptoms.htm" confusion were reported more frequently in elderly patients receiving Interferon alpha therapy compared to younger patients.

In general, therapy should be administered to elderly patients cautiously, reflecting the greater frequency of decreased hepatic, renal, bone marrow, and/or cardiac function and concomitant disease or other drug therapy. Interferon alpha is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, patients should be carefully monitored during treatment, and dose adjustments made based on symptoms and/or laboratory abnormalities.

Effect on ability to drive and use machines

No studies done.

Adverse Reactions

Flulike symptoms, malaise, fatigue, loss of appetite have been reported as most common adverse effects of interferon therpay. Rarely reported adverse effects include rash, abdominal pain, hypertension, tachycardia, gingival bleeding and decreased libido.

In clinical trials conducted using ReliFeron®, the most commonly reported adverse reactions were pyrexia (24%), myalgia (6.67%), headache (4%), diarrhoea (2.67%) and thrombocytopenia (2.67%). Otherwise, ReliFeron® therapy was well tolerated.

DOSAGE AND ADMINISTRATION

Chronic Hepatitis B

Adults

The recommended dose of interferon alpha 2b for the treatment of chronic hepatitis B is 30 to 35 million IU per week, administered subcutaneously or intramuscularly, either as 5 million IU daily (QD) or as 10 million IU three times a week (TIW) for 16 weeks.

Children (1-17 years)

3 million units/m2 3 times/ week for 1 week, increased to 6 million units/m2, 3 times/week; maximum: 10 million units / m2, 3 times a week; total duration of therapy 16-24 weeks.

Chronic Hepatitis C

The recommended dose of interferon alpha 2b for the treatment of chronic hepatitis C is 3 million IU three times a week (TIW) administered subcutaneously or intramuscularly. In patients tolerating therapy with normalization of ALT at 16 weeks of treatment, interferon alpha 2b therapy should be extended to 18 to 24 months (72 to 96 weeks) at 3 millon IU TIW to improve the sustained response rate. Patients who do not normalize their ALTs or have persistently high levels of HCV RNA after 16 weeks of therapy rarely achieve a sustained response with extension of treatment. Consideration should be given to discontinuing these patients from therapy.

Dose adjustment: If severe adverse reactions develop during interferon alpha 2b treatment, the dose should be modified (50% reduction) or therapy should be temporarily discontinued until the adverse reactions abate. If intolerance persists after dose adjustment, interferon alpha 2b therapy should be discontinued.

Hairy Cell Leukemia

Dose: The recommended dose for the treatment of hairy cell leukemia is 2 million IU/m2 administered intramuscularly or subcutaneously 3 times a week for up to 6 months. Patients with platelet counts of less than 50,000/mm3 should not be administered interferon alpha 2b intramuscularly, but instead by subcutaneous administration. Patients who are responding to therapy may benefit from continued treatment.

If severe adverse reactions develop, the dosage should be modified (50% reduction) or therapy should be temporarily with held until the adverse reactions abate and then resumed at 50% (1MIU/m2 TIW).

If severe adverse reactions persist or recur following dosage adjustment, interferon alpha 2b should be permanently discontinued.

Interferon alpha 2b should be discontinued for progressive disease or failure to respond after six months of treatment.

Malignant Melanoma

Interferon alpha 2b adjuvant treatment of malignant melanoma is given in two phases, induction and maintenance.

Recommended Induction Dose

The recommended daily dose of interferon alpha 2b in induction is 20 million IU/m2 as an intravenous infusion, over 20 minutes, 5 consecutive days per week, for 4 weeks.

Recommended Maintenance  Dose The recommended dose of interferon alpha 2b for maintenance is 10 million IU/m2 as a subcutaneous injection three times per week for 48 weeks.

Follicular Lymphoma

The recommended dose of interferon alpha 2b for the treatment of follicular lymphoma is 5 million IU subcutaneously three times per week for up to 18 months in conjunction with anthracycline- containing chemotherapy regimen and following completion of the chemotherapy regimen.

Condylomata Acuminata

The recommended dose is 1.0 million IU per lesion in a maximum of 5 lesions in a single course. The lesions should be injected three times weekly on alternate days for 3 weeks. An additional course may be administered at 12-16 weeks.

AIDS-Related   Kaposi's   Sarcoma The recommended dose of interferon alpha 2b for Kaposi's Sarcoma is 30 million IU/m2/day administered subcutaneously three times a week for 16 weeks or until maximal response has been achieved. Dose titration is frequently required.

Dosage adjustment in renal impairment is required since interferon is not removed by peritoneal or hemodialysis.

DRUG INTERACTIONS

Interactions between interferon alpha and other drugs have not been fully evaluated. Caution should be exercised when administering interferon alpha therapy in combination with other potentially myelosuppressive agents such as zidovudine. Concomitant use of alpha interferon and theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline levels.

INCOMPATIBILITIES

Not to be mixed with other medications

PRESENTATION

Each vial of ReliFeron® 3 MIU contains 3 million IU interferon alpha 2b, IP, in 0.5 mL of aqueous buffer.

Each vial of ReliFeron® 5 MIU contains 5 million IU interferon alpha 2b, IP., in 0.5 mL of aqueous buffer.

STORAGE

Store between 2oC and 8oC. Do not freeze. Do not shake. Protect from light.

For details of product's shelf life, please refer to Expiry Date mentioned on the label or carton.

PATIENT COUNSELING INFORMATION

The patients should be made aware of the warning for interferon alpha, including causing or aggravating fatal or life - threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be counselled and enquired for contraindications like hypersensitivity to interferon alpha or any component of the product, autoimmune hepatitis and decompensated liver disease.

Cardiovascular Disorders

Those patients with a history of myocardial infarction and/or previous or current arrhythmic disorder who require interferon alpha therapy need to be closely monitored. Inform regarding Cardiovascular adverse experiences, which include hypotension, arrhythmia, or tachycardia of 150 beats per minute or greater and rarely, cardiomyopathy and myocardial infarction.

Cerebrovascular Disorders

Information regarding ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha- based therapies.

Neuropsychiatric Disorders

Patients and relatives may be counselled regarding possibility of DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HOMICIDAL IDEATION, AND AGGRESSIVE BEHAVIOR SOMETIMES DIRECTED TOWARDS OTHERS.

Bone Marrow Toxicity

Patient shouls be informed that interferon alpha therapy suppresses bone marrow function and may result in severe cytopenias including aplastic anemia.

Ophthalmologic Disorders

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, papilledema, and serous retinal detachment may be induced or aggravated by treatment with interferon alpha-2b or other alpha interferons.

Endocrine  Disorders

Infrequent occurrence of thyroid abnormalities, either hypothyroid or hyperthyroid should be informed.

Gastrointestinal Disorders

Information regarding increase in the risk  of hepatic decompensation and death in patients with cirrhosis.

Pulmonary   Disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by interferon alpha.

Peripheral Neuropathy

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. Also keep the patient informed that use with Ribavirin may cause birth defects and/or death of the unborn child.

Drug Interactions

Patient to be informed that concomitant use of alpha interferon and theophylline decreases theophylline clearance, resulting in a 100% increase in serum theophylline levels.

Patients should be advised to remain well hydrated during the initial stages of treatment and that use of an antipyretic may ameliorate some of the flu-like symptoms.

Patients should be instructed on the importance of site selection for self-administering the injection, as well as the importance on rotating the injection sites. Requirement of puncture resistant container for the disposal of needles and syringes should be informed.

Patients and relatives can be informed of the most frequently reported adverse reactions were “flu-like” symptoms, particularly fever, headache, chills, myalgia, and fatigue. More severe toxicities are observed generally at higher doses and may be difficult for patients to tolerate.

DETAILS OF MANUFACTURER

Reliance Life Sciences Pvt. Ltd.

DALC, Plant 2, R-282, TTC Area of MIDC, Thane-Belapur Road, Rabale, Navi Mumbai - 400 701, INDIA.

DETAILS OF PERMISSION AND/OR LICENCE NUMBER WITH DATE

MF-103/08 dated 30 Jan 2008 License # KD/7

DATE OF REVISION

May 2019