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Interferon Alpha 2b, Recombinant

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Also known as: Interferon alfa-2b, recombinant, 98530-12-2, Schembl6041041, Q4391540

Molecular Formula

C₁₆H₁₇Cl₃I₂N₃NaO₅S

Molecular Weight

746.5 g/mol

InChI Key

MIXCUJKCXRNYFM-UHFFFAOYSA-M

Alpha interferon encoded by the human IFNA2 gene. Recombinant forms are used in the treatment of CHRONIC HEPATITIS B; CHRONIC HEPATITIS C; KAPOSI SARCOMA; MELANOMA; and HAIRY CELL LEUKEMIA.

1 2D Structure

Interferon Alfa-2B

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

sodium;diiodomethanesulfonate;N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide

2.1.2 InChI

InChI=1S/C15H16Cl3N3O2.CH2I2O3S.Na/c1-2-4-20(15(22)21-5-3-19-10-21)6-7-23-14-12(17)8-11(16)9-13(14)18;2-1(3)7(4,5)6;/h3,5,8-10H,2,4,6-7H2,1H3;1H,(H,4,5,6);/q;;+1/p-1

2.1.3 InChI Key

MIXCUJKCXRNYFM-UHFFFAOYSA-M

2.1.4 Canonical SMILES

CCCN(CCOC1=C(C=C(C=C1Cl)Cl)Cl)C(=O)N2C=CN=C2.C(S(=O)(=O)[O-])(I)I.[Na+]

2.2 Synonyms

2.2.1 MeSH Synonyms

1. Ifn-alpha 2

2. Ifn-alpha-2

3. Ifnalpha 2b, Recombinant

4. Ifnalpha-2b, Recombinant

5. Interferon Alfa 2a

6. Interferon Alfa 2b

7. Interferon Alfa-2a

8. Interferon Alpha 2

9. Interferon Alpha 2b, Recombinant

10. Interferon Alpha A

11. Interferon Alpha-2

12. Interferon Alpha-2a, Recombinant

13. Interferon Alpha-2b, Recombinant

14. Interferon Alpha-a

15. Interferon-alpha 2

16. Intron A (interferon)

17. Leif A

18. Reaferon

19. Recombinant Ifnalpha-2b

20. Recombinant Interferon Alpha 2a

21. Recombinant Interferon Alpha 2b

22. Recombinant Interferon Alpha-2a

23. Recombinant Interferon Alpha-2b

24. Ro 22 8181

25. Ro 22-8181

26. Ro 228181

27. Roferon A

28. Roferon-a

29. Roferona

30. Sch 30500

31. Sch-30500

32. Sch30500

33. Viferon

2.2.2 Depositor-Supplied Synonyms

1. Interferon Alfa-2b, Recombinant

2. 98530-12-2

3. Schembl6041041

4. Q4391540

2.3 Create Date

2013-05-09

3 Chemical and Physical Properties

Molecular Formula	C₁₆H₁₇Cl₃I₂N₃NaO₅S
Molecular Weight	746.5 g/mol
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	7
Exact Mass	744.79416 g/mol
Monoisotopic Mass	744.79416 g/mol
Topological Polar Surface Area	113 Å²
Heavy Atom Count	31
Formal Charge	0
Complexity	511
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	3

4 Drug and Medication Information

4.1 Therapeutic Uses

Recombinant Proteins; Interferon-alpha

National Library of Medicine's Medical Subject Headings online file (MeSH, 2013)

INTRON A is indicated for the treatment of patients 18 years of age or older with hairy cell leukemia. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for INTRON A (interferon alfa-2b) kit (August 2012). Available from, as of August 2, 2013: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd653d74-48ab-49e4-a42d-ec1cbc59badb

INTRON A is indicated for the treatment of selected patients 18 years of age or older with AIDS-Related Kaposi's Sarcoma. The likelihood of response to INTRON A therapy is greater in patients who are without systemic symptoms, who have limited lymphadenopathy and who have a relatively intact immune system as indicated by total CD4 count. /Included in US product label/

INTRON A is indicated for the initial treatment of clinically aggressive follicular Non-Hodgkin's Lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older. Efficacy of INTRON A therapy in patients with low-grade, low-tumor burden follicular Non-Hodgkin's Lymphoma has not been demonstrated. /Included in US product label/

For more Therapeutic Uses (Complete) data for Interferon Alfa-2b (17 total), please visit the HSDB record page.

4.2 Drug Warning

/BOXED WARNING/ Alpha interferons, including INTRON A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping INTRON A therapy.

Almost all patients experience adverse effects at some time during the course of interferon alfa therapy. However, evaluation of some adverse effects and establishment of a causal relationship to interferon alfa have been difficult since the drug has been used principally in patients with serious underlying diseases, such as acquired immunodeficiency syndrome (AIDS), various cancers, and/or viral hepatitis.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1072

A flu-like syndrome develops to some degree in almost all patients receiving 1 million units or more of interferon alfa but its severity appears to be dose related. The syndrome is characterized by the development of fever (in about 40-98% of patients), fatigue/malaise (in about 50-95% of patients), myalgia (in about 30-75% of patients), chills (in about 40-65% of patients), headache (in about 20-70% of patients), arthralgia (in about 5-24% of patients), rigors, tachycardia, anorexia, dry mouth, dysgeusia, back pain, sweating, and dizziness. Abdominal cramps and diarrhea also may be associated with the syndrome.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1072

Myalgia and arthralgia, often associated with a flu-like syndrome, are the most frequent adverse musculoskeletal effects of interferon alfa, occurring in up to 70 and 24% of patients, respectively. These effects generally are transient, mild, and self-limiting. More severe myalgias, generally involving the lower extremities and associated with limitation of movement, have been observed in patients with chronic myelogenous leukemia receiving the drug. Such myalgias frequently require 1-2 weeks of bed rest and corticosteroid and/or analgesic (e.g., opiate) therapy for relief. These severe myalgias generally were not associated with an increase in serum muscle enzymes, and electromyograms have failed to reveal evidence of myositis. Skeletal pain, which frequently is one of the first adverse effects associated with interferon alfa therapy, has been reported in some patients with multiple myeloma who were receiving the drug; however, arthralgias were not observed in patients with metastatic osseous lesions associated with renal cell carcinoma or other malignancies.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1073

For more Drug Warnings (Complete) data for Interferon Alfa-2b (47 total), please visit the HSDB record page.

4.3 Drug Indication

For the treatment of hairy cell leukemia, malignant melanoma, and AIDS-related Kaposi's sarcoma.

FDA Label

* Chronic hepatitis B:

Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis-B viral replication (presence of DNA of hepatitis-B virus (HBV-DNA) and hepatitis-B antigen (HBeAg), elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and / or fibrosis.

* Chronic hepatitis C:

Before initiating treatment with IntronA, consideration should be given to the results from clinical trials comparing IntronA with pegylated interferon.

Adult patients

IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for hepatitis-C virus-RNA (HCV-RNA).

The best way to use IntronA in this indication is in combination with ribavirin.

Children three years of age and older and adolescents

IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children three years of age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for HCV-RNA. When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that resulted in reduced final adult height in some patients.

The decision to treat should be made on a case-by-case basis.

* Hairy-cell leukaemia:

Treatment of patients with hairy cell leukaemia.

* Chronic myelogenous leukaemia:

Monotherapy

Treatment of adult patients with Philadelphia-chromosome- or bcr/abl-translocation-positive chronic myelogenous leukaemia.

Clinical experience indicates that a haematological and cytogenetic major / minor response is obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ leukaemic cells in the bone marrow, whereas a minor response is 34 %, but < 90 % Ph+ cells in the marrow.

Combination therapy

The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses and to significantly prolong the overall survival at three years when compared to interferon alfa-2b monotherapy.

* Multiple myeloma:

As maintenance therapy in patients who have achieved objective remission (more than 50% reduction in myeloma protein) following initial induction chemotherapy.

Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the plateau phase; however, effects on overall survival have not been conclusively demonstrated.

* Follicular lymphoma:

Treatment of high-tumour-burden follicular lymphoma as adjunct to appropriate combination induction chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), systemic symptoms (weight loss > 10 %, pyrexia > 38C for more than eight days, or nocturnal sweats), splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or epidural involvement, serous effusion, or leukaemia.

* Carcinoid tumour:

Treatment of carcinoid tumours with lymph node or liver metastases and with 'carcinoid syndrome'.

* Malignant melanoma:

As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic recurrence, e. g. patients with primary or recurrent (clinical or pathological) lymph-node.

* Chronic Hepatitis B: :

Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral replication (presence of HBV-DNA and HBeAg), elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or fibrosis.

* Chronic Hepatitis C: :

Adult patients:

IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for serum HCV-RNA or anti-HCV (see section 4. 4).

The best way to use IntronA in this indication is in combination with ribavirin.

Chidren and adolescents:

IntronA is intended for use, in a combination regimen with ribavirin, for the treatment of children and adolescents 3 years of age and older, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for serum HCV-RNA. The decision to treat should be made on a case by case basis, taking into account any evidence of disease progression such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load. The expected benefit of treatment should be weighed against the safety findings observed for paediatric subjects in the clinical trials (see sections 4. 4, 4. 8 and 5. 1).

5 Pharmacology and Biochemistry

5.1 Pharmacology

Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R.

5.2 MeSH Pharmacological Classification

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Antiviral Agents

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

5.3 FDA Pharmacological Classification

5.3.1 Pharmacological Classes

Interferon-alpha [CS]; Interferon alpha [EPC]

5.4 ATC Code

L03AB05

L - Antineoplastic and immunomodulating agents

L03 - Immunostimulants

L03A - Immunostimulants

L03AB - Interferons

L03AB05 - Interferon alfa-2b

5.5 Absorption, Distribution and Excretion

Absorption

Absorption is high (greater than 80%) when administered intramuscularly or subcutaneously.

For systemic effects, interferon alfa is administered parenterally because the drug is susceptible to degradation by proteolytic enzymes in the GI tract. Interferon alfa is well absorbed following IM or subcutaneous injection; the apparent fraction of the dose absorbed after IM or subcutaneous injection exceeds 80%. Peak serum interferon alfa concentrations following IV administration of the drug generally occur within 15-60 minutes and are substantially greater than those attained after IM or subcutaneous administration. However, serum interferon alfa concentrations following IM or subcutaneous administration generally are maintained for longer periods of time than those produced by rapid IV injection or rapid (e.g., 40 minutes or less) IV infusion.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1084

After intravenous administration, serum INTRON A concentrations peaked (135-273 IU/mL) by the end of the 30-minute infusion, then declined at a slightly more rapid rate than after intramuscular or subcutaneous drug administration, becoming undetectable 4 hours after the infusion.

The pharmacokinetics of INTRON A were studied in 12 healthy male volunteers following single doses of 5 million IU/sq m administered intramuscularly, subcutaneously, and as a 30-minute intravenous infusion in a crossover design. The mean serum INTRON A concentrations following intramuscular and subcutaneous injections were comparable. The maximum serum concentrations obtained via these routes were approximately 18 to 116 IU/mL and occurred 3 to 12 hours after administration. Serum concentrations were undetectable by 16 hours after the injections.

Limited data on the tissue distribution of interferon in animals suggest that mixtures of naturally occurring human or animal interferons are widely and rapidly distributed into body tissues after parenteral administration, with the highest concentrations occurring in spleen, kidney, liver, and lung.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1084

For more Absorption, Distribution and Excretion (Complete) data for Interferon Alfa-2b (7 total), please visit the HSDB record page.

5.6 Biological Half-Life

The elimination half-life following both intramuscular and subcutaneous injections was approximately 2 to 3 hours. The elimination half-life was approximately 2 hours following intravenous injection.

The elimination half-life was approximately 2 hours /after intravenous administration/.

The elimination half-life of INTRON A following both intramuscular and subcutaneous injections was approximately 2 to 3 hours.

5.7 Mechanism of Action

Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which upon dimerization activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription)which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies demonstrated that these include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.

Following binding to specific cellular receptors, interferons (INFs) activate the JAK_STAT signal-transduction pathway and lead to the nuclear translocation of a cellular protein complex that binds to genes containing an INF-specific response element. This, in turn, leads to the synthesis of over two dozen proteins that contribute to viral resistance mediated at different stages of viral penetration. Inhibition of protein synthesis is the major inhibitory effect for many viruses. INF-induced proteins include 2',5'-oligoadenylate (2-5(A)) synthetase and a protein kinase, either of which can inhibit protein synthesis in the presence of double stranded RNA. The 2-5(A) synthetase produces adenylate oligomers that activate a latent cellular endoribonuclease (RNase L) to cleave both cellular and viral single stranded RNAs. The protein kinase selectively phosphorylates and inactivates a protein involved in protein synthesis, eukaryotic initiation factor 2 (eIF-2). IFN-induced protein kinase also may be an important effector of apoptosis. In addition, INF induces a phosphodiesterase that cleaves a portion of transfer RNA and thus prevents peptide elongation.

Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2006., p. 1261

The precise mechanisms of action of interferons have not been fully elucidated but appear to be complex, and the resultant activities appear to be substantially interrelated. Unlike classic antiviral and cytotoxic agents, the antiviral and antineoplastic properties of interferons appear to result from a complex cascade of biologic modulation and pharmacologic effects rather than from direct virucidal or cytocidal effects. The drugs affect many cell functions producing restoration, augmentation, and/or modulation of the host's immune system; direct antiproliferative and antineoplastic activities; modulation of cell differentiation; and modulation of cellular transcription and translation, including a reduction in oncogene expression. Some or all of these effects may be interrelated and ultimately responsible for the antiviral and antineoplastic activity of interferons. Interferons must bind to specific cell surface receptors in order to exert biologic and pharmacologic effects (e.g., antiviral activity); such binding appears to involve high-affinity sites. In addition, some evidence suggests that the principal effects of interferons result not from direct intracellular actions but rather from ligand-receptor complexes at the cell surface that can mediate and induce intracellular events.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 1080

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