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ISMAFRON® Vial
Natural Human Leukocyte Interferon Alpha
(Balanced natural mixture of all interferon alpha subtypes)
Immune-Stimulating & Malignant Antiproliferative Interferon

<< COMPOSITION >>

Each vial contains:Lyophilised natural human leukocyte interferon alpha (23 subtypes).

1 Million International Units (IU) to be dissolved before use in 1 ml water for injection provided in the attached ampoule.


<< DESCRIPTION >>

ISMAFRON® is a purified, lyophilised, sterile natural leukocyte interferon alpha preparation. It contains all the known interferon alpha subtypes (at least 23) adjusted to proportions ensuring optimal immune response regulation and natural body defence against viral infections and neoplastic diseases. The composition of the mixture guarantees optimal synergistic co-operation of individual subtypes to exert the maximal efficiency of the drug.

ISMAFRON® is prepared by the most advanced biotechnology methods from normal human peripheral leukocytes of carefully selected and tested healthy volunteers, whom are free from any infectious diseases. The production method developed by the scientific research team of ACAPI Research and Development Centre has been awarded Patent Licenses in the:

  • United States of America under Patent number: 6,156,542
  • European Community under Patent number: EP 0 945 463
  • Japan under Patent number: 11-253192
  • South Africa under Patent number: ZA 9811554
  • Canada under Patent number: CA 2234369

The technology utilises a mixture of normal healthy human leukocytes corresponding to the natural proportions of different white blood cell types to ensure optimal in vitro conditions most resembling to that found in the human body. The final product is a high quality purified internationally standardised sterile interferon alpha mixture of natural subtypes, in proportion, which is produced by the healthy human immune system in response to pathophysiological stresses.

ISMAFRON® is free from any foreign proteins, cellular remnants and infectious agents. The product manufactured by this patented new technology provides high antiviral and antitumor potency, and excellent therapeutic efficacy without any adverse immunological imbalance, which regularly occurs upon the use of recombinant interferon preparations (e.g. interferon alpha 2a, 2b, or consensus interferon) or other forms of corrupted or incomplete mixtures of natural interferon subtypes (e.g. lymphoblastoid or buffy coat interferon).

Unlike known recombinant interferon alpha products, ISMAFRON® does not induce interferon antibody formation since it is a natural human leukocyte alpha preparation containing only the naturally occurring forms of all the 23 known subtypes.

ISMAFRON® is, therefore, considered as a unique human leukocyte alpha preparation, which is produced by healthy human leukocytes, purified and standardised specially to maintain the natural proportion of the 23 subtypes, free from any immunogenic material, and is completely identical to the endogenous interferon alpha mixture, consequently not immunogenic in itself.

ISMAFRON® can be used over an extended period without developing any adverse immunological reaction to it, continuously maintaining its immunomodulatory, antiviral and antitumor activities.

 ISMAFRON® is suggested to be used in smaller doses and simpler therapeutic regimens in comparison to other available brands of interferon alpha, since the natural complex mixture of the subtypes act synergistically in concentrations and distribution corresponding to the levels produced in the course of natural immune response.

ISMAFRON® triggers a cytokine cascade resulting in a naturally timed and controlled production and release of endogenous interferons as well as other cytokines.

 Consequently, ISMAFRON® ensures a balanced superdynamic therapeutic action. ISMAFRON® does not contain any biological or chemical preservative.


<< ACTION >>

ISMAFRON® is Immune Stimulatory and Malignant neoplasms Antiproliferative interferon. ISMAFRON® can be characterised by its dose-dependent biphasic (paradoxical) biological action:         

  • In small doses ranging from 1-1.5 Million IU ISMAFRON® has a potent immune stimulatory as well as antiviral potency, and it initiates a cascade of endogenous cytokine release with activation of the normal Th1 type cellular immune response and selective proliferation of the corresponding stem cells.
  • In higher doses it produces an immunosuppressive effect by activating the suppressor T cells, suppressing the immune progenitor cells proliferation, and probably by other mechanisms as well. It should also be noted that these high doses would lack the sustained effects of the smaller doses.

Using ISMAFRON® in small therapeutic doses (e.g. 1 Million IU i.m.) provides an immune stimulatory effect, which involves triggering a natural cytokine cascade, including among others the release of different interleukins, chemokines and growth factors. The events occurring upon ISMAFRON® induction include also the induction of the interferon subtype genes (23) on chromosome 9 and release of endogenous interferon into the bloodstream, resulting in a sustained presence and action of natural interferon mixture in therapeutic concentration.

The antiviral activity of the natural mixture of the 23 interferon alpha subtypes is mediated by binding each subtype to their receptors on the target cell surface in a naturally timed sequence order thus ensuring the desired effect. Some or all of the following interferon actions prevents the intracellular synthesis of viral proteins and nucleic acids:

  • Induction of 2'-5'-oligoadenylate synthetase, which converts ATP to 2'-5'-oligoadenylate, an activator of a latent endonuclease that hydrolyses viral mRNA,
  • Induction of a protein kinase, which specifically phosphorilates a protein synthesis initiating factor (eIF2), rendering it inactive, thus resulting in inhibiting protein synthesis,
  • Inhibition of viral adsorption, penetration, uncoating, assembly and release. Besides these direct antiviral effects, the immunostimulatory action of low dose ISMAFRON® is also contributing to sustained viral clearance.

The use of small dose ISMAFRON® is also accompanied by improvement of the quality of life of chronic virologic or oncologic patients as the sustained immune stimulatory cascade also initiates the release of several neurotropic substances participating in restoration of healthy psychological condition of the patients.

 Low dose ISMAFRON® antiviral therapy proved to be highly effective in the following diseases:

  • Acute hepatitis B, C, D and G
  • Chronic active hepatitis B and C
  • Cryoglobulinemia and membranoproliferative glomerulonephritis, as complications of HCV
  • Genital warts
  • Herpes zoster and Herpes simplex infections

Low dose ISMAFRON® anticancer therapy is also based on double action. Direct antitumor activity involves one or more of the mechanisms below:

  • Selective inhibition of cell proliferation in certain types of tumours,
  • Induction of apoptosis in malignant cells via at least three different mechanisms,
  • Inhibition of angiogenesis in solid tumours by blocking the production of angiogenetic cytokines (e.g. IL-8, bFGF),
  • Suppression of the activity of certain cellular oncogenes (e.g. c-myc, c-fos, etc.),
  • Inhibition of the c-ras oncogene transcription,
  • Neutralisation of the effect of growth factors.

ISMAFRON® also acts as anticancer agent by activating the natural defence mechanism against malignant neoplasms, enhancing the proliferation and differentiation of the elements of the cellular immune system, including NK-cells, macrophages, monocytes and helper and cytotoxic T-cells. These cells in turn act against the malignant cells directly by phagocytosis and cytotoxic activity, and indirectly by producing and releasing endogenous alpha, beta, gamma and omega interferons and other cytokines with antitumor activity (e.g. IL-2, IL-12, tumour necrosis factor-α, etc.). ISMAFRON® further augments the anticancer action of these immune elements via enhancing the expression of class I MHC molecules on the surface of tumour cells, facilitating their recognition and binding by the activated immune system elements.

High dose ISMAFRON® therapy in doses of 3-5 Million IU i.m. is based solely upon the direct antitumor effects described above. Note that at these doses ISMAFRON® is immunosuppressive and might cause leucopaenia and thrombocytopaenia.

ISMAFRON® is effective in the following malignant neoplasms:

  • AIDS-associated and sporadic Kaposi's sarcoma
  • Hairy cell leukaemia
  • Chronic myeloid leukaemia
  • Non-Hodgkin's lymphoma
  • Multiple myeloma
  • Renal cell carcinoma
  • Nasopharyngeal carcinoma
  • Bladder carcinoma
  • Ovarian carcinoma
  • other assorted solid tumours, particularly in metastatic cases.

Intramuscular administration of ISMAFRON® proved to be effective as post-operative adjuvant treatment in metastatic melanoma and carcinomas of the kidney, breast, prostate and others. It is also successful in treatment of basal and squamous cell carcinomas of the skin.

 Generally, the use of ISMAFRON® in combination with surgery and/or chemotherapy in assorted tumours increases the recovery rate and prolongs the survival period. In benign haemangiomas ISMAFRON® is capable of inducing regression in smaller doses than those recommended for other tumours.

The unique therapeutic superiority of ISMAFRON® is attributed to the following advantages:

  1. No anti-interferon antibodies formation occurs even in prolonged application over one year or more. Consequently no need arises for dose escalation; neither resistance develops against ISMAFRON® during the therapeutic course.
  2. There is no need to initiate high dose or escalating dose therapeutic regimens.
  3. ISMAFRON® is a natural human leukocyte interferon alpha mixture. Its use is safe and effective in children for short term as well as long term therapy.


<< THERAPEUTIC INDICATIONS >>

1. Viral infections:  

  • Acute hepatitis B, C, D, and G
  • Chronic active hepatitis B and C
  • Genital warts (condylomas)
  • Herpes zoster
  • Herpes simplex 1 and 2

2-Malignant neoplasms:

  • AIDS-associated and sporadic Kaposi's sarcoma
  • Hairy cell leukaemia
  • Chronic myeloid leukaemia
  • Non-Hodgkin's lymphoma
  • Multiple myeloma
  • Renal cell carcinoma
  • Osteogenic sarcoma
  • Malignant melanoma
  • Metastatic breastcancer
  • bladder cancer and other solid tumours.

3. Vascular tumours:

  • Haemangioma


<< DOSAGE AND ROUTE OF ADMINISTRATION >>

ISMAFRON® should always be used as intramuscular injection. It never should be applied intravenously! Recommended therapeutic doses of ISMAFRON® are relatively smaller in comparison to those using other brands of interferon alpha preparations. This is due to the fact that ISMAFRON® is a natural human leukocyte interferon alpha mixture containing all the natural subtypes in optimal proportions. Since it does not induce antibodies, its prolonged use in smaller, yet effective doses is well tolerated, and in the meantime, it will not lose its therapeutic potential.


<< RECOMMENDED DOSES >>

1. In viral infections:

  • Acute hepatitis C infection:One Million IU ISMAFRON® 3 times/week i.m. injection for 6-24 weeks. The duration depends on PCR, liver biopsy and transaminases levels.
  • Chronic hepatitis B and C: One Million IU ISMAFRON® 3 times/week i.m. injection for 6-24 weeks. Monitoring the viral nucleic acid level by PCR during the treatment and liver biopsy are essential to follow up the virologic response and the efficacy in reduction of hepatic fibrosis and inflammation scores.
  • Hepatitis D: Although optimal recommended dosage of ISMAFRON® in hepatitis D is not yet properly established, an elevated dosage (over 1 Million IU 3 times weekly) or daily application is only justified, if the usual doses applied in other types of hepatitis do not induce a beneficial response after 6 weeks of application.
  • Condyloma acuminata, Genital warts: One Million IU ISMAFRON® in 0.1 ml water for intralesional injection (use fine 30 gauge needle) 2 times weekly for 4 weeks. Up to 5 lesions may be treated simultaneously. Large lesions can be treated by multiple injections. Up to 15 Million IU of ISMAFRON® may be used weekly.
  • Herpes zoster, Herpes simplex: One Million IU ISMAFRON® 3 times/week i.m. injection for 2-4 weeks.

2. In malignant neoplasms:

  • Hairy cell leukaemia: Combination with 2'-chlorodeoxyadenosine (cladribine) and deoxycoformycin is more durable regimen. Three Million IU daily i.m. for 12-14 weeks, then 1 Million IU 3 times/week as maintenance therapy. S.C. administration is preferred only for thrombocytopaenic patients or patients at risk of bleeding.
  • AIDS-related Kaposi's sarcoma: ISMAFRON® monotherapy gives complete response in 25-50% of the cases. Low doses may effectively be combined with other anti-AIDS drugs as Zidovudine or Zalcitabine.
  • Multiple myeloma: One Million IU 3 times/week, i.m.
  • Chronic myeloid leukaemia: ISMAFRON® is very effective in CML patients in dosages of 3-6 Million IU daily to be reduced to one Million 3 times/week maintenance dose, once complete haematologic remission has been achieved.
  • Useful symptomatic achievement can be obtained in patients with T-cell cutaneous lymphomas and functional endocrine tumours with ISMAFRON®. It prolongs the duration of response when used in combination with chemotherapy.
  • High tumour burden non-Hodgkin''s lymphoma: One Million IU 3 times/week in combination with appropriate chemotherapy.
  • Waldenström's macroglobulinaemia: One Million IU 3 times/week in combination with appropriate chemotherapy.
  • Primary thrombocytopaenia: One Million IU 3 times/week in combination with hydroxyurea. The combination should be maintained until complete haematologic response is achieved, then ISMAFRON® monotherapy should be maintained in one Million IU doses 3 times weekly.

3-To be used as antiangiogenic drug:

  • Malignant melanoma and metastatic carcinomas: ISMAFRON® should be used postoperatively in combination with appropriate chemotherapy.
  • Haemangioma in infancy: In infancy and childhood benign haemangioma ISMAFRON® is recommended in reduced dose of 0.5 Million IU/m2 body surface daily until therapy success, then a 3 times weekly maintenance therapy should be applied in the same dosage for 3-12 months to prevent tumour recurrence.

4-Paediatric doses: In infants and children the recommended ISMAFRON® doses are 0.5-1 Million IU/m2 body surface either daily or 3 times weekly, depending upon the adult therapeutic protocol of the corresponding disease.


<< MODE OF ADMINISTRATION >>

Reconstitute the content of the vial in 3 ml water for injection for the 3 Million IU vials, in 1 ml for the 1 Million IU vials (finally 1 ml of solution should contain 1 Million IU of ISMAFRON®). Inject ISMAFRON® intramuscularly or subcutaneously only for patients in risk of prolonged bleeding. Never apply ISMAFRON® intravenously! It is recommended to inject ISMAFRON® at bedtime to reduce the side effects and enhance its efficacy (as immune stimulation appears to be most effective at night rest time).



<< SIDE EFFECTS AND ADVERSE REACTIONS >>

ISMAFRON® is much better tolerated than other available brands of interferon alpha preparations. No intolerable or dose-reduction requiring side effects can be expected at the recommended doses. However fever, flu-like symptoms, pain, redness and swelling at the injection site might occur. Fever and myalgia can be reduced if paracetamol or similar suitable antipyretic is given preventively.
In the case of continued use transitory gastrointestinal symptoms, reversible weight loss or allopecia rarely might occur.
It is important to note, that in high doses more severe side effects (like depression, thyroid disorders, and lichen planus) might also develop.  These symptoms are similar to that of reported using any other brands of human alpha interferon, but using ISMAFRON® they are comparatively milder and more tolerable.



<< PRECAUTIONS >>

The use of other brands of interferon alpha preparations is contraindicated in patients with severe cardiac diseases, diabetic ketosis, coagulation disorders, autoimmune diseases and severe depression or debilitating conditions. Since ISMAFRON® could be used in comparatively smaller doses and is more physiologic, it can be used even in such patients, although only under strict medical supervision. Bedtime administration and preventive use of paracetamol or other recommended antipyretic will prevent or reduce the immediate side effects.

Although interferon alpha teratogenicity risk in pregnant patients is not known, and in spite of animal experiments, where 20-500 times higher doses of those regularly used apparently did not have any teratogenic effect on pregnant Rhesus monkeys, yet use of ISMAFRON® is advised to be postponed during pregnancy, unless absolutely indicated. In such cases small doses should be used. Although no data are known indicating such risk, breast-feeding is not advisable during use of ISMAFRON®, as it might interfere with normal thriving of the healthy infant.


<< CONTRAINDICATIONS >>

As all other interferon alpha preparations, ISMAFRON® should not be given intravenously. Although no hypersensitivity was reported to ISMAFRON®, in case it should occur, its use should be discontinued. ISMAFRON® use should be discontinued, if diabetes, thyroid disorders, lichen planus, or autoimmune disorders develop during its application.


<< INTERACTIONS >>

As all other alpha interferons, ISMAFRON® may affect the oxidative metabolism by reducing the activity of hepatic microsomal cytochrome P450 enzyme, reduction of the clearance of theophylline, and some antiviral drugs (e.g. Iododeoxyuridine, Acyclovir) and cytotoxic drugs (5'-fluorouracil, Adriamycin, etc.) may occur upon concomitant use of alpha interferons. Consequent relative overdosage of these drugs could precipitate augmentation of undesirable side effects and reduce the maximal tolerated doses of the drugs. The dosage of such drugs should be readjusted when concomitantly used with ISMAFRON® to avoid toxic manifestations. ISMAFRON® should never be used in combination with Adriamycin!


<< HANDLING INSTRUCTIONS >>

ISMAFRON® should be transported and stored at 2-8 C. Do not freeze! Protect from light! When dissolved, it should be stored at +4oC and should be utilised within one week.


<< WARNING >>
This drug should be used only upon medical prescription! During its use continuous medical surveillance is obligatory.


Manufactured by
ALPHA-CHEM
Advanced Pharmaceutical Industries S.A.E
(ACAPI)
Badr City, Third Industrial Zone, Cairo, EGYPT

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