RONCOLEUKIN ®

International unlicensed name:

Recombinant human INTERLEUKIN-2

Approved by order № 249 of Ministry of Health, Russian Federation, August 31, 1995,

Registration Certificate № ЛС- 001810

DRUG FORMULATION

Roncoleukin ® - recombinant interleukin-2 (rIL-2) - is a structural and functional analogue of endogenous human interleukin-2. Roncoleukin ® is isolated from cells of non-pathogenic brewer’s yeast Saccharomyces cerevisiae containing gene of human interleukin-2 (IL-2).

DOSAGE

Roncoleukin a is produced in a form of solution, final volume 1ml, in the following doses: 1.0 mg (1000000 IU), 0.5 mg (500000 IU), 0.25 mg (250000 IU), 5 ampoules in the box containing polymer bearing brass for fixation of ampoules.

COMPOSITION

recombinant interleukin-2 (rIL-2);
sodium dodecyl sulphate (SDS) – solubilizer;
D-mannit (stabilizer);
dithio treitol (reduction agent).

PHARMACOLOGICAL GROUP

Pharmacological group – 6.5. Immune modulators.

BIOLOGICAL PROPERTIES

Roncoleukin ®restores synthesis of endogenous interleukin-2 by activated CD4+ and CD8+ cells. Compensates deficit of endogenous of interleukin-2.
Roncoleukin ® acts on cells-targets: NK-cells, T-helpers, cytotoxic T-lymphocytes, B-lymphocytes, monocytes, being for them factor of activation, proliferation and differentiation.

Roncoleukin ® regulates Th1/Th2 balance.
Roncoleukin ® abolishes immune tolerance, preserves activated T-cells from untimely death.
Roncoleukin ® performs regulation and cooperation of mechanisms of inherent and acquired immunity.
Roncoleukin ® stimulates realization of antigen-dependent and independent immune response, acts on cellular and humoral immunity.

Roncoleukin ® possesses anti-neoplastic and anti-infectious activity, activates processes of tissue reparation and regeneration, promotes adequate interaction of immune, endocrine and nervous systems.

PHARMACOKYNETICS

At intravenous infusion it has been noticed quick growth of IL-2 concentration in plasma, its half-life period in serum is 5-7 minutes. In subcutaneous infusion the half-life period is increased three times. Elimination is performed through kidneys by proteolysis until separate amino acids.

METHODS OF USE AND DOSAGES

Roncoleukin a is administered intravenously, by drops, once per day in single dose 0,25 to 2 mg, during 4-6 hours (velocity 1-2 ml/min). For preparation of infusion solution the content of ampoule is transferred into 400 ml of isotonic solution of sodium chloride (at limitation of solution volume – 200 ml). To prevent the loss of bioactivity of Roncoleukin a it is desirable to add 10% solution of human serum albumin at the following quantity:

8 ml, if ampoule containing 1 mg of rIL-2 (1000000 IU) is used;

6 ml, if ampoule containing 0.5 mg of rIL-2 (500000 IU) is used;

4 ml, if ampoule containing 0.25 mg of rIL-2 (250000 IU) is used.

Subcutaneously Roncoleukin a is injected once per day in dosage 0,25-0,5 mg. For preparation of solution for injection the content of ampoule is dissolved in 1,5-2 ml of water for injections. It is advisable to perform subcutaneous injections in different points, in one point not more than 0,25 mg of Roncoleukin a can be injected.
Into cavity of maxillary or frontal sinus Roncoleukin a is administered during puncture, dosage 0,25-0,5 mg of drug dissolved in 5 ml of water for injections or isotonic physiological solution of sodium chloride (duration of exposition is 2-3 hours).
Into cavity of urine bladder 1,0 mg of Roncoleukin a dissolved in 50 ml of physiological solution of sodium chloride (duration of exposition is 3 hours).
Roncoleukin a may be administered orally in dose 1-2 mg dissolved in 15-20 ml of distilled water.

CONTAINDICATIONS

Acute and decompensated chronic cardiac insufficiency, respiratory and renal insufficiency, disseminated intravascular coagulation (DIC-syndrome), non-sanitary purulent site, non-arrested infectious-toxic shock, cerebral brain metastases, pregnancy, allergy on yeast, individual intolerance of the drug.

SIDE EFFECTS

The experience of use of Roncoleukin a provides data on its good tolerability. Noticed by some patients short fever-like syndrome is the consequence of activation process of immune system and, usually, does not demand treatment. Antipyretic remedies are used if fever appears.

INTERACTION WITH MEDICINAL MEANS

It is prohibited to mix Roncoleukin a with other drugs in one solution.
If the methods of efferent therapy are used it is recommended to administer Roncoleukin a after mentioned procedures.

Valid for 2 years.

DIRECTIONS FOR USE

Prophylaxis and compensation of immune deficiency status:

Surgery: sepsis, peritonitis, pancreatitis, osteomielitis, wounds and trauma, burns, abscess and phlegmon, diabetic foot, correction of secondary immune deficiency after operations.

Internal diseases: pneumonia, bronchial asthma, stomach ulcer, pyelonephritis.

Phthisiology: tuberculosis.

Infectious diseases: HIV-infection, hepatitis C, herpes virus infection, hemorrhagic fever with renal syndrome, pseudotuberculosis, brucellosis, erysipelas, borreliosis, tick-borne encephalitis, meningitis.

Skin and venereal diseases: chlamidiosis, micoplasmosis, chronic prostatitis, furunculosis, persistent pyodermia, atopic dermatitis.

Gynecology: endometritis, endomeriosis, secondary sterility.

Neurology: multiple sclerosis.

Cardiology: infectious endocarditis.

Otolaryngology: purulent sinusitis, otitis.

Oncology: renal cell cancer, urine bladder cancer, colorectal cancer, melanoma, uveal melanoma, glyoblastoma, metastatic pleuritis, prevention of development and correction of lymphopenia in operation and radial and chemo therapies.

SURGERY

SEPSIS

According to data of trial performed by GCP (2003-2005) use of Roncoleukin a in complex treatment of sepsis decreases 28-days lethality two times (24,4% - with Roncoleukin a , 42,2% - placebo), reliably reduces duration of treatment, decreases average points of condition’s severity by APACHE and SAPS, declines severity of manifestation of endotoxicosis, decreases needs in anti-bacterial preparations.

Direction for use:

lymphopenia – decrease of absolute (less than 1,4 x 10 9 cells/l) and/or relative quantity of lymphocytes in peripheral blood;
decreased absolute quantity of CD3-positive lymphocytes in peripheral blood.

Scheme of use:

From 2 to 6 infusions with a time interval 48 hours. More than 2 infusions must be performed if lymphopenia lasts.

PERITONITIS

Use of Roncoleukin a reliably decreases integral points of condition’s severity by APACHE, number of complications in post-operational period, level of lethality, shorten period of hospitalization of patients with positive outcome.

Scheme of use:

2 intravenous infusions (dose 0,25-0,5 mg) with a time interval 48 hours.

ACUTE PANCREATITIS.

Inclusion of Roncoleukin a in complex treatment of acute pancreatitis (AP) reliably decreases lethality, frequency of development of purulent complications, sepsis, reliably increases probability of resorption of infiltrate, shorten cost and period of treatment of patients with positive outcome.

Scheme of use:

fermentative period: one intravenous infusion (dose 0,25-0,5 mg);

peripancreatic infiltration: 2 intravenous or subcutaneous infusions in dose 0,25 mg if body weight is less than 70 kg and 0,5 mg if body weight is more than 70 kg on 6-7 and 8-9 days from the onset of AP;

purulent complications of acute pancreatitis: 2-5 intravenous infusions in dose 0,25-1,0 mg every 24-48 hours; immune therapy is performed until restoration of indices of clinical blood test and formula of leucocytes.

SEVERE WOUND AND TRAUMA

Administration of Roncoleukin ® in early post-shock period reliably decreases lethality, frequency of development of severe sepsis, specific weight of severe infectious-inflammatory complications (first of all, pneumonia and sepsis); shorten period of hospitalization of patients with positive outcome.

Scheme of use:

early post-shock period: 2 intravenous infusions (dose 0,5 mg) on 2-3 and 4-5 days from the moment of trauma or wound;

purulent complications, post-trauma sepsis: see scheme used for treatment of sepsis.

BURN

Use of Roncoleukin ® provides quick positive dynamics of burn disease: decreases symptoms of intoxication, normalizes temperature curve, reliably improves wound condition, accelerates epithelization and healing, prevents development of severe infectious complications, shorten period of anti-bacterial therapy.

Scheme of use:

2-3 intravenous infusions (dose 0,5 mg) with a time interval 2-4 days during periods of toxemia and septic toxemia.

CHRONIC OSTEOMIELITIS

Introduction of Roncoleukin ® in complex therapy of chronic osteomielitis leads to quick liquidation of purulent process in bones, acceleration of processes of reparation of post-operational wound, decrease of probability of relapse of the disease.

Scheme of use:

2-3 intravenous infusions (dose 0,5 mg): one day prior operation and on second and third day post operation.

DIABETIC FOOT

Therapy by Roncoleukin ® reliably decreases probability of relapses of pyo-necrotic processes that lead to repeated hospitalization, increases percentage of patients possessing supportive function of lower extremity, reliably decreases amount of amputations on the level of thigh.

Scheme of use:

2-3 intravenous or endolymphatic infusions (dose 0,5 mg) with a time interval 3 days;

pre-operational preparation: Roncoleukin ® is infused once in dose 0,5 mg 2-4 days before operation.

PROPHYLAXIS OF POST-OPERATIONAL INFECTIOUS COMPLICATIONS

Prophylaxis with Roncoleukin ® grades consequences of surgical stress and reliably decreases frequency of post-operational infectious complications.

Scheme of use:

scheme 1: one infusion of 0,5 mg (intravenous or subcutaneous) 1-4 days before operation;

scheme 2: infusions of 0,5 mg (intravenous or subcutaneous) on 2 and 5 days of post-operational period.

INTERNAL DISEASES

PNEUMONIA

Introduction of Roncoleukin ® in complex treatment of pneumonia is accompanied by decrease of degree of intoxication, shortening of duration of fever period, significant decrease of probability of chronic process and relapse.

Well-timed introduction of Roncoleukin ® in complex of treatment of cerebral stroke shorten probability of development of pneumonia.

Directions for use :

severe pneumonia
atypical forms of pneumonia
pneumonia in elderly patients
hospital acquired pneumonia

Scheme of use:

in the phase of stabilization of infiltration: 2 up to 5 intravenous infusions (dose 0,5 mg) with a time interval 48-72 hours on 7-9 day of the onset of the disease;

in cerebral stroke: starting from fifth day of cerebral stroke – 2 subcutaneous injections (dose 0,5 mg) into external surface of healthy upper arm with a time interval 2-3 days.

BRONCHIAL ASTHMA

Therapy by Roncoleukin ® in complex treatment of bronchial asthma leads to decrease of IgE-mediated activity of immune inflammation in bronchus and let to lower doses of glucocortical steroids in hormone-dependent patients (including steroid-resistant patients).

Directions for use :

hormone-dependent bronchial asthma

Scheme of use:

2-3 intravenous infusions (dose 0,5 -1,0 mg) with a time interval 48 hours simultaneously with standard anti-inflammatory and broncholytic therapy; such a course is repeated every 6-12 months.

STOMACH ULCER

Systemic and local use of Roncoleukin ® leads to healing of ulcer process in duodenum, accelerates process of treatment, decreases frequency of relapses and leads to elimination of Helicobacter pylori without use of anti-bacterial drugs.

Scheme of use:

3-5 intravenous infusions (dose 0,5 mg) with a time interval 72 hours: 0,1 mg – para uceral injection into submucous membrane in 4-6 points; 0,4 mg - simultaneous intravenous infusion.

PYELONEPHRITIS

Inclusion of Roncoleukin ® in complex treatment of pyelonephritis leads to acceleration of elimination of pathogen, quick shortening of major clinical symptoms, significant shorten period of hospitalization of patients with positive outcome, reliable decrease of relapse cases.

Directions for use :

acute pyelonephritis;
chronic pyelonephritis, including those on the background of urolithiasis.

Scheme of use:

acute pyelonephritis: 3 intravenous infusions (dose 0,5 mg) during first 10 days of the disease with a time period 48 hours (no albumin should be added into the infusion solution);

chronic pyelonephritis: 4-5 infusions (dose 0,5 mg) with a time period 48 hours (no albumin should be added into the infusion solution).

PHTHSIOLOGY

PROGRESSIVE TUBERCULOSIS

Use of Roncoleukin ® on the background of performed polychemotherapy leads to positive clinical effect in treatment of severe and chemo-resistant tuberculosis.

In infiltrative tuberculosis (IT) Roncoleukin ® causes discontinuation of bacterial discharge and closing of cavities of desintergration.

In fibrous-cavernous tuberculosis (FCT) Roncoleukin ® leads to stabilization of process, closing of cavities of disintegration, promotes continuation of bacterial discharge, reduce frequency of post-operational specific pleural pulmonary complications.

Directions for use :

progressive tuberculosis;
severe and chemo resistant tuberculosis;
pre-operational preparation.

Scheme of use:

one-sided FCT: 3 intravenous infusions (dose 1,0 mg) with a time period 48 hours;

disseminated double-sided FCT: 7 intravenous infusions (dose 1,0 mg) during 3 weeks according to the following scheme: first week – 3 infusion with a time period 48 hours; second and third week - 2 infusions per week;

IT in phase of disintegration and semination: 3 intravenous infusions (dose 0,5 mg) with a time period 48 hours.

For prescription of immune therapy the deficit of body mass of patient should not be more than 30%.

INFECTIOUS DISEASES

HIV-INFECTION

Roncoleukin ® decreases amount of catarrhal diseases and opportunistic infections, prolongs periods of remission, improves quality of life of patients and tolerance of anti-retroviral therapy.

Directions for use :

appearance of signs of secondary immune deficiency;
decrease of CD4+ content in blood lower than 500 cells/?l;
pre-operational preparation for planned operations;
beginning of anti-retroviral therapy.

Scheme of use:

if count CD4+ 300 cells/?l and higher: during one year every 8 weeks: one subcutaneous injection per day (dose 0,5 mg) or two subcutaneous injections per day (dose 0,25 mg) every day during 5 days (course dose – 2,5 mg); for convenience of patient it is possible to inject Roncoleukin ® with an interval 24 hours, course dose should not be changed;

if count CD4+ less than 300 cells/?l: during one year every 8 weeks: one intravenous infusion per day (dose 1,0 mg) or two subcutaneous injections per day (dose 0,5 mg) every day during 5 days (course dose – 5,0 mg).

CHRONIC HEPATITIS C

Therapy by Roncoleukin ® provides compensation of immune deficiency, shortening of inflammatory process in liver and improvement of quality of life.

Directions for use :

chronic hepatitis C without signs of liver cirrhosis;
contra-indications to interferon therapy.

Scheme of use:

scheme 1: 2 intravenous infusions (dose 0,5 mg) per week during 8-12 weeks;

scheme 2: 3 intravenous infusions (dose 0,5 mg) per week during 2 weeks, then 3 subcutaneous injection per week during 6 weeks.

At the present time optimal schemes of treatment of chronic hepatitis C are evaluated.

HERPESVIRUS INFECTIONS

Use of Roncoleukin ® leads to reliable shortening of period of the disease, prolongation of remission period and relief of courses of recurrent cases.

Directions for use :

often recurrent herpes simplex;
genital herpes;
generalized herpes;
herpes type 6;
generalized and bullous forms of chicken pox;
cytomegalovirus infection.

Scheme of use:

2 to 5 intravenous infusions or subcutaneous injections (dose 0,5 – 1,0 mg) every day or every 48 hours on the background of anti-viral treatment.

HEMORRHAGIC FEVER WITH RENAL SYNDROME

Introduction of Roncoleukin ® in complex treatment of patients with severe forms and middle degree of severity of HFRS reliably shorten duration of oliguria and duration of pain syndrome, reliably decreases level of creatinine and urea in blood, lower cytolysis.

Scheme of use:

2 and more intravenous infusions (dose 0,5 mg) every 48 hours in early (first 10 days) stage of the disease on the background of standard pathogenic therapy.

PSEUDOTUBERCULOSIS

Inclusion of Roncoleukin ® in complex treatment of pseudotuberculosis provides quick shortening of major clinical symptoms, shortening of duration of intoxication and fever, decreases frequency of recurrent cases of the disease.

Directions for use :

generalized forms of acute pseudotuberculosis;
protracted and recurrent course of pseudotuberculosis with acute conditions;
erythema nodosum.

Scheme of use:

2 intravenous infusions every 48 hours: children under 7 - dose 0,25 mg, older than 7 and adults – dose 0,5 mg.

CHRONIC BRUCELLOSIS

Introduction of Roncoleukin ® in complex treatment of chronic brucellosis provides quick shortening of major clinical symptoms, decreases probability of recurrence of the disease; in osteomyelitis of brucellous etiology use of Roncoleukin ® let to avoid operation.

Directions for use :

chronic brucellosis with any furnace signs;
osteomyelitis of brucellous etiology.

Scheme of use:

subcompensated chronic brucellosis with 2-3 nidus of infection: 3 - 5 intravenous infusions or subcutaneous injections (dose 0,5 mg) every 48-72 hours;

decompensated chronic brucellosis with many furnace signs: up to 10 intravenous infusions or subcutaneous injections (dose 0,5 mg) every 48-72 hours.

Roncoleukin ® is prescribed simultaneously or 5-7 days after beginning of anti-bacterial therapy.

ERYSIPELAS

Therapy by Roncoleukin ® promotes disappearance of symptoms of intoxication, normalizes body temperature and reduces signs of local inflammation; prolongs relapse-free period .

Directions for use :

primary and recurrent forms of erythremic, erythremic-bullous and bullous-hemorrhagic erysipelas.

Scheme of use:

1-2 intravenous infusions (dose 0,5 mg) every 24-48 hours.

VIRAL MENINGITIS

Use of Roncoleukin ® in severe and average forms of viral meningitis shorten duration of symptoms of intoxication, reliably decreases risk of development of residual events in nervous system.

Scheme of use:

1-3 intravenous infusions every 48 hours on the background of complex treatment on 1-5 days of the disease: children under 7 - dose 0,1 mg, older than 7 and adults – dose 0,25 mg.

SKIN AND VENERAL DISEASES

URINO-GENITAL CHLAMIDIOSIS

Use of Roncoleukin ® shorten course of therapy and frequency of relapses.

Scheme of use:

scheme 1: 5 intravenous infusions (dose 0,5 mg) with a time period three days;

scheme 2: 10 subcutaneous injections (dose 0,25 mg) every 48 hours with a combination of everyday instillations of 0,05 mg of Roncoleukin ® into urethra.

URINO-GENITAL MICOPLASMOSIS

Use of Roncoleukin ® shorten course of therapy, sanitizes nidus of secondary infection, accelerates healing of cervical erosion and resolution of commissure in pelvis minor.

Scheme of use:

scheme 1: 5 subcutaneous injections (dose 0,5 mg) every 48 hours with a combination of etiotropic therapy;

scheme 2: 3 paracervical injections in 4 points (dose 0,25 mg dissolved in 5 ml of physiological solution) with time interval 72 hours; it is recommended to prescribe etiotropic therapy 48 hours after the end of immune therapy.

CHRONIC PROSTATITIS

Use of Roncoleukin ® on the background of standard therapy leads to quick sanitation and clinical recovery.

Scheme of use:

2-3 intravenous infusions (dose 0,5 mg) with a 2-3 days interval simultaneously with the beginning of standard treatment course.

RECURRENT FURUNCULOSIS

Addition of Roncoleukin ® to complex therapy leads to quick clinical recovery and reliable prevention of recurrence of the disease.

Scheme of use:

3 intravenous infusions (dose 0,5 mg) with a time interval 3 days.

ATOPIC DERMATITIS

Monotherapy by Roncoleukin ® reliably shorten duration of exacerbations, prolongs course of remission, decreases risk of development of drug allergy.

Scheme of use:

2-5 intravenous infusions (dose 0,5 mg) with a time interval 2-3 days.

GYNAECOLOGY

ENDOMETRITIS

Prescription of Roncoleukin ® in purulent complications in post-partum period promotes quick decrease of degree of intoxication, disappearance of signs of inflammation, shorten duration of stay in hospital and let to restrict use of antibiotics.

Scheme of use:

1-2 intravenous infusions (dose 0,5 -1,0mg) every 48 hours starting from 3-5 post-partum day. Use of Roncoleukin ® is compatible with breastfeeding.

ENDOMETRIOSIS

Addition of Roncoleukin ® to complex therapy of endometriosis leads to normalization of menstrual cycle, discontinuation of pain syndrome and dyspareunia, restoration of reproductive function.

Scheme of use:

3 intravenous infusions (dose 0,5 mg): in day of operation, on 3 rd and 5 th day of post-operational period.

NEUROLOGY

REMITTENT MULTIPLE SCLEROSIS

Monotherapy by Roncoleukin ® shorten exacerbation of the disease and treatment course in hospital, prolongs period of remission.

Scheme of use:

2 intravenous infusions (dose 1,0 mg) once per week during exacerbation period.

OTOLARINGOLOGY

PURULENT SINUSITIS

Use of Roncoleukin ® in regiment of monotherapy leads to quick clinical recovery, decreases risk of development of complications, accelerates period of purification of sinus.

Directions for use :

frequent and long time sick patients;
intolerance of antibiotics;
ineffective antibacterial treatment.

Scheme of use:

into cavity of sinus: 1 infusion of 0,25-0,5 mg dissolved in 5 ml of physiological solution; after exposition of the drug during 2-3 hours cavity of sinus must be washed by physiological solution. According to clinical indications it is possible to repeat infusion after 1-2 days.

ONCOLOGY

Roncoleukin ® is used as major component of combined treatment of some tumors: renal cell cancer, urine bladder cancer, metastatic and uveal melanoma, colorectal cancer, melanoma, glyoblastoma.

For prevention of beginning and correction of lymphopenia it is necessary to use Roncoleukin ® before and after operation, during radiotherapy and chemotherapy.

Introduction of Roncoleukin ® in scheme of treatment of oncological patients leads to decrease of frequency of metastasis, improvement of quality and duration of life of patients.

RENAL CELL CANCER

Scheme of use:

3 intravenous infusions (dose 2,0 mg) per week during 3 weeks in combination with recombinant interferon and drugs from fluoropyrimidine group (5-fluorouracil, Kseloda). The course has to be repeated 3 weeks later.

URINE BLADDER TUMORS

Directions for use :

superficial urine bladder cancer
invasive forms of urine bladder cancer.

Scheme of use:

superficial urine bladder cancer: intravesically (dose 1,0 mg dissolved in 50,0 ml of physiological solution) twice a day 4 days in a row, interval between instillations - 3 hours; course of immune therapy must be performed after transurethral resection in adjuvant regiment once per month during 5-6 months.

Invasive forms of urine bladder cancer: intravesically (dose 1,0 mg dissolved in 20,0 ml of physiological solution) twice a day 5 days in a row, interval between instillations - 3 hours; course of immune therapy must be performed once per month in an interval between 15 th and 22 nd days of course of poly chemotherapy according to scheme M-VAC.

GLYOBLASTOMA

Scheme of use:

1,0 mg of Roncoleukin ® per day, course dose – 10-40 mg (in complex with interferon-? 2b, interferon-?, LAK-cells).

MELANOMA

Scheme of use:

scheme 1: 5 intravenous infusions (dose 1,5 mg) every 48 hours in complex with dakarbazine, bleomicine, vinkristin, cisplatin, reaferon.

scheme 2: 5 intravenous infusions (dose 1,5 mg) every 48 hours in complex with cisplatin and reaferon.

Total course consists of 4-6 cycles with an interval between cycles 3-4 weeks.

UVEAL MELANOMA

Scheme of use:

5 intravenous infusions (dose 1,0 mg) every 48 hours in complex scheme of treatment beginning from the day of enucleation.

Research and Production Company BIOTECH, Ltd