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Instruction for use: Intron A
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Dosage form: Solution for intravenous and subcutaneous administration
Active substance: Interferonum alpha-2b
ATX
L03AB01 Interferon alfa
Pharmacological groups:
Antiviral drugs (excluding HIV)
Interferons
The nosological classification (ICD-10)
B18.0 Chronic viral hepatitis B with delta-agent: Chronic viral hepatitis B; Chronic active hepatitis B; Chronic viral hepatitis B; Chronic hepatitis B HBeAg-positive
B18.2 Chronic viral hepatitis C: Hepatitis C; Recurrence of chronic hepatitis C; Chronic active hepatitis C; Chronic viral hepatitis C; Chronic hepatitis C without cirrhosis; Chronic hepatitis C with compensated cirrhosis; Chronic hepatitis C
B21.0 HIV disease, with manifestations of Kaposi's sarcoma: Kaposi angioreticulosis; Endotheliosarcoma; Kaposi angiosarcomatosis; Kaposi hemangiosarcoma; Kaposi hemorrhagic sarcoma; Kaposi multiple hemorrhagic sarcoma; Kaposi telangiectatic pseudo-sarcoma; Kaposi's Sarcoma in AIDS; Kaposi's sarcoma on AIDS; Kaposi's sarcoma on the background of AIDS
C43 Malignant melanoma of skin: Malignant melanoma; Localized malignant melanoma; Localized form of malignant melanoma; Melanoma; Melanoma after surgical resection; Metastatic melanoma; Common metastatic malignant melanoma; Metastasizing form of malignant melanoma; Disseminated malignant melanoma
C46 Kaposi's sarcoma: Kaposi angioreticulosis; Endotheliosarcoma; Kaposi angiosarcomatosis; Kaposi hemangiosarcoma; Kaposi haemorrhagic sarcoma; Kaposi multiple hemorrhagic sarcoma; Kaposi telangiectatic pseudo-sarcoma; Kaposi's Sarcoma in AIDS patients; Varioleiform pustulosis of Kaposi; Kaposi's Sarcoma in AIDS; Kaposi's sarcoma on AIDS; Kaposi's sarcoma on the background of AIDS; AIDS-associated Kaposi's sarcoma
C64 Malignant neoplasm of kidney, other than renal pelvis: Wilms tumor; Kidney Cancer; Metastatic Renal Cell Carcinoma; Renal carcinoma; Inoperable kidney carcinomas; Metastatic kidney carcinoma; Metastatic Renal Cell Carcinoma; Wilms tumor; Wilms swelling; Adenomyosarcoma; Adenomyocystosarcoma; Adenosarcoma of the kidney; Kidney Cancer; Common renal cell carcinoma; Nephroblastoma; Nephroma; Embryonal nephroma; Recurrent carcinoma of the kidney; Birch-Hirschfeld Tumor; Common renal cell carcinoma; Tumors of the kidney
C77 Secondary and unspecified malignant neoplasm of lymph nodes: Metastases in retroperitoneal lymph nodes; Metastases in the lymph nodes
C78.7 Secondary malignant neoplasm of the liver: Metastasis in the liver; Metastatic liver disease; Metastatic liver tumors
C82 Follicular [nodular] non-Hodgkin's lymphoma: Brill-Simmers disease; Malignant lymphoma; Hepatic Lymphoma; Recurrent non-Hodgkin's lymphoma; Follicular B-cell non-Hodgkin's lymphoma; Follicular lymphoma; Lymphoma of the liver
C85.0 Lymphosarcoma
C91.4 Hairy-cell leucosis
C92.1 Chronic myeloid leukemia: Myeloleukemia chronic; Myeloid leukemia chronic Ph-negative; Exacerbation of chronic myelogenous leukemia; The subleukemic form of chronic myelogenous leukemia; Chronic leukemia myeloid leukemia; Chronic myeloblastic leukemia; Chronic myelogenous leukemia; Chronic myelomonocytic leukemia; Idiopathic hypereosinophilic syndrome
D09 In situ carcinoma of other and unspecified locations
J38.1 Polyp of the vocal fold and larynx: Juvenile papillomas of the larynx; Laryngopapillomatosis; Respiratory papillomatosis of the larynx; Air cysts of the larynx; Polyps of vocal cords
Composition and release form
Solution for injection 1 fl.
Recombinant interferon alpha-2b 10 million IU; 18 million IU; 25 million IU
Auxiliary substances: sodium hydrophosphate anhydrous; Sodium dihydrogen phosphate monohydrate; Disodium edetate; sodium chloride; Meta-cresol (preservative); Polysorbate 80; water for injections
In vials with a volume of 1 ml / 10 million IU (1 dose), 3 ml / 18 million IU (6 doses of 3 million IU), 2.5 ml / 25 million IU (5 doses of 5 million IU); In a pack of cardboard 1 bottle.
Solution for injection 1 syringe pen
Recombinant interferon alpha-2b 18 million IU; 30 million IU; 60 million IU
Auxiliary substances: sodium hydrophosphate anhydrous; Sodium dihydrogen phosphate monohydrate; Disodium edetate; sodium chloride; Meta-cresol (preservative); Polysorbate 80; water for injections
In 1.2 ml syringes (6 doses of 3 million IU - 18 million IU, 6 doses of 5 million IU - 30 million IU, 6 doses of 10 million IU - 60 million IU); Complete with 6 needles and 6 napkins in a plastic pallet; In a pack of cardboard 1 set.
Description of dosage form
Clear colorless solution.
Characteristic
The preparation is a water-soluble globular protein with a molecular mass of about 19,300 daltons, synthesized by a strain of Escherichia coli containing a plasmid hybrid obtained by genetic engineering, into the genetic apparatus of which the human leukocyte interferon alpha-2β gene is inserted.
Pharmachologic effect
Mode of action - Antiviral, immunomodulating, antitumor.
Pharmacological and immunological properties
Interferons have an effect on cells by binding to specific receptors on their surface.
The results of several studies suggest that after binding to the cell membrane interferon causes a complex sequence of intracellular reactions, including. Induction of certain enzymes. It is believed that at least partially these processes determine the cellular effects of interferon, including suppression of viral replication in infected cells, inhibition of cell proliferation, and immunomodulatory properties of interferon-enhancing phagocytic activity of macrophages and increasing specific cytotoxicity of lymphocytes relative to "target cells." These effects determine the therapeutic effect of interferon.
Recombinant interferon alpha-2β has an antiproliferative effect on both human and animal cell cultures and against human and animal tumor xenografts. A significant immunomodulatory activity of recombinant interferon alpha-2β in vitro is shown. Recombinant interferon alpha-2β also inhibits viral replication in vitro and in vivo
Pharmacodynamics
Although the exact mechanism of antiviral action of recombinant interferon alfa-2β is not known, it is established that it disrupts the metabolism of the cell into which the virus has penetrated. This leads to suppression of viral replication, and in cases where replication still occurs, virions with a damaged genome are unable to leave the cell.
Chronic hepatitis B. Clinical studies of the use of interferon alpha-2β for 4-6 months show that therapy can lead to the elimination of hepatitis B virus (HBV) DNA and an improvement in the histological pattern of the liver.
Chronic hepatitis C. The use of Intron® A as monotherapy or in combination with ribavirin was studied in 4 randomized phase III clinical trials in 2552 patients with chronic hepatitis C who had not previously received interferon therapy. The study compared the effectiveness of monotherapy or combination therapy with ribavirin. The effectiveness of therapy was determined on the basis of the lack of replication of the virus 6 months after the end of treatment.
All patients had chronic hepatitis C, confirmed by a positive polymerase chain reaction (PCR reaction of more than 100 copies / ml) on hepatitis C virus (HCV) RNA, liver biopsy data with histological confirmation of chronic hepatitis and no other cause for it, And increased ALT activity.
Intron ® A was given at a dose of 3 million IU 3 times a week as a monotherapy or in combination with ribavirin. Most patients received treatment for 1 year. All patients were observed for 6 months after the end of therapy to determine the duration of the preservation of the results. The data of these 2 studies are given in Table 1.
Combined therapy with ribavirin and Intronom ® A significantly increased the effectiveness of therapy in all subgroups of patients. The genotype of HCV and the amount of RNA of the virus before the start of therapy are prognostic factors. Improvement of the results with combined therapy is noted especially in patients who are difficult to treat (with genotype 1 of the virus and high content of HCV RNA in the blood serum).
Table 1
Number of patients who achieved a sustained virologic response (%) after a one-year course of treatment
| HCV genotype | I* (n=503) Ñ95-132/195-143 | I/R** (n=505) C95-132/I95-143 | I/R** (n=505) Ñ/198-580 |
| All genotypes | 16% | 41% | 47% |
| Genotype 1 | 9% | 29% | 33% |
| Genotype 1 (number of copies ≤2 million / ml) | 25% | 33% | 45% |
| Genotype 1 (number of copies> 2 million / ml) | 3% | 27% | 29% |
| Genotype 2/3 | 31% | 65% | 79% |
Strict adherence to the treatment regimen significantly improves the results of treatment. Regardless of the genotype of the virus, patients who received 80% or more of course therapy (ribavirin + Intron ® A) had better long-term results than patients who received less than 80% of course therapy (a sustained virologic response in 56% of cases compared with 36% According to the CI98 / 580 study).
Relapse treatment: 345 patients received Intron® A as monotherapy or in combination with ribavirin for recurrence. In this group of patients, the addition of ribavirin to Intron ® A caused a 10-fold increase in treatment effectiveness compared to Intronom® A monotherapy (48.6% and 4.7%), which was manifested by elimination of HCV RNA from serum (less than 100 copies / ml Carrying out a PCR reaction), reducing inflammation of the liver and normalizing ALT. And these results were preserved after 6 months after the end of therapy (stable virologic response).
Pharmacokinetics
The pharmacokinetics of Intron ® A have been studied in healthy volunteers with a single dose of 5 million IU / m 2 v / m, s / c and by intravenous infusion for 30 min. Mean concentrations of interferon in the serum were comparable after SC and I / m administration. At the same time, Cmax was reached after 3-12 hours; T1 / 2 both after IM and after SC administration was approximately 2-3 hours: the content of interferon after 16-24 hours in serum was not determined. Bioavailability of the drug with n / k introduction was 100%.
After intravenous administration, the concentration of interferon in the plasma reached the maximum values (135-273 IU / ml) at the end of the infusion, then decreased somewhat faster than after SC or IM injections, and was not determined 4 hours after the end of the infusion; T1 / 2 was about 2 hours.
The concentration of interferon in urine was below the determined value, regardless of the route of administration.
In patients who received Intron ® A during controlled clinical trials, interferon-neutralizing antibodies were determined. The incidence of their detection was 2.9% in patients who received Intronom ® A for cancer, and 6.2% for patients with chronic hepatitis. Antibody titers were low in almost all cases, and their detection was not associated with a decrease in the effectiveness of therapy or other autoimmune disorders.
Preclinical data on drug safety
Despite the fact that interferon is considered a species-specific substance, studies of its toxicity in animals have been conducted.
The introduction of human recombinant interferon alfa-2β for 3 months was not accompanied by signs of toxicity in mice, rats, rabbits. Administration of the drug to monkeys cynomolgus for 3 months daily at a dose of 20 · 106 IU / kg / day also did not lead to significant signs of toxicity. An increase in the dose in monkeys to 100 · 106 IU / kg / day for 3 months resulted in a toxic effect.
In studies using interferon in non-human primates, violations of the menstrual cycle were observed.
The results of studies of the effect of interferon alpha-2β on reproductive performance in animals indicate a teratogenic effect in rats and rabbits. The drug also does not affect the course of pregnancy, fetal development and reproductive function in the offspring of rats receiving interferon alfa-2β.
In studies conducted on rhesus macaques, it has been shown that the use of high doses (exceeding the recommended 90 and 180 times) of interferon alpha-2β causes abortion.
When carrying out appropriate studies, no mutagenic effect of interferon alpha-2β has been established.
Indication of the Intron A
Treatment of adults and children (from 1 year) with chronic hepatitis B with confirmed replication of the hepatitis B virus (the presence of HBV or HBeAg DNA in the blood serum) in combination with an increase in ALT activity in the blood plasma and histologically confirmed by an active inflammatory process and / or liver fibrosis;
Chronic hepatitis C:
- monotherapy or in combination with ribavirin in adult patients who have increased transaminase activity, there are no signs of decompensated liver function and HCV RNA or anti-HCV antibody (anti-HCV) in the blood serum is determined;
- in children (from 3 years old) with compensated liver disease who were not previously treated with interferon alpha-2β, and in adult patients with relapse after therapy with interferon alpha-2β (preferably in combination with ribavirin);
Treatment of adults and children from 1 year with papillomatosis of the larynx;
Treatment of hairy cell leukemia in adults in the form of monotherapy or in combination with ribavirin;
Chronic myelogenous leukemia (CML):
- monotherapy of adult patients with CML in the presence of the Philadelphia chromosome (Ph +) or translocation of bcr / abl (clinical data show that hematological remission and cytogenetic response (large / small) is achieved in most patients, with a large cytogenetic response determined as the amount of Ph + Cells in the bone marrow <34%, and small - from 34 to 90%);
- combined therapy in combination with cytarabine (during the first 12 months of treatment it can significantly increase the number of large cytogenetic responses and significantly increase the overall survival of patients compared with interferon alpha-2β monotherapy after 3 years of treatment);
Treatment of thrombocytosis in adult patients with CML (some effect);
As a supportive therapy for multiple myeloma in adult patients who achieved partial response (a 50% reduction in serum paraprotein level) after initial induction therapy (prolongs the plateau phase, but the effect of the drug on overall survival is not yet established);
Treatment of follicular lymphoma (in combination with adequate induction chemotherapy, for example, CHOP-regimen) with high tumor mass in adult patients with at least one of the signs - a large tumor size (> 7 cm), involvement of 3 or more lymph nodes (each> 3 Cm), general symptoms (weight loss more than 10%, fever over 38 ° C for more than 8 days, increased sweating at night), splenomegaly (the border of the spleen is beyond the navel), compression of important organs, or the onset Computer Sis syndrome, involvement of epidural space or orbital area, leukemia, significant effusion. The efficacy of Intronom® A therapy in patients with low-grade follicular non-Hodgkin's lymphomas and low tumor burden has not been established;
Treatment of patients with Kaposi's sarcoma on the background of AIDS in the absence of opportunistic infections (if the number of CD4 cells exceeds 250 / mm3);
Treatment of adult patients with progressive kidney cancer;
Treatment of carcinoid tumors in adult patients with lymph node involvement or with liver metastases and carcinoid syndrome;
Malignant melanoma - adjuvant therapy of adult patients operated on for a primary tumor, with a high risk of systemic relapse.
Contraindications
Hypersensitivity to any component of the drug;
Severe cardiovascular diseases (including heart failure in the stage of decompensation, recently suffered myocardial infarction, severe arrhythmia);
Expressed violations of the liver or kidney, incl. Caused by metastases, chronic hepatitis with cirrhosis of the liver in the stage of decompensation, chronic hepatitis in patients receiving or receiving immunosuppressants (except for a short-term course of GCS therapy), autoimmune hepatitis;
Epilepsy and other disorders of the central nervous system, mental illness and disorders in children and adolescents;
An autoimmune disease in the anamnesis;
Use of immunosuppressants after transplantation;
Thyroid disease in the event that it is not controlled by appropriate therapy;
Creatinine clearance below 50 ml / min - when administered in combination with ribavirin;
pregnancy;
Lactation period;
Appointment to men whose partners are pregnant.
With caution: mental illness in the anamnesis.
When prescribing Intron ® A in combination with ribavirin, contraindications in the ribavirin application should also be considered.
Application in pregnancy and breastfeeding
Clinical data on the use of interferon alfa-2β during pregnancy are absent.
In experimental animal studies, a toxic effect on reproductive performance has been identified. The significance of this data for a person is not known.
During pregnancy, Intron® A is used only when the expected benefit from therapy for the mother exceeds the potential risk to the fetus.
It is not known whether the components of Intron® A are excreted in breast milk.
Because of the possible risk of undesirable effects of the drug in infants who are breastfed, if the drug is needed, the mother should stop breastfeeding.
Side effects
In clinical trials conducted with a wide range of indications and with a large dose range (from 6 million IU / m2 per week - with hairy cell leukemia, up to 100 million IU / m2 per week - in melanoma), the most frequent adverse events were fever, fatigue, Headache, myalgia. Fever and fatigue passed 72 hours after discontinuation of the drug. Although fever may be one of the symptoms of influenza-like syndrome, often encountered in the treatment of interferons, a survey should be conducted in order to rule out other possible causes of persistent fever.
The following safety profile was obtained from 4 clinical trials in patients with chronic hepatitis C who received Intron ® A as monotherapy or in combination with ribavirin for 1 year. All patients received 3 million ME Intron® A 3 times a week.
Table 2 shows undesirable events with a frequency greater than or equal to 10% in patients previously untreated and receiving Intron® A (or Intron® A in combination with ribavirin) for 1 year. In general, these adverse events were mild or moderate.
Table 2
| Adverse events | Intron® À (n=806) | Intron® À + Ribavirin (n=1010) |
| Local Reactions | ||
| Inflammatory reactions at the site of administration | 9–16% | 6–17% |
| Other reactions at the site of administration | 5–8% | 3–36% |
| General reactions | ||
| Headache | 51–64% | 48–64% |
| Fatigue | 42–79% | 43–68% |
| Chills | 15–39% | 19–41% |
| Fever | 29–39% | 29–41% |
| Flu-like syndrome | 19–37% | 18–29% |
| Asthenia | 9–30% | 9–30% |
| Weight loss | 6–11% | 9–19% |
| Reactions from the digestive tract | ||
| Nausea | 18–31% | 25–44% |
| Anorexia | 14–19% | 19–26% |
| Diarrhea | 12–22% | 13–18% |
| Stomach ache | 9–17% | 9–14% |
| Vomiting | 3–10% | 6–10% |
| Reactions from the musculoskeletal system | ||
| Myalgia | 41–61% | 30–62% |
| Arthralgia | 25–31% | 21–29% |
| Pain in the bones and muscles | 15–20% | 11–20% |
| Reactions from the central nervous system | ||
| Depression | 16–36% | 25–34% |
| Irritability | 13–27% | 18–34% |
| Insomnia | 21–28% | 33–41% |
| Anxiety | 8–12% | 8–16% |
| Violation of the ability to concentrate | 8–14% | 9–21% |
| Emotional lability | 8–14% | 5–11% |
| Reactions from the skin | ||
| Alopecia | 22–31% | 26–32% |
| Itching | 6–9% | 18–37% |
| Dryness of the skin | 5–8% | 5–7% |
| Rash | 10–21% | 15–24% |
| Reactions from the respiratory system | ||
| Pharyngitis | 3–7% | 7–13% |
| Cough | 3–7% | 8–11% |
| Dispnoe | 2–9% | 10–22% |
| Other | ||
| Dizziness | 8–18% | 10–22% |
| Viral infection | 0–7% | 3–10% |
The adverse events observed in patients with viral hepatitis C are consistent with those that were observed when Intron ® A was used for other indications, with some dose-related increase in the frequency of development.
When Intron ® is used for other indications (in clinical and out-of-clinical studies), the following phenomena were rarely observed (> | 1/10000, <1/1000) or very rarely (<1/10000).
From the whole body: very rarely - swelling of the face.
Asthenic conditions (asthenia, malaise and fatigue), dehydration, palpitation, psoriasis, fungal infection and bacterial infection (including sepsis) have been reported.
From the immune system: very rarely - sarcoidosis or its aggravation.
When alpha interferons were used, the development of various autoimmune and immune-mediated disorders was reported, incl. Idiopathic or thrombotic thrombocytopenic purpura, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, and Vogt-Koyanagi-Harada syndrome.
Cases of acute hypersensitivity reactions have been reported, including hives, angioedema, and allergic edema and anaphylaxis.
From the cardiovascular system: rarely - arrhythmia (usually occurred in patients with previous history of cardiovascular disease or with previous cardiotoxic therapy), transient reversible cardiomyopathy (noted in patients without a history of cardiovascular disease); Very rarely - arterial hypotension, myocardial ischemia and myocardial infarction.
From the side of the central nervous system and the peripheral nervous system: rarely - suicidal tendencies; Very rarely - aggressive behavior, incl. Directed on other people, suicide attempts, suicide, psychosis (including hallucinations), impaired consciousness, neuropathy, polyneuropathy, encephalopathy, cerebrovascular ischemia, cerebrovascular hemorrhage, peripheral neuropathy, convulsions.
From the side of the hearing organ: very rarely - hearing impairment.
On the part of the endocrine system: very rarely - diabetes, worsening of the current diabetes.
From the digestive tract: very rarely - pancreatitis, increased appetite, bleeding gums, colitis.
From the liver and biliary tract: very rarely - hepatotoxicity (including fatal).
Changes in the teeth and periodontal. Patients receiving combination therapy with Nitron ® A and ribavirin showed pathological changes in the teeth and periodontium. Dry mouth with prolonged combination therapy with ribavirin and Intronom® A can contribute to damage to the teeth and mucous membranes of the mouth. Patients should brush their teeth 2 times a day and regularly undergo examination at the dentist. In addition, some patients may experience vomiting.
From the side of metabolism: rarely - hyperglycemia, hypertriglyceridemia.
From the musculoskeletal system: rarely - rhabdomyolysis (sometimes severe), leg cramps, back pain, myositis.
From the skin: very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis at the injection site.
From the respiratory system: rarely - pneumonia; Very rarely - pulmonary infiltrates, pneumonitis.
From the urinary system: very rarely - nephrotic syndrome, impaired renal function, renal failure.
On the part of the hematopoiesis system: very rarely with the use of Intron ® A in the form of monotherapy or in combination with ribavirin, aplastic anemia and complete aplasia of the red bone marrow were noted.
From the side of the organ of vision: rarely - hemorrhage in the retina, focal changes in the fundus, thrombosis of the arteries and veins of the retina, decreased visual acuity, reduced visual fields, optic neuritis, edema of the optic nerve.
Clinically significant changes in laboratory parameters: (more often when the drug was prescribed in doses more than 10 million IU / day) - a decrease in the number of granulocytes and leukocytes, a decrease in hemoglobin and platelet count, an increase in activity of AP, LDH, serum creatinine and urea nitrogen. Increased activity of ALT and ACT in blood plasma is marked as pathological when applied for all indications, except for hepatitis, and also for some patients with chronic hepatitis B in the absence of HBV DNA.
If during the application of Intron ® A for any indication of undesirable phenomena, you should reduce the dose or temporarily discontinue treatment until the undesirable phenomena are not eliminated. If constant or repeated intolerance develops with an adequate dosing regimen or the disease progresses, Intronom® A therapy should be discontinued.
Interaction
Caution should be applied Intron ® A concomitantly with opioid analgesics, hypnotics and sedatives, drugs potentially having a mielosupressive effect, such as zidovudine.
Interferons can affect oxidative metabolic processes. This should be taken into account when used simultaneously with drugs metabolized by oxidation (including with xanthine derivatives - aminophylline and theophylline). With the simultaneous use of Intron ® A with theophylline it is necessary to monitor the concentration of the latter in the blood serum and, if necessary, adjust the dosing regimen.
When Intron ® is used in combination with chemotherapeutic drugs (cytarabine, cyclophosphamide, doxorubicin, teniposide), the risk of toxic effects (their severity and duration), which can be life threatening or fatal (due to increased toxicity in the joint use of drugs ).
When combined with Intron ® A and hydroxyurea, the incidence of skin vasculitis may increase.
Pharmaceutical interaction. Intron® A should not be mixed with other medicinal substances other than 0.9% sodium chloride solution.
Dosing and Administration
SC, IV (only with malignant melanoma).
Treatment is appointed by a doctor who has experience in the treatment of the corresponding disease.
According to the doctor's decision, the patient can independently administer the drug SC to continue the selected treatment regimen.
Chronic hepatitis B. The recommended dose for adults is 30 to 35 million IU per week, either at a dose of 5 million IU daily, or 10 million IU 3 times a week for 4 months (16 weeks).
For children from 1 to 17 years of age, Intron ® A is administered at an initial dose of 3 million IU / m2 3 times a week (every other day) during the first week of treatment, followed by a dose increase of up to 6 million IU / m2 (maximum to 10 million IU / m2) 3 times a week (every other day). Duration of treatment 4-6 months (16-24 weeks).
Treatment is discontinued in the absence of positive dynamics (according to the data of the study of hepatitis B virus DNA (HBV) after 3-4 months of treatment with the drug at the maximum tolerated dose.
Recommendations for dose adjustment: the dose of the drug should be reduced by 50% with the development of violations from the hemopoietic system (leukocytes less than 1500 / mm3, granulocytes - less than 1000 / mm3 in children and less than 750 / mm3 in adults, platelets - less than 100,000 / mm3 in children And less than 50,000 / mm3 in adults).
Therapy should be discontinued in case of severe leukopenia (less than 1200 / mm3 leukocytes), neutropenia (granulocytes less than 750 / mm3 in children and less than 500 / mm3 in adults) or thrombocytopenia (platelets less than 70,000 / mm3 in children and less than 30,000 / mm3 In adults). Treatment can be resumed at the previous dose after normalization or return to the baseline level of the number of leukocytes, granulocytes and platelets.
Chronic hepatitis C. SC at a dose of 3 million IU 3 times a week (every other day) as monotherapy or in combination with ribavirin (doses and recommendations for their selection - see "Instructions for the use of ribavirin in capsules as part of combination therapy" ).
Treatment of patients with relapse after a course of monotherapy with alpha interferon. Intron ® A is prescribed only in combination with ribavirin. Based on the results of clinical trials conducted for 6 months, the recommended duration of combined treatment with ribavirin is 6 months.
Treatment of patients who had not previously received therapy. The efficacy of Intron® A increases with simultaneous use with ribavirin. Monotherapy with the drug is carried out only if there are contraindications to the use or intolerance of ribavirin.
Application of Intron A in combination with ribavirin. Based on the results of clinical trials conducted for 12 months, the recommended duration of combination therapy with ribavirin is at least 6 months.
In patients with genotype 1 of the virus and a high content of RNA of the virus (according to the results of a pre-treatment study) who do not detect hepatitis C RNA (HCV RNA) by the end of the first 6 months of therapy, the treatment continues for another 6 months Ie a total of 12 months). When deciding whether to perform combination therapy for 12 months, other negative prognostic factors should also be considered: age over 40 years, male sex, progressive fibrosis. Clinical studies have established that in patients who, after 6 months of therapy, still determine HCV RNA, continued treatment does not lead to the elimination of HCV RNA.
When Intron ® A is used in combination with ribavirin, careful monitoring of patients with impaired hepatic function and patients older than 50 years should be carried out in connection with the possible development of anemia.
Children from 3 years of age and older receive a dose of 3 million IU / m2 twice a week in combination with oral administration of ribavirin at a dose of 15 mg / kg daily, dividing this dose into morning and evening.
Monotherapy Intron® A. It is recommended to use for at least 3-4 months, then a determination of HCV RNA should be performed. The treatment is then continued only if HCV RNA is not detected.
For patients who tolerate therapy well, with normalization of ALT for 16 weeks of treatment, the recommended course of treatment is from 18 to 24 months.
Papillomatosis of the larynx. The recommended dose is 3 million IU / m2 p / c 3 times a week (every other day). Treatment begins after surgical (laser) removal of tumor tissue. The dose is selected taking into account the tolerability of the drug. To achieve a positive response, treatment may be required for more than 6 months.
Hairy cell leukemia. The recommended dose of Intron ® A for administration to patients after splenectomy and without it is 2 million IU / m2 3 times a week. In most cases, the normalization of one or more hematological indicators occurs after 1-2 months of treatment. To normalize the parameters of peripheral blood (the number of leukocytes, platelets and hemoglobin), it may take up to 6 months of treatment. Such a dosing regimen should be adhered to continuously, unless there is a rapid progression of the disease or the occurrence of severe intolerance to the drug.
Chronic myelogenous leukemia. The recommended dose is from 4 to 5 million IU / m2 daily, p / k.
In some cases, the combination of Intron® A at a dose of 5 million IU / m2, administered daily, is effective with cytarabine (Ara-C) at a dose of 20 mg / m2 p / c for 10 days per month (maximum daily dose - 40 mg). After the normalization of the number of leukocytes, Intron A® is administered at the maximum tolerated dose (4 to 5 million IU / m2 / day) to maintain hematological remission. Intron ® A should be discontinued after 8-12 weeks of treatment if at least partial hematologic remission or clinically significant decrease in the number of leukocytes is not achieved.
Thrombocytosis in patients with chronic myelogenous leukemia. The same doses are recommended as in the treatment of chronic myelogenous leukemia. Dose adjustment, used to control the number of leukocytes, can also be used to control the number of platelets. Clinical evidence suggests that approximately one-fourth (26%) of patients with chronic myeloid leukemia have concomitant thrombocytosis (platelet counts greater than 500 · 109 / L). Decrease in the number of platelets was achieved in all patients after 2 months of treatment. The number of platelets has never been less than 80 · 109 / l, with monthly monitoring.
Multiple myeloma. Supportive therapy: Patients who have reached the plateau phase as a result of induction therapy (decrease of paraprotein by more than 50%), Intron ® A can be prescribed as monotherapy, 3 mg / m2 3 times a week.
Follicular lymphoma. In combination with chemotherapy, Intron ® A is prescribed SC in a dose of 5 million IU 3 times a week (every other day) for 18 months. It is recommended to use CHOP-regimens of chemotherapy. Clinical data are available only for the use of CHVP (a combination of cyclophosphamide, doxorubicin, teniposide and prednisolone) in the form of 6-month cycles and subsequent 6 cycles, conducted every 2 months.
Kaposi's Sarcoma AIDS-related. The optimal dose is not established. The efficacy of Intron® A at a dose of 30 million IU / m2 was demonstrated with the administration 3-5 times a week of SC. The drug was also used in smaller doses (10-12 million IU / m2 / day) without a noticeable decrease in efficacy. If the disease is stabilized or there is a clinical response to treatment, therapy is continued until tumor growth is noted or drug withdrawal is required due to the development of a severe opportunistic infection or side effect. Therapy can be carried out on an outpatient basis.
Simultaneous use with zidovudine. In clinical trials, patients with AIDS and Kaposi's sarcoma received Intron® A in combination with zidovudine. In most cases, the following treatment scheme was well tolerated by patients: Intron® A at a dose of 5-10 million IU / m2; Zidovudine - 100 mg every 4 hours. The main toxic effect that limited the dose was neutropenia.
Treatment of Intronom® A can begin with a dose of 3-5 million IU / m2 / day. After 2-4 weeks, the dose can be increased by 5 million IU / m2 / day - up to 10 million IU / m2 / day, taking into account the portability; The dose of zidovudine can be increased to 200 mg every 4 hours. The dose should be selected individually - taking into account the effectiveness and tolerability.
Kidney cancer. Monotherapy: the optimal dose and scheme of application are not established. Intron ® A was used SC in doses from 3 to 30 million IU / m2 3 or 5 times a week or daily. The maximum effect was observed with n / k application in doses from 3-10 million IU / m2 3 times a week.
In combination with other drugs, such as IL-2: the optimal dose is not established. In combination with IL-2, Intron® A was used SC in doses of 3-20 million IU / m2. In clinical trials, the frequency of response to treatment was maximal when injected Intron® A at a dose of 6 million IU / m2 3 times a week; The dose was selected individually during treatment.
Carcinoid tumors. The standard dose is 5 million ME (3-9 million ME) SC three times a week (every other day). Patients with a common process may require a dose of up to 5 million IU daily. In surgical treatment, Intronom A is temporarily suspended for the duration of the operation and the recovery period after it. The drug therapy is continued until a clinical response to the treatment is observed.
Malignant melanoma. For the induction of postoperative remission, Intron ® A - iv in a dose of 20 million IU / m2 / day 5 days a week for 4 weeks. The dose thus calculated is added to 100 ml of a 0.9% solution of sodium chloride and administered as an infusion for 20 minutes. Treatment should be started up to 56 days after surgery. For maintenance therapy, the recommended dose is 10 million IU / m2 p / c 3 times a week (every other day) for 48 weeks.
With the development of severe side effects during therapy with Intronom® A (in particular, when the number of granulocytes is less than 500 / mm3 or ALT / AST is increased to values exceeding the upper limit of the norm by 5 times), the drug is temporarily stopped before the normalization of the indices. The treatment is then resumed using a dose reduced by 50%. If intolerance persists or the number of granulocytes decreases to 250 / mm3, or the activity of ALT and / or ACT increases to values exceeding the upper limit of the norm by a factor of 10, the drug is canceled.
Although the optimal (minimal) dose for achieving an adequate clinical effect has not been established, Intron® A should be given at recommended doses, taking into account their possible correction due to toxic effects, as described above.
Rules for the preparation and administration of solutions
Before the introduction, it is necessary to visually verify the absence of visible particles and the color change of the solution. The contents of the vial or syringe-pen are used to treat only one patient.
Intron ® A solution for injections in vials can be used for IV or SC administration immediately after the necessary dose is removed from the vial with a sterile syringe for injection (glass or plastic).
Preparation of solution for intravenous administration. Infusion should be carried out immediately after the preparation of the solution. A vial of any volume can be used to measure the required dose of the drug; The final concentration of interferon alpha-2β in the sodium chloride solution should be at least 0.3 million IU / ml. Appropriate dose of the drug is taken from the vial, add to 100 ml of 0.9% sodium chloride solution in a bag of PVC or a glass vial for infusion and injected / drip for 20 minutes.
Simultaneous administration of other drugs together with Intron ® A is not allowed.
The use of other solvents is unacceptable.
Intron® A solution for injection in syringe pens is injected w / c immediately after attaching the needle for injection and recruiting the required dose.
The drug should be taken from the refrigerator 30 minutes before the injection so that the solution warms up to room temperature (up to 25 ° C).
After opening the package, the drug is recommended to be used for 4 weeks if stored at a temperature of 2 to 8 ° C. A new needle should be used to administer each dose. After injection, the needle should be discarded and the syringe pen immediately placed in the refrigerator.
Overdose
To date, no cases of overdose, accompanied by any clinical symptoms.
Treatment: as with any drug overdose - symptomatic therapy, monitoring of vital organs functions, regular monitoring of the patient's condition.
Special instructions
For all patients. In the case of developing immediate-type hypersensitivity reactions (urticaria, angioneurotic edema, bronchospasm, anaphylaxis) with Intron® A, the drug should be immediately discontinued and appropriate treatment should be prescribed. Transient skin rash does not require discontinuation of treatment.
With the development of severe and moderate severity of side effects, it may be necessary to adjust the dosage regimen or, in some cases, discontinue therapy. If there are signs of a violation of liver function in the presence of Intron ® A, it is necessary to establish a careful observation and, in the course of the progression of the symptoms, to cancel the drug.
Against the background of the use of Intron ® A or within 2 days after the withdrawal of treatment may develop arterial hypotension, requiring the appointment of appropriate therapy.
In the treatment of Intron ® A it is necessary to provide adequate hydration of the body by additional injection of the liquid, In some cases, arterial hypotension may develop as a result of a decrease in BCC.
Fever can be a manifestation of the flu-like syndrome that often occurs with interferon alfa-2β, but other causes should be avoided.
Intron® A with caution is prescribed for patients with severe chronic diseases, such as COPD, diabetes mellitus with a tendency to ketoacidosis. Special caution is required when using the drug in patients with bleeding disorders (including thrombophlebitis, pulmonary embolism), as well as with pronounced myelosuppression.
In patients treated with interferon alfa (including Intronom® A), pneumonitis and pneumonia (in some cases with a fatal outcome) of an unclear etiology are observed in rare cases. Similar symptoms were more common against the background of the application of "shosaikoto" - a means of Chinese traditional medicine of plant origin. Any patient with a cough, fever, dyspnea, or other symptoms on the part of the respiratory system should perform an x-ray examination of the chest. If infiltrates or other pulmonary function disorders are detected, the patient should be carefully monitored and, if necessary, discontinued therapy with Intronom® A. Timely withdrawal of interferon alfa and the appointment of GCS promotes the coping of pulmonary syndromes.
Impaired vision appears after a few months of treatment, but their occurrence is described after less prolonged therapy. All patients need to have an ophthalmological examination before starting therapy. When complaints of visual impairment, changes in visual fields or any other ophthalmic disorders, immediate consultation of the oculist is necessary. Patients with diseases in which retinal changes can occur, such as diabetes mellitus or hypertension, are recommended to undergo an ophthalmic examination regularly during Intron® A therapy. When there is or worsening of vision disorders, consideration should be given to discontinuing Intron® A therapy.
Serious mental disorders, in particular depression, suicidal thoughts and attempts, psychosis, including hallucinations, aggressive behavior, incl. Directed at other people, are known side effects of alpha interferons. Suicidal thoughts and attempts were more often observed in children, primarily adolescents (2.4%) than adults (1%).
It should be used with caution in patients with anamnestic indications for the presence of mental disorders.
If the patient develops changes in the psychic sphere and / or the CNS, including the development of depression, it is recommended that the doctor be monitored for such a patient throughout the treatment period, and also within 6 months after the end. These side effects are usually rapidly reversible after cessation of therapy, but in some cases it took up to 3 weeks for them to reverse their development. If the symptoms of a mental disorder do not regress or worsen, suicidal thoughts or aggressive behavior directed at other people appear, it is recommended that Intron® A be discontinued and that a psychiatrist be consulted.
In some patients, especially the elderly, who received the drug in high doses, there was a violation of consciousness, coma and convulsions, including cases of encephalopathy. In case of ineffectiveness of dose reduction and / or pharmacological correction of these disorders, it is necessary to solve the problem of discontinuing therapy with Intron ® A.
Patients with diseases of the cardiovascular system (for example, myocardial infarction, chronic heart failure, arrhythmia) require careful medical supervision in the appointment of Intron A. Patients with heart disease and / or progressive oncological disease are recommended to carry out ECG before and during therapy with Intron A. The resulting arrhythmia (mainly supraventricular), as a rule, lends itself to standard therapy, but may require the withdrawal of Intron ® A.
Intron® A is not prescribed to patients with psoriasis and sarcoidosis due to the possibility of exacerbation of these diseases, unless the intended benefit of the treatment justifies the potential risk.
Preliminary data suggest that interferon alpha therapy may increase the risk of kidney transplant rejection. It has also been reported that liver transplantation has been rejected, but the cause-and-effect relationship of this phenomenon with interferon alpha therapy has not been established.
In the treatment of alpha interferons, the occurrence of autoantibodies and the occurrence of autoimmune diseases were noted. The risk of these phenomena is higher in patients with an existing predisposition to autoimmune diseases. When symptoms similar to those of autoimmune diseases appear, a thorough examination of the patient should be conducted and the possibility of continued therapy with interferon should be assessed.
When monotherapy with Intronom ® A, hypo- or hyperthyroidism was rarely observed. In clinical studies, 2.8% of patients receiving Intron ® A developed thyroid pathology, which was controlled by appropriate therapy. The mechanism of development of such an action is unknown. Before the start of Intronom® A therapy, the concentration of TSH should be determined. If any pathology is detected, appropriate treatment should be performed. If drug therapy allows you to maintain TSH at the level of normal, the purpose of Intron ® A is possible. If during treatment there was a suspicion of thyroid dysfunction, the level of TSH should be determined. In the case of impaired thyroid function, treatment with Nitron ® A can be continued if TSH levels can be maintained within normal limits with the help of medications. The abolition of Intron® A did not lead to the restoration of thyroid function.
It is necessary to stop therapy with Intron A in patients with chronic hepatitis with prolonged coagulation time, This may be a sign of decompensation of liver function.
For patients with chronic hepatitis C. When using Intron ® A in combination with ribavirin, the instructions for the medical use of ribavirin should also be followed.
In clinical trials, all patients underwent liver biopsy before the initiation of Intron® A therapy. However, in certain cases (including in patients with genotypes 2 and 3 of the virus), treatment can be initiated without histological confirmation of the diagnosis. When deciding on the need for biopsies beforehand, the existing recommendations on the management of these patients should be followed.
Combined infection with the hepatitis C virus and HIV. In patients infected simultaneously with the hepatitis C virus and HIV and receiving highly active antiretroviral therapy (HAART), lactic acidosis may develop. Therefore, in the appointment of Nitron® A and ribavirin, in addition to HAART, caution should be exercised.
In the presence of formed cirrhosis, the risk of decompensation of liver function and death in patients infected with the hepatitis C and HIV virus is increased. The use of Intron ® A (without ribavirin or in combination with ribavirin) in addition to ongoing therapy in this group of patients may further increase this risk.
Simultaneous chemotherapy. The use of Intron ® A in combination with chemotherapeutic drugs (cytarabine, cyclophosphamide, doxorubicin, teniposide) increases the risk of toxic effects (contributes to their increased severity and duration), which can endanger life or cause death (due to increased toxicity in the joint use of drugs ). The most frequent toxic effects are mucositis, diarrhea, neutropenia, impaired renal function and electrolyte balance. Given the risk and severity of toxic effects, it is necessary to carefully select the dose of Intron ® A and chemotherapeutic agents.
Data from laboratory studies. Before the treatment of Intron® A and systematically during the therapy, all patients undergo a general clinical blood test (with the definition of the leukocyte formula and the number of platelets), blood biochemical parameters, including the determination of the level of electrolytes, hepatic enzymes, bilirubin, total protein and creatinine.
During the therapy of patients with chronic hepatitis B or C, the following scheme for monitoring laboratory indicators is recommended: 1, 2, 4, 8, 12, 16 weeks and then monthly, even after discontinuation of therapy, until the doctor decides about its necessity. If ALT rises to a value twice or more than the baseline value, Intron® A treatment can be continued, provided there are no signs of hepatic insufficiency. In this case, the determination of ACT, PV, AF, albumin and bilirubin should be carried out every 2 weeks.
In patients with malignant melanoma, liver function and the number of leukocytes should be monitored every week during the first phase of treatment (remission induction) and monthly - with maintenance therapy.
When Intron ® A is prescribed in combination with ribavirin to patients with impaired renal function and those over the age of 50, careful monitoring should be made for them in connection with the possible development of anemia.
Application in pediatrics. Intron ® can be used in children aged 1 year with chronic hepatitis B and laryngeal papillomatosis. Clinical data on the use of Intron ® A in children with other pathologies are absent.
Female patients and male partners should use 2 methods of contraception during treatment and for 6 months after its completion.
In women who received therapy with human leukocyte interferon, there was a decrease in the level of estradiol and progesterone.
The drug should be used with caution in men of reproductive age.
Impact on the ability to drive vehicles and mechanisms
The patient should be warned about the possibility of developing weakness, drowsiness, and consciousness disorders on the background of therapy and recommend avoiding the management of vehicles and mechanisms.
Dispose of used bottles and syringes-pens in accordance with the current order.
Transportation at a temperature of up to 25 ° C is allowed for not more than 7 days. During this period, the drug can be returned for further storage in the refrigerator (storage temperature from 2 to 8 ° C), the shelf life of the drug is preserved. If the drug has not been used and returned to storage in the refrigerator for 7 days, then its further use is not recommended.
Storage conditions of the drug Intron A
At a temperature of 2-8 ° C (don’t freezing).
Keep out of the reach of children.
Shelf life of the drug Intron A
Solution for intravenous and subcutaneous administration of 10 million IU - 1.5 years.
Solution for intravenous and subcutaneous administration of 18 million IU - 1 year 3 months.
Solution for intravenous and subcutaneous administration of 25 million IU - 2 years.
Solution for intravenous and subcutaneous administration 30 million IU - 1 year 3 months.
Solution for intravenous and subcutaneous administration 60 million IU - 1 year 3 months.
Do not use after the expiry date printed on the package.
