Pegasis

Pegasis – the immunomodulatory medicine with antiviral action applied at treatment of chronic hepatitis.

Form of release and structure

Pegasis release in the form of solution for hypodermic introduction: transparent liquid, from light yellow color to colourless (on 0,5 or 0,6 ml in the syringe tubes with a needle (needles), 1 unit-dose syringe in a cardboard pack; on 0,5 ml in the syringe tubes with the built-in protected needle in an autoinjector Proklik, 1 autoinjector in a cardboard pack; on 1 ml in bottles (bottles), 1 or 4 bottles in a cardboard pack).

Is a part of 0,5 ml of solution:

• Active ingredient: peginterferon alpha 2а (40 kd) – 0,135 or 0,18 mg;
• Additional components: benzyl alcohol – 5 mg; sodium chloride – 4 mg; sodium acetate trihydrate – 1,3085 mg; glacial acetic acid – 0,0231 mg; polysorbate of 80 - 0,025 mg; 10% acetic acid – to pH 6,0; 10% sodium acetate solution – to pH 6,0; water for injections – to 0,5 ml.

Indications to use

• Chronic Hepatitis C (CHC): at adults from positive VGS RNA, with the compensated cirrhosis or without cirrhosis, including and with clinically stable coinfection of HIV. In combination with ribaviriny Pegasis appoint the patient with HGS which did not receive therapy earlier, or to patients who have a previous monotherapy by interferon an alpha (not pegylated or pegylated) or the therapy combined with ribaviriny was inefficient. As monotherapy drug is appointed at intolerance or existence of contraindications to a ribavirin;
• Chronic hepatitis B (HGV): HBeAg-positive and HBeAg-negative at adults with the compensated damage of a liver and symptoms of virus replication, a superactivity of alaninaminotranspherase and histologically the confirmed fibrosis and/or an inflammation of a liver.

Contraindications

• Autoimmune hepatitis;
• Liver failure in a heavy current;
• Dekompensirovanny cirrhosis;
• Cirrhosis on a scale of Chayld-Pyyu – with score ≥6 at patients with VICh-HGS coinfection under a condition if increase in this indicator is not connected with an indirect hyperbilirubinemia because of administration of drugs, such as индинавир and атазанавир;
• Serious cardiovascular illnesses in a decompensation stage, including with badly controlled unstable current for the previous 6 months;
• Age up to 3 years (because of Pegasis who is a part of benzyl alcohol);
• Pregnancy and period of breastfeeding;
• Hypersensitivity to the genetically engineered drugs received by means of E.coli, interferon an alpha to polyethyleneglycol or other components of Pegasis.

At purpose of the combined treatment with ribaviriny it is necessary to consider contraindications for two drugs.

Route of administration and dosage

Pegasis's solution should be entered into the area of a hip or a front abdominal wall subcutaneously.

Therapy needs to be carried out under observation of the experienced doctor.

At purpose of the combined treatment with ribaviriny it is also necessary to consider instructions on its use.

At the standard mode of dosing Pegasis appoint in a dose 0,18 mg once a week. Before introduction solution needs to be examined regarding discoloration and lack of foreign impurity.

At treatment of HBeAg-positive and HBeAg-negative HGV duration of a course of monotherapy makes 48 weeks.

At HGS at the patients who were not receiving earlier therapy Pegasis appoint independently or in combination with oral administration of a ribavirin (during food).

The recommended dosing mode at the prompt virologic reply (a dose of a ribavirin (at body weight) / course duration; the low virus loading (LVL) – ≤ 800 000 ME/ml, the high virus loading (HVL) –> 800 000 ME/ml):

• Genotype 1: NVN – 1000 mg (<75 kg) or 1200 mg (≥75 kg) of/24 or 48 weeks; VVN – 1000 mg (<75 kg) or 1200 mg (≥75 kg) of/48 weeks;
• Genotype 2 or 3: NVN – 800 mg / 16 or 24 weeks; VVN – 800 mg / 24 weeks;
• Genotype 4: 1000 mg (<75 kg) or 1200 mg (≥75 kg) of/24 or 48 weeks.

The recommended dosing mode without prompt virologic reply (a dose of a ribavirin (at body weight) / course duration):

• Genotype 1 or 4: 1000 mg (<75 kg) or 1200 mg (≥75 kg) of/48 weeks;
• Genotype 2 or 3: 800 mg / 24 weeks.

Irrespective of initial virus loading, course duration at patients with a genotype 1 at whom on the 4th week of use of drug VGS RNA is defined, has to make 48 weeks.

Therapy lasting 24 weeks can be associated more likely a recurrence, than lasting 48 weeks.

Clinical data at patients with a genotype 5 and 6 are limited therefore in this case carrying out a combination therapy with ribaviriny (1000/1200 mg) for 48 weeks is recommended.

The recommended monotherapy duration – 48 weeks.

For the patients who were earlier receiving treatment usually appoint: Pegasis – once a week on 0,18 mg, рибавирин – 1000/1200 mg a day (body weight <75 / ≥ 75 kg).

If the virus is found on the 12th week of treatment, drug is cancelled.

The recommended general duration of a course – 48 weeks. At the solution of a question of purpose of therapy to patients with the genotype 1 which did not answer the previous treatment with pegylated interferon with ribaviriny duration of a course is increased up to 72 weeks.

At VICh-HGS coinfection Pegasis in a standard dose apply separately or along with ribaviriny (800 mg). Course duration irrespective of a genotype makes 48 weeks.

In case of need dose adjustment because of laboratory or clinical reactions of average and heavy severity, as a rule, has enough to reduce dose to 0,135 mg. However the dose decline to 0,09 or 0,045 mg in some cases is required. After improvement of a state increase in a dose is possible up to standard.

At reduction of number of neutrophils it is less than 750 cells / мкл the dose decline is recommended. At the absolute number of neutrophils (ANN) it is less than 500 cells / мкл therapy it is necessary to interrupt until this indicator does not exceed 1000 cells / мкл. Pegasis's use in a dose of 0,09 mg can be resumed under periodic control of number of neutrophils.

The dose decline to 0,09 mg is shown at reduction of quantity of thrombocytes less than 50 000 cells / мкл. If the number of thrombocytes is less than 25 000 cells / мкл, cancel drug. At the anemia which arose during therapy it is recommended:

• Reduction of a daily dose of a ribavirin to 600 mg (200/400 mg in the morning and in the evening) is recommended in one of the following situations: decrease in hemoglobin is less than 10 g/dl, but patients have more than 8,5 g/dl without the accompanying cardiovascular pathologies; decrease in hemoglobin by 2 g/dl or more within any 4 weeks of treatment in the presence of stable cardiovascular diseases. Increase in a dose of a ribavirin to initial is not recommended;
• The termination of reception of a ribavirin is shown in one of the following situations: decrease in hemoglobin is less than 8,5 g/dl at patients without the accompanying cardiovascular pathologies; preservation of hemoglobin at the level of less than 12 g/dl in 4 weeks, despite reduction of a dose in the presence of stable cardiovascular diseases. At the discretion of the doctor after improvement of indicators resuming of reception of a ribavirin in a daily dose of 600 mg with the subsequent increase up to 800 mg is possible. Increase in a dose to standard (1000/1200 mg) is not recommended. In case of intolerance of a ribavirin further carry out monotherapy by Pegasis.

During therapy increase in activity of alaninaminotranspherase (ALT) above an indicator before treatment, including patients with the virologic answer is observed. At the progressing increase in activity of ALT in comparison with indicators before treatment, the dose is reduced to 0,135 mg in the beginning. If, despite it, the indicator of ALT continues to increase or treatment proceeds with increase in concentration of bilirubin or symptoms of a decompensation of hepatic process, therapy is cancelled.

At patients with HGV perhaps passing increase in activity of ALT in certain cases exceeding the upper bound of norm by 10 times that can testify to an immune clearance (therapy is not appointed). After normalization of activity of ALT resuming of a medical course is possible.

At the compensated cirrhosis (on a scale of Chayld-Pyyu – a class A) use of drug is considered safe and effective. At dekompensirovanny cirrhosis (on a scale of Chayld-Pyyu – the class B/C or bleeding from varicose veins of a gullet) the profile of safety of Pegasis is not studied.

To patients with an end-stage of a renal failure Pegasis appoint 0,135 mg in a dose. Such patients need careful monitoring of a state and, cases of development of side effects, further dose adjustment.

Correction of the mode of dosing is not required to patients of advanced age.

For children of 3-18 years the profile of safety of drug was not studied.

When performing therapy by Pegasis (monotherapy or the combined use with ribaviriny) cases of rejection of renal and hepatic transplants are recorded.

Side effects

At treatment of HGS the most widespread disturbances are expressed, as a rule, in easy or moderate degree, and dose adjustments or cancellations of therapy do not demand. The profile of safety of Pegasis at treatment of HGV is similar to that at HGS, however at HGV side effects develop with considerably smaller frequency, except the frequency of developing of fever.

Possible disturbances during Pegasis's use (it is very frequent (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), it is rare (≥1/10 000 and <1/1000), it is very rare (<1/10 000)):

• Cardiovascular system: often – heartbeat, tachycardia, peripheral hypostases; infrequently – arterial hypertension; seldom – a cardiomyopathy, congestive heart failure, stenocardia, a myocardial infarction, arrhythmia, hemorrhage in a brain, supraventricular tachycardia, fibrillation of auricles, a pericardis, a vasculitis;
• Skeletal and muscular system: very often – arthralgias, mialgiya; often – pains (in bones, a back, a neck), muscular weakness, arthritis, muscular spasms, musculoskeletal pain; seldom – a miositis;
• Respiratory system: very often – диспноэ, cough; often – nasal bleeding, диспноэ at an exercise stress, a nasopharyngitis, pharyngalgias, a nose congestion, hypostasis of bosoms, an inflammation of a mucous membrane of a nasal cavity; infrequently – goose breathing; seldom – an embolism of a pulmonary artery, an intersticial pneumonitis;
• Gepatobiliarny system: infrequently – functional disturbances of a liver; seldom – a cholangitis, a liver failure, fatty dystrophy of a liver;
• Alimentary system: very often – nausea, diarrhea, an abdominal pain; often – bleeding of gums, vomiting, a dysphagy, dyspepsia, an ulceration of a mucous oral cavity, a glossitis, a meteorism, stomatitis, dryness of a mucous oral cavity; infrequently – gastrointestinal bleeding; seldom – pancreatitis, a round ulcer;
• Immune system: infrequently – a disease of Benye-Beka-Shaumana, a thyroiditis; seldom – a system lupus erythematosus, an anaphylaxis, a pseudorheumatism; very seldom – a trombotichesky or idiopathic Werlhof's disease, a Quincke's disease;
• Urinary system: seldom – a renal failure;
• Lymphatic system and blood: often – anemia, thrombocytopenia, a limfoadenopatiya; seldom – a panhemocytopenia; very seldom – aplastic anemia;
• Reproductive system: often – impotence;
• Endocrine system: often – a hyperthyroidism, a hypothyroidism; infrequently – a diabetes mellitus; seldom – diabetic ketoacidosis;
• Nervous system: very often – dizziness, a headache, disturbance of concentration of attention; often – syncopal states, memory disturbances, weakness, nightmares, migraine, a hyperesthesia, a hypesthesia, paresthesia, disturbance of flavoring feelings, a tremor, drowsiness; infrequently – a peripheral neuropathy; seldom – spasms, a coma, neuritis of a facial nerve;
• Infections: often – a herpes simplex, bronchitis, upper respiratory tract infections, candidiasis of a mucous membrane of an oral cavity, an infection of a fungal and bacterial etiology; infrequently – skin infections, pneumonia; seldom – outside otitis, an endocarditis;
• New growths (high-quality and malignant): infrequently – a liver new growth;
• Metabolism: very often – anorexia; infrequently – dehydration;
• Mentality: very often – concern, a depression, sleeplessness; often – changes of mood, decrease in a libido, emotional frustration, nervousness, aggression; infrequently – suicide thoughts, hallucinations; seldom – mental disorders, a suicide;
• Sight: often – a xerophthalmia, pain in an eyeglobe, a vision disorder, diseases of eyes of an inflammatory etiology; infrequently – a retinal apoplexy; seldom – defeats of vessels of a retina, neuritis and a papilledema, a retinopathy, a helcoma; very seldom – sight loss;
• Hearing: often – ear pain, вертиго; infrequently – a hearing loss;
• Skin and its appendages: very often – an itch, an alopecia, dermatitis, a xeroderma; often – reactions of a photosensitization, the increased sweating, rash, psoriasis, eczema, urticaria, skin reactions, night sweating; very seldom – Stephens-Johnson's syndrome, a toxic epidermal necrolysis, a mnogoformny erythema;
• Organism in general: very often – fever, irritability, a fever, pain, an adynamy, weakness, reactions in the place of an injection; often – block, decrease in body weight, a grippopodobny syndrome, thorax pains, an indisposition, thirst, inflows.

As a result of carrying out post-marketing observations the following side effects were recorded:

• Hemopoietic system: very seldom at use with ribaviriny – a partial krasnokletochny aplasia of marrow;
• Nervous system: with an unknown frequency – an ischemic stroke;
• Skeletal and muscular system: with an unknown frequency – рабдомиолиз;
• Mentality: very seldom at use with ribaviriny – the gomitsidalny ideas;
• Organ of sight: with an unknown frequency – retina amotio;
• Another: rejection of renal and hepatic transplants.

During Pegasis's use such changes of these laboratory analyses can be observed:

• Laboratory indicators: increase in activity of alaninaminotranspherase, a gipertriglitseridemiya, a hyperbilirubinemia, electrolytic disturbances (a hypocalcemia, a hypopotassemia, a hypophosphatemia), hyper - and a hypoglycemia;
• Hematologic indicators: decrease in hematologic indicators (in the form of a leukopenia, a neutropenia, a lymphopenia, thrombocytopenia and decrease in hemoglobin). Improvement is observed at change of a dose. In 1-2 months after the treatment termination indicators are returned to norm;
• Antibodies to interferon: formation of neutralized antibodies to interferon (is more often – at HGV);
• Laboratory indicators of function of a thyroid gland: clinically significant changes that demands medical intervention;
• Laboratory indicators at VICh-HGS coinfection: phenomena of hematologic toxicity (thrombocytopenia, neutropenia, anemia). As a rule, are adjusted by change of a dose and use of growth factors. Premature cancellation of treatment is required in rare instances.

Special instructions

In certain cases during therapy and for half a year after its termination heavy side effects from the central nervous system in the form of a depression are observed, suicide mood and suicide attempts. In this regard, irrespective of age, patients need careful monitoring of a state. At emergence of dangerous symptoms treatment cancellation is possible.

It is necessary to consider that progressing of fibrosis at patients usually happens to the normal level of activity of ALT more slowly, than at the increased level of activity of ALT.

Prior to Pegasis's use carrying out standard general clinical and biochemical analyses of blood is recommended to all patients. The course is appointed at the following indicators: absolute number of neutrophils of ≥1500 cells / мкл; number of thrombocytes of ≥90 000 cells / мкл; the compensated function of a thyroid gland (TTG and T4 have to is in limits of normal indicators); the quantity ^{of CD4+} of lymphocytes of ≥200 cells / мкл or ^CD4+ is in range of ≥100-<200 cells / мкл, at patients with VICh-HGS coinfection – VICh-1 RNA <5000 copies/ml. At hemoglobin less than 12 g/dl Pegasis (independently or in combination with ribaviriny) need to be applied with care.

After the beginning of a medical course biochemical analysis of blood needs to be repeated in 4 weeks, the general clinical – in 2 and 4 weeks. Also during therapy periodic carrying out laboratory analyses is shown.

Pegasis appoint with care in combination with other miyelotoksichny drugs.

During use of drug dysfunctions of a thyroid gland or deterioration in the diseases of a thyroid gland existing earlier can be observed. If the level of thyritropic hormone (TTG) within normal values can be supported medicamentally, treatment is continued.

At development during use of drug of a hypoglycemia, a hyperglycemia and a diabetes mellitus, therapy needs to be cancelled.

Patients with cardiovascular pathologies before an initiation of treatment are recommended to make an ECG. In case of an aggravation of symptoms therapy is interrupted. Also drug is cancelled when developing a liver failure, serious reactions of immediate hypersensitivity, dysfunctions of breath or resistant (persistent) infiltrates or infiltrates of not clear genesis.

Patients with the signs similar to symptoms of autoimmune diseases, before purpose of a course have to undergo careful inspection.

Fever during use of drug can be connected with the grippopodobny syndrome which is often developing at therapy by interferon, however it is necessary to exclude other reasons, including serious infections of a fungal, virus and bacterial etiology, in particular at patients with a neutropenia.

All patients for detection of pathology of an eyeground before purpose of a medical course need to conduct ophthalmologic examination. At complaints to the worsening visual acuity or narrowing of its fields carrying out full ophthalmologic inspection is required, in the presence of associated diseases of an organ of sight during therapy perform additional inspections.

In case of an aggravation or induction of a sarcoidosis and psoriasis Pegasis appoint with care, and at an aggravation or emergence of signs of development of these diseases therapy cancellation is possible.

Because of high probability of developing of anemia the combined use of a ribavirin and zidovudine is not recommended.

At patients with coinfection it is necessary to carry out careful monitoring for identification of signs of a hepatic decompensation (including encephalopathy, ascites, bleeding from varicose veins).

At development of weakness, drowsiness, dizziness and confusion of consciousness it is recommended to refuse control of vehicles.

Medicinal interaction

At the combined use of Pegasis or Pegasis's combination with ribaviriny with some medicinal means / substances there can be following effects:

• Theophylline: increase in its AUC (control, especially after 4 weeks of use of Pegasis is necessary);
• Methadone: increase in the average levels of its metabolites (careful control of symptoms of intoxication is necessary), at high doses – increase in probability of lengthening of an interval of QTS;
• Didanozin and his active metabolite (interaction with ribaviriny): development of pancreatitis, fatal liver failure, peripheral neuropathy, symptomatic giperlaktatemii/laktatsidoza;
• Zidovudine (interaction with ribaviriny): deterioration in anemia; simultaneous use is not recommended, especially in the presence in the anamnesis of data on the anemia caused by a zidovudine;
• Telbivudin (in a daily dose of 600 mg): increase in probability of development of a peripheral neuropathy;
• Azathioprinum: strengthening of its myelotoxic action; co-administration is possible after an advantage ratio with risk, at the same time it is necessary to carry out careful monitoring of composition of blood regarding development of a miyelotoksichnost, in case of its development the combination therapy is cancelled.

Due to the lack of data, it is impossible to mix with other drugs Pegasis.

Terms and storage conditions

To store in protected from light, the place, unavailable to children, at a temperature of 2-8 °C, not to freeze. Transportation is carried out with observance of the same conditions.

Drug period of validity in an autoinjector Proklik – 2 years, the syringe tubes – 3 years.