Stelara

General characteristics. Structure:

Active component: one filled syringe contains 45 mg (45 mg / 0,5 ml) or 90 mg (90 mg / 1,0 ml) an ustekinumaba.

Excipients: for a dosage of 45 mg / 0,5 ml: sucrose - 38 mg, a L-histidine (including a hydrochloride L-histidine monohydrate) - 0,5 mg, polysorbate of 80 - 0,02 mg, water for injections - to 0,5 ml. For a dosage of 90 mg / 1,0 ml: sucrose - 76 mg of mg, a L-histidine (including a hydrochloride L-histidine monohydrate) - 1,0 mg, polysorbate of 80 - 0,04 mg, water for injections - to 1,0 ml.

Description. Transparent or slightly opalescent solution from colourless till light yellow color. Solution may contain single transparent particles of protein. 

Pharmacological properties:

Pharmacodynamics.

Action mechanism. Ustekinumab represents completely human monoclones of the class IgG1k with a molecular weight about 148600 дальтон, produced by the recombinant cellular line and undergoing multistage cleaning, including an inactivation and removal of virus particles. Ustekinumab has high specificity to subunit r40 interleykin (IL) of the person of SILT-12 and SILT-23. Drug blocks biological activity of SILT-12 and SILT-23, preventing linkng of p40 with receptor ИЛ-12R-β1 expressed on a surface of immune cells. Ustekinumab cannot contact the SILT-12 and SILT-23 which are already connected with receptor ИЛ-12R-β1. Therefore drug will hardly influence a complement - or an antibody - dependent cytotoxicity of the cells expressing receptors to SILT-12 and/or SILT-23.

SILT-12 and SILT-23 are heterodimeric cytokines which cosecrete the cells activated antigen-prezentiruyushchimi, in particular, macrophages and dendritic cells. SILT-12 activates NK cells, stimulates differentiation of CD4+ of T-cells to T-helperov 1 (Th1), and also scale (ИФНγ) strengthens production of interferon. SILT-23 stimulates formation of T-helperov 17 (Th17) and increases secretion of IL-17A, IL-21 and IL-22. The SILT-12 and SILT-23 levels are increased in blood and skin at patients with psoriasis. Concentration of IL12/23p40 in blood serum is the fact of differentiation of patients with psoriasis arthritis that confirms participation of SILT-12 and SILT-23 in a pathogeny of psoriasis diseases. Polymorphism of the genes coding IL-23A, IL-23R and IL-12V defines predisposition to such diseases. Genes of SILT-12 and SILT-23 have the raised expression in the skin affected with psoriasis, and development ИФНγ caused by SILT-12 is directly proportional to expressiveness of a psoriasis disease. T-cells, sensitive to SILT-23, were found in entezisa on mouse models of inflammatory arthritis in which SILT-23 caused an entezialny inflammation.

The drug Stelara® shows clinical performance at psoriasis and psoriasis arthritis, by means of binding of subunit r40 SILT-12 and SILT-23 and disturbances of production of Th1 and Th17 cytokines which are key links of a pathogeny of these diseases. The pharmacodynamics leads Use of the drug Cтелара® to considerable weakening of histologic displays of psoriasis, including a hyperplasia and proliferation of cells of epidermis. These data will be coordinated with clinical performance.

At patients with psoriasis and/or psoriasis arthritis устекинумаб has no significant effect on a ratio of the immune cells circulating in blood, including memory cells and not activated T-cells, and also on concentration of cytokines in blood. Concentration of system markers of an inflammation at the patients accepting устекинумаб is in norm limits, and indicators of 4 markers (MDC, VEGF, MCSF-1 b YKL-40) slightly differ at the patients accepting the drug Stelara® in comparison with group of placebo.

The analysis of MRNK allocated from biopsy samples of the skin centers of psoriasis initially and in 2 weeks of treatment showed that use of the drug Cтелара® led to decrease in an expression of the genes coding its molecular targets – SILT-12 and SILT-23, and also genes coding inflammatory cytokines and chemokines – a monocytic chemotactic factor (MSR)-1, a factor of a necrosis of a tumor (TNF) - an alpha, interferon - scale – indutsibelny protein (IP)-10 and IL-8. These data will be coordinated with considerable clinical effect of treatment at patients with psoriasis.

The clinical effect of treatment of psoriasis and psoriasis arthritis, apparently, depends on concentration of an ustekinumab in a blood plasma. Patients with psoriasis with the best result on a scale have estimates of the area and weight of psoriasis of PASI average value of concentration of an ustekinumab in a blood plasma was higher, than at patients with smaller clinical effect. In general, the share of patients at whom improvement on a scale of PASI reached 75% increased in process of increase in concentration of an ustekinumab in a blood plasma. At the patients with psoriasis arthritis who reached ACR 20 assessment higher average concentration of an ustekinumab in a blood plasma in comparison with the patients who did not answer treatment is observed. The number of the patients with psoriasis arthritis who reached improvement on a scale of ACR 20 and ACR 50 increased in process of increase in concentration of an ustekinumab in a blood plasma.

Immunization. In long-term clinical trial 3 phases at the patients receiving the drug Stelara® at least 3,5 years the immune response similar to that at control group of the patients sick with psoriasis, but not undergoing systematic treatment at introduction of the vaccine containing pneumococcal polysaccharide or an antitetanic vaccine developed. At approximately identical number (%) of the patients receiving treatment by the drug Stelara®, and patients from control group protective concentration of antipneumococcal and antitetanic antibodies was reached. Antiserum capacities were also approximately identical.

Pharmacokinetics.

Absorption. The average time of achievement of the maximum concentration in a blood plasma (Tmax) after single hypodermic introduction of 90 mg of an ustekinumab to healthy volunteers made 8,5 days. At patients with psoriasis this size at doses of drug 45 or 90 of mg was comparable to that at healthy volunteers. Absolute bioavailability of an ustekinumab after single hypodermic introduction by sick psoriasis made 57,2%.

Distribution. Average value of volume of distribution of an ustekinumab in a terminal phase of removal after single intravenous administration by sick psoriasis fluctuated from 57 to 83 ml/kg.

Metabolism. The metabolic way of an ustekinumab is not known.

Removal. The average size of system clearance of an ustekinumab after single intravenous administration by sick psoriasis fluctuated from 1,99 to 2,34 ml/days/kg. The average elimination half-life (T1/2) of an ustekinumab at patients with psoriasis and/or psoriasis arthritis made about 3 weeks, and in different researches varied from 15 to 32 days.

Linearity. System exposure of an ustekinumab (Cmax and the area under a curve "concentration time", AUC) at patients with psoriasis increased in proportion to the entered doses after single intravenous administration of doses in the range from 0,09 mg/kg up to 4,5 mg/kg, and also after single hypodermic introduction of doses in the range from 24 mg to 240 mg.

Change of concentration of an ustekinumab in a blood plasma eventually after single or repeated repeated administrations of drug are generally predictably. Equilibrium concentration of an ustekinumab in a blood plasma is reached by 28th week at the offered therapy mode (the second injection 4 weeks later after the first use, then each 12 weeks). On average, equilibrium concentration of drug at patients with psoriasis makes 0,21-0,26 mkg/ml for a dose of 45 mg and 0,47-0,49 mkg/ml for a dose of 90 mg. Cumulation of drug in blood serum was not observed throughout treatment at the dosing mode 1 injection each 12 weeks.

Influence of body weight of the patient on drug pharmacokinetics. Concentration of drug in a blood plasma depends on the body weight of the patient with psoriasis and/or psoriasis arthritis. At introduction of identical doses (45 mg or 90 mg), patients with body weight more than 100 kg in plasma had an average concentration of an ustekinumab less, than patients with body weight have less than 100 kg. However average minimum concentration of an ustekinumab in a blood plasma of patients with body weight more than 100 kg to which entered 90 mg of drug was comparable with that in group of patients with body weight less than 100 kg to which entered 45 mg of drug.

Population pharmacokinetic analysis. The seeming clearance (CL/F) and volume of distribution (V/F) was made by 0,465 l/days and 15,7 l, respectively, by data received at patients with psoriasis. The elimination half-life (T1/2) of drug made about 3 weeks. The sex, age and belonging to this or that race did not influence the seeming clearance of an ustekinumab. The seeming clearance (CL/F) of drug was influenced by the body weight of patients, at the same time patients with bigger body weight had a size CL/F more. The average seeming clearance at patients with body weight more than 100 kg was about 55% higher than that at patients with smaller body weight. The volume of distribution (V/F) at patients with body weight more than 100 kg was about 37% higher than that at patients with smaller body weight. Similar results are received in the confirmatory analysis of population data among patients with psoriasis arthritis.

Influence of komorbidny states (diabetes mellitus, arterial hypertension, lipidemia) on drug pharmacokinetics at patients with psoriasis was analyzed. At patients with a diabetes mellitus the size CL/F was on average 29% higher, than at healthy patients. The population pharmacokinetic analysis showed that there is a tendetion of increase in clearance of an ustekinumab at patients with an affirmative immune response. Data on drug pharmacokinetics at patients with a renal or liver failure are absent.

The population pharmacokinetic analysis among patients is more senior than 65 years did not reveal influence of age on sizes of the seeming clearance (CL/F) and volume of distribution (V/F).

Use of alcohol and tobacco did not influence pharmacokinetics of an ustekinumab.

Indications to use:

Treatment of patients is more senior than 18 years with average or heavy degree of blyashechny psoriasis.

Treatment of patients is more senior than 18 years with active psoriasis arthritis (DOG) as monotherapy or in a combination with a methotrexate. 

Route of administration and doses:

The drug Cтелара® is intended for subcutaneous injections at patients 18 years are more senior.

Blyashechny psoriasis.

The recommended dose makes 45 mg. The second injection is done 4 weeks later after the first use, then by each 12 weeks.

At patients with body weight more than 100 kg drug is recommended to use 90 mg in a dose.

At inefficiency of therapy within 28 weeks it is recommended to consider expediency of use of drug.

Dose adjustment. Patients at whom clinical performance of drug at use is expressed each 12 weeks insufficiently should increase a drug dose to 90 mg each 12 weeks. If such mode of dosing is not effective, it is necessary to enter a dose of drug of 90 mg each 8 weeks.

Treatment resuming. Resuming of treatment according to the offered scheme – the second injection in 4 weeks later after the first use, and then each 12 weeks – was also effective, as well as the therapy which for the first time is carried out.

Psoriasis arthritis.

The recommended dose makes 45 mg. The second injection is done 4 weeks later after the first use, then by each 12 weeks. At patients with body weight more than 100 kg drug is recommended to use 90 mg in a dose.

Use for elderly patients (65 years are more senior). From 4031 patients accepting the drug Stelara® 248 were patients aged 65 years are more senior (183 patients with psoriasis and 65 - with psoriasis arthritis). During clinical trials influence of age on clearance or volume of distribution of drug was not revealed. In spite of the fact that during the researches of drug distinctions in safety and efficiency of drug for elderly patients were not revealed 65 years in comparison with younger patients are more senior, the number of elderly patients are not enough for a final conclusion about influence of age (or about lack of influence) on clinical performance.

Use for children. Safety and efficiency of an ustekinumab at children was not studied.

Use at a renal and liver failure. Studying of drug at patients with a renal or liver failure it was not carried out.

Instructions on administration of drug.

Drug is intended for hypodermic introduction.

Before administration of drug attentively examine syringe contents. Solution can be transparent or slightly opalescent from colourless to light-yellow color, may contain single transparent particles of protein. Such outward is normal for proteinaceous solutions. At discoloration, opacification or existence of solid particles solution cannot be used. Ustekinumab does not contain preservatives therefore no unused rest of drug in the syringe can be used.

Drug should not be mixed with other liquids for an injection. If for introduction of a dose of 90 mg use 2 syringes on 45 mg of drug, it is necessary to make 2 consecutive injections. At the same time the second injection has to be made at once after the first. Injections should be done to different areas. Do not stir up drug. Long vigorous stirring can damage drug. Do not use drug if it was stirred up. In an initiation of treatment of an injection of the drug Stelara® has to do only medical personnel, however, in the subsequent if the doctor finds possible it, the patient can do himself drug Stelara® injections independently, observing all necessary precautions and having undergone previously compulsory education to the equipment of subcutaneous injections, with the subsequent control of the doctor.

The recommended places for an injection are an upper part of a hip or area of a stomach about 5 cm below a navel. It is also possible to use area of a shoulder. It is necessary to avoid injections to the area affected with psoriasis.

Get the syringe with drug from a cardboard pack, keeping it in the direction a needle from themselves. Make sure that the syringe is not damaged. Carefully wash up hands and process the place of an injection the cotton plug moistened with an antiseptic agent. Remove a protective cap from a needle. You can see a vial of air in the syringe. It is admissible, do not try to remove it. You can also see a liquid droplet on the end of a needle. It is also admissible.

Never remove a protective cap, did not decide on the place of an injection yet. Do not allow contact of a needle with foreign objects.

Accurately clamp skin in the field of an injection between big and index fingers, thrust a needle in skin and slowly lower the syringe piston to a limit. 

After that release skin and carefully take out a needle. As soon as you take away a finger from the piston, the needle will automatically flee by the syringe case. 

Apply the cotton plug moistened with an antiseptic agent to the place of an injection and take several seconds. Do not rub the place of an injection. If necessary stick with a plaster. The used syringe needs to be utilized according to local requirements for destruction of such waste.

Use during pregnancy and a lactation.

Pregnancy. During drug studying by an animal entered a dose by 45 times the exceeding recommended clinical dose for the person, at the same time the phenomena of teratogenecity, congenital anomalies or lag in development were not revealed. However results of researches on animals are not always applicable to the person. It is unknown whether can устекинумаб lead at use for pregnant women to adverse influence on a fruit or influence reproductive function. Adequate and strictly controlled researches at pregnant women were not conducted. It is not recommended to use drug during pregnancy, effective methods of contraception in time and 15 weeks after treatment have to be used by drug.

Lactation. Researches on monkeys showed what устекинумаб is allocated with breast milk. It is unknown whether drug systemically after absorption is absorbed. As many drugs and immunoglobulins are emitted with breast milk and as the drug Cтелара® can cause adverse reactions in babies, it is necessary to make the decision on the termination of breastfeeding during administration of drug or on therapy cancellation ustekinumaby.

Features of use:

Infections.

Ustekinumab is the selection immunosuppressant and can increase risk of development of infections and reactivation of the infections which are in a latent phase. In clinical trials at use of the drug Cтелара® for patients serious bacterial, fungal and viral infections were observed. Ustekinumab it is not necessary to apply at patients with clinically significant, active infections. It is necessary to show care at use of drug for patients with persistent infections or existence of recurrent infections in the anamnesis. Before use of drug it is necessary to hold testing of the patient for existence of tuberculosis. It is not necessary to apply устекинумаб at patients with active tuberculosis. In the presence of latent or active tuberculosis (including in the anamnesis) it is necessary to begin its treatment prior to drug Stelara® use. Also it is necessary to begin treatment of tuberculosis at patients at whom the sufficient effect of its previous treatment is not confirmed. During treatment ustekinumaby and after that it is necessary to watch carefully patients for identification of signs and symptoms of active tuberculosis.

Patients should be warned about need of the address to the doctor at emergence of the signs and symptoms allowing to assume an infection. At development of a serious infection use of the drug Stelara® needs to be cancelled, the patient has to be under control of medical personnel. It is not necessary to apply устекинумаб before the end of treatment of an infection.

Malignant new growths. The drug Cтелара® is the selection immunosuppressant. Immunodepressants can increase risk of development of malignant tumors. At some patients receiving устекинумаб in clinical trials emergence of malignant new growths (skin and not skin forms) was observed. Use of the drug Stelara® was not studied at patients with malignant tumors in the anamnesis. It is necessary to show care at purpose of drug to patients with malignant tumors in the anamnesis, and also by consideration of continuation of treatment by the drug Stelara® of patients with the diagnosed malignant new growths. At all patients 60 years, and also at patients which were earlier receiving long therapy by immunodepressants or Uv-radiation are aged more senior it is necessary to conduct examination on existence of a non-melanoma carcinoma cutaneum.

Hypersensitivity reactions. In post-registration use of the drug Stelara® cases of emergence of serious reactions of hypersensitivity, including a Quincke's disease and an anaphylaxis are known. At development of anaphylactic and other serious reactions of hypersensitivity use of an ustekinumab should be stopped immediately, and it is necessary to appoint the corresponding treatment.

Vaccination. It is not necessary to see vaccination of the patient live vaccines during treatment by the drug Stelara®, and also during 15 weeks to vaccination (after reception of the last dose of the drug Stelara®) and 2 weeks after vaccination. Data on secondary infection at use of live vaccines for the patients receiving the drug Stelara® no. It is necessary to be careful at use of live vaccines for immunization of members of the family of the patient receiving treatment by the drug Stelara® as there is a risk viruso-or a bakteriovydeleniya and transmissions of infection from these persons by the patient.

Prolonged treatment by the drug Stelara® does not suppress a humoral immune response on on the vaccines containing pneumococcal polysaccharide and an antitetanic vaccine. Together with ustekinumaby it is possible to apply the vaccines containing the inactivated microorganisms, however the induced immune response can be insufficient to prevent a disease.

The accompanying immunosuppressive therapy. Safety and efficiency of use of the drug Cтелара® in a combination with immunodepressive drugs and phototherapy was not studied in researches at patients with psoriasis. During the researches at patients with psoriasis arthritis combined use with a methotrexate did not influence safety and an effektivnostpreparat of Stelara®. It is necessary to show care by consideration of a possibility of simultaneous use of other immunodepressants and an ustekinumaba, and also upon transition from therapy by other antipsoriatic biological drug on therapy ustekinumaby.

Immunotherapy. Safety and efficiency of use of the drug Cтелара® for the patients who passed an immunotherapy of allergic diseases is not established. It is necessary to be careful at the patients who are receiving now or passed an immunotherapy of allergic diseases, especially anaphylactic states.

The general. The protective cap for a needle contains in the structure natural rubber (derivative latex) and with hypersensitivity to latex can cause allergic reactions.

Influence on ability to manage vehicles and mechanisms. Researches were not conducted.

Side effects:

(> 5%) in the controlled and not controlled clinical trials of use of drug at psoriasis and psoriasis arthritis the nasopharyngitis, a headache and upper respiratory tract infections were the most frequent adverse phenomena. The majority of these phenomena were moderately expressed and did not demand the treatment termination.

Side effects of drug are systematized concerning each of systems of bodies depending on occurrence frequency, with use of the following classification: very often (> 1/10), it is frequent (> 1/100, <1/10), infrequently (> 1/1000, <1/100), is rare (> 1/10000, <1/1000), is very rare (<1/10000), including isolated cases.

Infections:

Often: dontogenous infections, upper respiratory tract infections, nasopharyngitis.

Infrequently: inflammation of a hypodermic fatty tissue, shingles, viral upper respiratory tract infections.

In placebo - controlled researches at patients with psoriasis and/or psoriasis arthritis the frequency of an infection and serious infection at use of the drug Cтелара® and placebo was identical (infection frequency – соотв. 1,27 and 1,17 cases for a cheloveko-year of treatment, the frequency of serious infections – соотв. 0,01 (5/616) and 0,01 (4/287) cases for a cheloveko-year of treatment).

During controlled and uncontrollable clinical trials at patients with psoriasis and psoriasis arthritis the frequency of infections at use of the drug Cтелара® made 0,87 cases for a cheloveko-year of treatment. Frequency of developing of a serious infection made 0,01 cases for a cheloveko-year of treatment (104/9548). Serious infections included a diverticulitis, an inflammation of a hypodermic fatty tissue, appendicitis, cholecystitis and sepsis.

Mental disturbances:

Infrequently: depression.

From the central nervous system:

Often: dizziness, headache.

From respiratory system:

Often: pharyngalgia and throats;

Infrequently: nose congestion.

From digestive tract:

Often: diarrhea, vomiting.

From skin and hypodermic fabrics:

Often: itch.

From a musculoskeletal system:

Often: dorsodynia, mialgiya, arthralgia.

The general frustration and reactions in an injection site:

Often: fatigue, an erythema in an injection site, pain in an injection site;

Infrequently: reactions in an injection site (including hemorrhage, to haemo volume, consolidation, a swelling and an itch).

Malignant tumors.

In 3 clinical placebos - controlled researches at patients with psoriasis and psoriasis arthritis the frequency of development of malignant tumors (not including a non-melanoma form of a carcinoma cutaneum) at the patients receiving устекинумаб and placebo, made соотв. 0,16 (1/615) and 0,35 (1/287) cases for 100. Frequency of development of others, than a melanoma, forms of a carcinoma cutaneum at use of the drug Cтелара® and placebo made соотв. 0,65 (4/615) and 0,70 (2/287) cases for 100. Frequency of development of malignant tumors in the patients receiving the drug Cтелара® was comparable with a frequency of developing of tumors among the population in general.

Most often, in addition to a non-melanoma carcinoma cutaneum, malignant tumors of a prostate, intestines, mammary glands and a melanoma were observed. Frequency of development of a non-melanoma carcinoma cutaneum in the patients receiving the drug Cтелара® made 0,61 cases for 100 (41/6770).

Hypersensitivity reactions. In clinical trials rash and urticaria were observed less than at 1% of patients.

Immunogenicity. Approximately at 6% of the patients with psoriasis and psoriasis arthritis receiving the drug Cтелара® antibodies to an ustekinumab which usually had a low caption formed. Explicit correlation between formation of antibodies and existence of reactions together the injection is not revealed. In the presence of antibodies to an ustekinumab patients had lower performance of drug more often though existence of antibodies does not exclude achievement of clinical effect. Most of the patients with psoriasis who had antibodies to an ustekinumab possessed as well the antibodies neutralizing such antibodies.

The undesirable phenomena revealed in post-registration use of the drug Stelara®.

From immune system:

Infrequently: hypersensitivity reactions (including rash and urticaria);

Seldom: serious reactions of hypersensitivity (including an anaphylaxis and a Quincke's disease).

From skin and hypodermic fabrics:

Infrequently: blyashechny psoriasis.

Interaction with other medicines:

Researches of medicinal interaction in public were not conducted.

Effects of SILT-12 and SILT-23 on CYP450 enzymes were studied by in vitro on hepatocytes of the person. The research showed that SILT-12 and/or SILT-23 in concentration of 10 ng/ml did not influence CYP450 enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6 or 3A4). The received results do not assume need of dose adjustment at the patients accepting along with the drug Cтелара® drugs, metaboliziruyemy to CYP450 enzymes.

It is not necessary to apply the vaccines containing the weakened causative agents of infectious diseases along with ustekinumaby. At combined use of the drug Cтелара® and such drugs as paracetamol (acetaminophen), an ibuprofen, acetylsalicylic acid, Metforminum, аторвастатин, Naproxenum, left thyroxine and a hydrochlorothiazide of interaction it was not revealed. Safety and efficiency of combined use of the drug Cтелара® with other immunodepressants (a methotrexate, cyclosporine) or biological drugs for treatment of psoriasis was not estimated.

Contraindications:

- Clinically significant hypersensitivity to an ustekinumab or any excipient of drug;

- Children's age (up to 18 years);

- Pregnancy and lactation;

- Serious infectious diseases in an acute phase, including tuberculosis;

- Malignant new growths.

With care:

- Chronic or recurrent parasitic and infectious diseases of the virus, fungal or bacterial nature.

- Malignant tumors in the anamnesis.

- Advanced age. 

Overdose:

During conduct of clinical trials to patients once intravenously entered doses to 6 mg/kg without development of dozolimitiruyushchy toxicity. In case of overdose it is recommended to control a condition of the patient for identification of signs and symptoms of side effects and at their development it is necessary to begin the corresponding symptomatic therapy immediately. 

Storage conditions:

To store in original packaging in the place protected from light at a temperature from 2 to 8 °C. Not to freeze. Not to stir up. To store in the place, unavailable to children. 

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction of 90 mg/ml. On 0,5 ml or 1,0 ml in syringes from borosilicate glass (type I) with the UltraSafe Passive® device. Each syringe contains 45 mg (45 mg / 0,5 ml) or 90 mg (90 mg / 1,0 ml) an ustekinumaba. On 1 syringe together with the instruction on a medical use place in a pack cardboard.