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Instructions

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Instruction for use: Stelara

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Dosage form: Solution for subcutaneous administration

Active substance: Ustekinumabum

ATX

L04AC05 Ustekinumab

Pharmacological group:

Psoriasis treatment, interleukin inhibitor [Immunodepressants]

The nosological classification (ICD-10)

L40 Psoriasis: Chronic plaque psoriasis with diffuse; generalized psoriasis; Psoriasis of the scalp; hairy parts of the skin; A generalized form of psoriasis; Psoriazoformny dermatitis; Psoriasis complicated with erythroderma; disabling psoriasis; Isolated psoriatic plaque; Eksfolliativny psoriasis; psoriatic erythroderma; Psoriasis with eczematization; Hyperkeratosis in psoriasis; Inverse psoriasis; Psoriasis ekzemopodobnye; dermatoses psoriazoformny; Psoriasis genitals; Psoriasis lesions with hairy areas of the skin; erythrodermic psoriasis; Chronic psoriasis of the scalp; Chronic psoriasis; ordinary psoriasis; refractory psoriasis; Koebner phenomenon; psoriasis

Composition

Solution for subcutaneous administration 1 ml

active substance: Ustekinumab 90 mg

Auxiliary substances: sucrose - 76 mg; L-histidine (including L-histidine hydrochloride monohydrate) - 1 mg; Polysorbate 80 - 0.04 mg; Water for injection - up to 1 ml

Description of dosage form

Solution for SC introduction in vials: opalescent solution from colorless to light yellow color. The solution can contain single transparent protein particles.

Solution for SC introduction in syringes: a clear or slightly opalescent solution from colorless to light yellow color. The solution can contain single transparent protein particles.

Pharmachologic effect

Mode of action - immunosuppressive.

Pharmacodynamics

Mechanism of action. Ustekinumab is a fully human monoclonal antibody of class IgG1k with a molecular weight of about 148600 Da, produced by the recombinant cell line and undergoing multistep purification, including inactivation and removal of viral particles. Ustekinumab has a high affinity and specificity for the p40 subunit of human IL-IL-12 and IL-23. The drug blocks the biological activity of IL-12 and IL-23, preventing their binding to the IL-12R-β1 receptor expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 and IL-23, already associated with the IL-12R-β1 receptor. Therefore, the drug is unlikely to affect the complement or antibody-dependent cytotoxicity of cells carrying these receptors.

IL-12 and IL-23 are heterodimeric cytokines that are secreted by activated antigen-presenting cells, in particular macrophages and dendritic cells. IL-12 and IL-23 are involved in immune responses, promoting activation of NK cells (natural killers) and differentiation and activation of CD4 + -T cells. However, in diseases associated with impaired immune system functions (such as psoriasis), there may be a disruption in the regulation of IL-12 and IL-23. Ustekinumab blocks the effects of IL-12 and IL-23 on the activation of immune cells, in particular the intracellular signaling and secretion of cytokines caused by these cytokines. Thus, it is believed that ustekinumab interrupts the cascade of signal transduction and cytokine secretion, which play a key role in the development of psoriasis.

The use of Stelara® leads to a significant weakening of histological manifestations of psoriasis, including hyperplasia and proliferation of epidermal cells. These data are consistent with clinical efficacy. Ustekinumab has no significant effect on the ratio of circulating immune cells in the blood, including memory cells and non-activated T cells, as well as the concentration of cytokines in the blood.

Analysis of mRNA (matrix RNA) isolated from biopsy specimens of skin lesions of psoriasis initially and after 2 weeks of treatment showed that the use of Stelara® resulted in a decrease in the expression of genes encoding its molecular targets-IL-12 and IL-23, as well as genes , Encoding inflammatory cytokines and chemokines - monocyte chemotactic factor (MCP) -1, tumor necrosis factor (TNF) -alpha, interferon-gamma-inducible protein (IP) -10 and IL-8. These data are consistent with the significant clinical effect of treatment.

The clinical effect (improvement in the scale of assessment of the area and severity of psoriasis PASI - the index of the area and severity of psoriasis) appears to depend on the concentration of ustekinumab in the blood plasma. In patients with the best result in PASI average value of ustekinumab concentration in blood plasma was higher than in patients with less clinical effect. In general, the proportion of patients with a PASI improvement of 75% increased as the concentration of ustekinumab increased in plasma.

Pharmacokinetics

Suction. The mean Tmax in blood plasma after a single administration of 90 mg of ustekinumab to healthy volunteers was 8.5 days. In patients with psoriasis, this value at doses of the drug 45 or 90 mg was comparable to that of healthy volunteers.

Absolute bioavailability of ustekinumab after a single administration of psoriasis was 57.2%.

Distribution. The average value of Vd of ustekinumab in the terminal elimination phase after a single IV injection of psoriasis patients ranged from 57 to 83 ml / kg.

Metabolism. The metabolic pathway of ustekinumab is not known.

Excretion. The average value of systemic clearance of ustekinumab after a single intravenous administration of psoriasis patients ranged from 1.99 to 2.34 ml / day / kg.

The mean T1 / 2 of ustekinumab in patients with psoriasis was approximately 3 weeks and varied from 15 to 32 days in different studies.

Linearity. Systemic exposure of ustekinumab (Cmax and AUC) in patients with psoriasis increased in proportion to the administered doses after a single IV dose in the range of 0.09 to 4.5 mg / kg, as well as after a single dose of doses ranging from 24 Up to 240 mg.

The change in the concentration of ustekinumab in the blood plasma over time after single or repeated repeated administration of the drug was basically predictable. Css ustekinumab in blood plasma was achieved by the 28th week with the proposed regimen of therapy (second injection 4 weeks after the first application, then every 12 weeks). On average, Css of the drug was 0.21-0.26 μg / ml for a dose of 45 mg and 0.47-0.49 μg / ml for a dose of 90 mg. Cumulation of the drug in the blood serum was not observed during treatment lasting 12 weeks.

The influence of the patient's body weight on the pharmacokinetics of the drug. The concentration of the drug in the blood plasma depends on the patient's body weight. When the same doses (45 or 90 mg) were administered in patients with a body weight of more than 100 kg, the average concentration of ustekinumab in the plasma was less than in patients weighing less than 100 kg. However, the average Cmin of ustekinumab in the blood plasma of patients weighing more than 100 kg administered with 90 mg of the drug was comparable to that in the group of patients weighing less than 100 kg administered with 45 mg of the drug.

Population pharmacokinetic analysis. The apparent clearance and Vd were 0.465 l / h day and 15.7 l, respectively. T1 / 2 of the drug was approximately 3 weeks. Sex, age and belonging to a particular race did not affect the apparent clearance of ṇ̃å uskinumab. The apparent clearance of the drug was influenced by the body weight of patients, while in patients with a larger body weight the apparent clearance was larger. The average apparent clearance in patients with a body weight of more than 100 kg was approximately 55% higher than that in patients with a lower body weight. Vd in patients with a body weight of more than 100 kg was approximately 37% higher than that in patients with a lower body weight.

In the course of the analysis, the influence of existing diseases (diabetes mellitus or in the past, arterial hypertension, hyperlipidemia) on the pharmacokinetics of the drug was studied. In patients with diabetes, the apparent clearance value was on average 29% higher than in healthy patients.

Data on the pharmacokinetics of the drug in patients with renal or hepatic insufficiency do not.

Population pharmacokinetic analysis among patients older than 65 years did not reveal the effect of age on apparent apparent clearance and Vd.

The use of alcohol and tobacco did not affect the pharmacokinetics of ustekinumab.

Indication of the drug Stelara

Treatment of patients older than 18 years with moderate or severe degree of plaque psoriasis.

Contraindications

Severe hypersensitivity to ustekinumab or any auxiliary substance of the drug;

Serious infectious diseases in the acute phase, incl. Tuberculosis (see "Special instructions");

Malignant neoplasms (see "Special instructions");

Children's age (up to 18 years);

Pregnancy and lactation (see "Application in pregnancy and lactation").

With caution: chronic or recurrent parasitic and infectious diseases of a viral, fungal or bacterial nature; Malignant tumors in the anamnesis; elderly age.

Application in pregnancy and breastfeeding

During the study of the drug, a dose of 45 times the recommended clinical dose for humans was administered to the animals, and no teratogenicity, congenital anomalies, or developmental deficits were detected. However, the results of animal studies are not always applicable to humans.

It is not known whether ustekinumab, when used in pregnant women, can lead to adverse effects on the fetus or affect reproductive function. Adequate and strictly controlled studies in pregnant women were not conducted.

It is recommended to avoid the use of the drug during pregnancy and to use effective methods of contraception during and for 15 weeks after treatment with the drug.

Studies in monkeys have shown that ustekinumab is excreted in breast milk. It is not known whether the drug is absorbed systematically after exposure to the newborn. Since many drugs and immunoglobulins are excreted in breast milk in lactating women, and since Stelara® can cause adverse reactions in infants, a decision should be made to stop breastfeeding during the period of taking the drug or to cancel the treatment with ustekinumab.

Side effects

The most serious side effects in the treatment with Stelara® were malignant neoplasms and serious infections.

The most frequent adverse events (> 10%) in controlled and uncontrolled clinical trials of drug use in psoriasis were nasopharyngitis and upper respiratory tract infections. Most of these phenomena were mild and did not require discontinuation of treatment.

Side effects of the drug are systematized relative to each of the organ systems depending on the frequency of occurrence, using the following classification: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000), including isolated cases.

Infections: very often - infections of the upper respiratory tract, nasopharyngitis; Often - viral infections of the upper respiratory tract, inflammation of the subcutaneous fat; Infrequently - herpes zoster.

In controlled trials in patients with psoriasis, the incidence of infection, incl. Serious infection with the use of the drug Stelara ® and placebo was the same (the incidence of infections - respectively 1.39 and 1.21 cases per person / year of treatment, the frequency of serious infections - respectively 0.01 (5/407) and 0.02 (3 / 177) of the case per person / year of treatment).

In controlled and uncontrolled clinical trials, the incidence of infections with Stelara® was 1.24 (24/2251) per person / year of treatment. Cases of serious infection included inflammation of subcutaneous fat, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia and urinary tract infections.

From the side of the central nervous system: often - dizziness, headache, depression.

On the part of the respiratory system: often - pain in the throat and larynx, nasal congestion.

From the digestive tract: often - diarrhea.

From the skin and subcutaneous tissues: often - itching, hives.

From the musculoskeletal system: often - myalgia, pain in the back.

General disorders and reactions at the injection site: often - fatigue, erythema at the injection site; Infrequently - reactions at the injection site (pain, swelling, itching, tightness, bleeding, hemorrhage, irritation).

Malignant tumors. In clinical placebo-controlled trials in patients with psoriasis, the incidence of malignant tumors (not including non-melanoma skin cancer) in patients receiving utekinumab and placebo was 0.25 (1/406) and 0.57 (1/177), respectively For 100 people / year. The incidence of cancer, other than melanoma, with the use of Stelara and placebo was 0.74 (3/406) and 1.13 (2/176) per 100 people / year, respectively.

The incidence of malignant tumors in patients treated with Stelara® was comparable to the incidence of tumors in the general population.

Most often, in addition to non-melanoma skin cancer, malignant tumors of the prostate, intestines, mammary glands and melanoma in situ were observed. The incidence of non-melanoma skin cancer in patients receiving Stelara® was 0.61 (41/6770) per 100 people / year.

Hypersensitivity reactions: In clinical trials, rash and urticaria were observed in less than 2% of patients.

Immunogenicity: approximately 5% of patients receiving Stelara® received antibodies to ustekinumab, which usually had a low titer. There was no clear correlation between the formation of antibodies and the presence of reactions at the injection site. In the presence of antibodies to ustekinumab, patients often had a lower efficacy of the drug, although the presence of antibodies does not exclude the achievement of a clinical effect.

Undesirable phenomena revealed in the post-marketing application of Stelara®

From the immune system: often - hypersensitivity reactions (including rash and hives); Rarely serious reactions of hypersensitivity (including anaphylaxis and angioedema).

Interaction

Studies of drug interactions in humans have not been conducted.

Effects of IL-12 and IL-23 on CYP450 enzymes were studied in vitro on human hepatocytes. The study showed that IL-12 and / or IL-23 at a concentration of 10 ng / ml did not affect the enzymes CYP450 (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 or CYP3A4). The results obtained do not imply the need for dose adjustment in patients taking drugs metabolized by CYP450 enzymes concurrently with the preparation of Celar.

Do not use vaccines containing weakened pathogens of infectious diseases, concomitantly with ustekinumab.

With the joint use of Stelara® and such drugs as paracetamol (acetaminophen), ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine and hydrochlorothiazide, no interaction was found.

The safety and efficacy of the combined use of Stelara® with other immunosuppressants (methotrexate, cyclosporine) or biological agents for the treatment of psoriasis has not been evaluated.

Dosing and Administration

Patients over 18 years of age.

The recommended dose is 45 mg. The second injection is done 4 weeks after the first application, then every 12 weeks.

In patients with a body weight of more than 100 kg, the drug is recommended to use a dose of 90 mg.

If the therapy is ineffective for 28 weeks, it is recommended to consider the expediency of using the drug.

Correction of the dose. Patients in whom the clinical efficacy of the drug every 12 weeks is not enough, the dose should be increased to 90 mg every 12 weeks. In the event that such a dosing regimen is not effective, a dose of 90 mg should be given every 8 weeks.

Renewal of treatment. The resumption of treatment according to the proposed scheme - the second injection 4 weeks after the first application, and then every 12 weeks - was just as effective as the first therapy.

Use in elderly patients (over 65 years). In clinical trials, no effect of age on clearance or Vd of the drug was detected. During drug studies, there was no difference in the safety and efficacy of the drug for elderly patients over 65 years of age compared with younger patients.

Use in children. The safety and efficacy of ustekinumab in children have not been studied.

Application in renal and hepatic insufficiency. The study of the drug in patients with renal or hepatic insufficiency was not carried out.

Instructions for the administration of the drug

Before administering the drug, carefully inspect the contents of the syringe or vial. The solution may be clear or slightly opalescent from colorless to light yellow, may contain single transparent protein particles. If the color changes, turbidity or the presence of solid particles, the solution cannot be used. Ustekinumab does not contain preservatives, so any unused drug residue in a syringe or vial cannot be used.

The preparation should not be mixed with other injectable liquids. If two injections or a 45 mg vial are used to administer a dose of 90 mg, two consecutive injections should be made. The second injection should be done immediately after the first injection. Injections do in different areas.

Do not shake the drug. Prolonged vigorous shaking can damage the drug. Do not use the drug if it is shaken.

At the beginning of the treatment, Stelara® should be injected only by medical personnel, but in the future, if the doctor deems it possible, the patient can inject himself with Stelara® on his own, observing all necessary precautions and after having been obligatory trained in injection technique, followed by Control of the doctor.

Recommended places for injection are the upper part of the thigh or abdomen (about 5 cm below the navel). You can also use the shoulder area. Avoid injections into the area affected by psoriasis.

- For solution for SC infusion in vials

Wash hands thoroughly and treat the injection site with a cotton swab moistened with antiseptic.

Remove the protective cap from the bottle with the drug. Do not remove the rubber cap. Wipe the rubber cap with a cotton swab moistened with an antiseptic. Remove the protective cap from the needle of the syringe (the syringe is not included in the package of the preparation). Do not allow the needle to come into contact with foreign objects and do not touch the needle.

Put the vial with the drug on a flat surface and insert the needle of the syringe into the rubber cap of the vial. Turn the vial with the drug and insert it into the syringe.

Type the contents of the vial into the syringe. In order to avoid air bubbles entering the syringe, the tip of the needle, when typing the drug in the syringe, should always be in the liquid.

Remove the syringe from the vial. Hold the syringe with the needle in the direction away from you and check for air bubbles in it. If there are air bubbles in the syringe, gently tap on the syringe wall until the air bubbles move up.

Press the syringe onto the piston to release air bubbles. Do not put a syringe and do not allow the needle to come into contact with foreign objects.

Gently squeeze the skin in the area of injection between the thumb and forefinger, insert the needle into the skin and slowly lower the plunger of the syringe to the limit.

After this, release the skin and gently remove the needle. A small amount of blood can be released from the injection site, which is normal. Apply a cotton swab, moistened with antiseptic, to the injection site and hold for a few seconds. Do not rub the injection site. If necessary, stick a band-aid.

The used syringe must be disposed of in accordance with local requirements for the destruction of such waste. Never reuse needles.

- For solution for SC injection in syringes

Get the syringe with the drug from the cardboard bundle, keeping it in the direction of the needle from itself. Make sure that the syringe is not damaged. Wash hands thoroughly and treat the injection site with a cotton swab moistened with antiseptic. Remove the protective cap from the needle. In the syringe there may be an air bubble, which is permissible, you should not remove it. At the end of the needle there may be a droplet of liquid, which is also permissible.

Never remove the protective cap until the injection site has been determined. Do not allow needle contact with foreign objects.

Gently squeeze the skin in the area of injection between the thumb and forefinger, insert the needle into the skin and slowly lower the plunger of the syringe to the limit.

After this, release the skin and gently remove the needle. As soon as the finger is removed from the piston, the needle automatically disappears in the syringe body.

Apply a cotton swab, moistened with antiseptic, to the injection site and hold for a few seconds. Do not rub the injection site. If necessary, stick a band-aid.

The used syringe must be disposed of in accordance with local requirements for the destruction of such waste.

Overdose

At the time of clinical trials, patients once IV received doses of up to 4.5 mg / kg without development of dose-limiting toxicity.

Treatment: in case of an overdose, it is recommended to monitor the patient's condition to identify signs and symptoms of side effects and, when they develop, immediately begin appropriate symptomatic therapy.

Special instructions

Infections. Ustekinumab is a selective immunosuppressant and may increase the risk of infections and the reactivation of infections in the latent phase.

In clinical studies with the use of the drug Stelara ® in patients there were serious bacterial, fungal and viral infections. Ustekinumab should not be used in patients with clinically relevant, active infections. Care should be taken when using the drug in patients with chronic infections or the presence of recurrent infections in the anamnesis.

Before starting the drug, the patient should be tested for tuberculosis. Do not use ustekinumab in patients with active tuberculosis. In the presence of latent or active tuberculosis (including in the anamnesis), it is necessary to begin its treatment before the use of the drug Stelara®. Also, it is necessary to begin treatment of tuberculosis in patients who have not had sufficient effect from their previous treatment. During the treatment with usekinumab and after that, we should carefully monitor the patients to identify signs and symptoms of active tuberculosis.

Patients should be warned about the need to see a doctor if signs and symptoms appear that suggest infection. With the development of severe infection, Stelara® should be discontinued and the patient must be under the supervision of medical personnel. Do not use ustekinumab until after the treatment of the infection.

Malignant neoplasms. The drug Stelara ® is a selective immunosuppressant. Immunosuppressants can increase the risk of developing malignant tumors. In some patients who received ustekinumab in clinical studies, malignant neoplasms (cutaneous and non-dermal forms) were observed.

Hypersensitivity reactions. In the post-marketing application of Stelar®, cases of serious hypersensitivity reactions are known, including angioedema and anaphylaxis. With the development of anaphylactic and other serious hypersensitivity reactions, the use of ustekinumab should be stopped immediately and appropriate treatment prescribed.

Vaccination. During the treatment with Stelara®, vaccines containing weakened pathogens of infectious (viral or bacterial) diseases are not recommended. The use of the drug is not recommended in the period 15 weeks before vaccination (after taking the last dose of Stelara®) and within 2 weeks after vaccination.

Data on secondary infection with the use of live vaccines in patients receiving the preparation of Stelara® are absent. Caution should be exercised when using live vaccines to immunize family members of the patient receiving Stelara®.

Together with ustekinumab, vaccines containing inactivated microorganisms can be used.

Concomitant immunosuppressive therapy. The safety and efficacy of Stelara® in combination with immunosuppressive drugs and phototherapy has not been studied. Caution should be exercised when considering the possibility of simultaneous use of other immunosuppressants and utekinumab, as well as during the transition from therapy with another antipsoriasis biological agent to ustekinumab therapy.

Immunotherapy. The safety and efficacy of Stelara® in patients who underwent immunotherapy for allergic diseases have not been established. Caution should be exercised in patients currently receiving or undergoing immunotherapy for allergic diseases, especially anaphylactic conditions.

General. For solution for SC injection in syringes - protective cap for the needle contains in its composition natural rubber (latex derivative) and in the presence of hypersensitivity to latex can cause allergic reactions.

Impact on the ability to drive a car or perform work that requires an increased speed of physical and mental reactions. Studies have not been conducted.

Release form

A solution for subcutaneous administration, 90 mg / ml.

For 0.5 or 1 ml in a borosilicate glass syringe (type I) with an UltraSafe Passive® device. 1 syringe in a pack of cardboard.

For 0.5 or 1 ml in a bottle of borosilicate glass (type I), a capacity of 2 ml, corked with a rubber stopper, crimped with an aluminum cap, and equipped with a flip-off cap. On 1 ôë. In a pack of cardboard.

Each syringe or vial contains 45 mg (45 mg / 0.5 ml) or 90 mg (90 mg / 1 ml) of ustekinumab.

Manufacturer

The holder of the registration certificate and the organization accepting the claims: Johnson & Johnson LLC, Russia.

For a solution for administration in bottles

Manufacturer, primary and secondary packaging, which issues quality control: Silag AG, Hochstrasse 201, Schaffhausen CN-8205, Switzerland.

For a solution for SC injection in syringes

Manufacturer: Silag AG, Hochstraße 201, Schaffhausen CN-8205, Switzerland or Baxter Pharmaceutical Solutions LLS, 927 C Curry Pike Bloomington, IN 47403, USA.

Primary and secondary packaging, which issues quality control: Silag AG, Switzerland.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Stelara

In the original packaging, protected from light, at a temperature of 2-8 ° C (do not freeze, do not shake).

Keep out of the reach of children.

Shelf life of the drug Stelara

Solution for subcutaneous administration 45 mg / 0.5 ml - 2 years.

Solution for subcutaneous administration of 90 mg / ml - 2 years.

Do not use after the expiry date printed on the package.

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