Ustekinumab - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation

Stelara®

solution PC

Johnson & Johnson, LLC Russia

Stelara®

solution PC

Johnson & Johnson, LLC Russia

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

L.04.A Immunosuppressive drugs

L.04.A. C.05 Ustekinumab

Pharmacodynamics:

An interleukin inhibitor, a fully human monoclonal antibody of IgG1k class with a molecular weight of about 148,600 daltons, 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 interleukins (IL) of human IL-12 and IL-23. It 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 can not bind to IL-12 and IL-23, already associated with the IL-12R-β1 receptor. Therefore, no effect on the complement or antibody-dependent cytotoxicity of cells carrying these receptors is expected.

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 reactions, 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 considered that ustekinumab interrupts the cascade of signal transduction and cytokine secretion, which play a key role in the development of psoriasis.

Ustekinumab leads to a significant weakening of histological manifestations of psoriasis, including hyperplasia and proliferation of epidermal cells. These data are consistent with clinical efficacy. It 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 isolated from biopsy samples of skin lesions of psoriasis initially and after 2 weeks of treatment showed that the use of ustekinubam led to 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, TNFα, 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 of the PASI (area and severity index of psoriasis) appears to depend on the concentration of ustekinumab in the blood plasma.In patients with the best PASI score, the average plasma кикикинумамамама концентрации концентрации было concentration was higher, than in patients with less clinical effect.In general, the proportion of patients with an improvement in the PASI score of 75% increased with the increase in the concentration of ustekinumab in the blood plasma.

Pharmacokinetics:

After a single sc administration at a dose of 90 mg to healthy volunteers, the mean T_max in blood plasma was 8.5 days. In patients with psoriasis, this value at doses of the drug 45 mg or 90 mg was comparable to that of healthy volunteers. Absolute bioavailability of ustekinumab after a single administration of psoriasis patients was 57.2%.

The average value of Vd of ustekinumab in the terminal phase of elimination after a single intravenous administration of psoriasis patients was 57-83 ml / kg.

System exposure ustekinumab (C_max and AUC) in patients with psoriasis increased in proportion to the administered doses after a single intravenous dose in the range of 0.09 mg / kg to 4.5 mg / kg,as well as after a single dose of doses in the range from 24 mg to 240 mg.

Change ustekinumab plasma concentration over time after single or multiple repeated injections of the drug were largely predictable. C_ss ustekinumab plasma levels achieved by 28 weeks of therapy with the proposed mode (second injection 4 weeks after the first application, then every 12 weeks). Average C_ss is 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 in serum was not observed during treatment for a duration of 12 weeks.

The metabolic path of ustekinumab is not known.

The average value of systemic clearance ustekinumab after a single on / in the patient with psoriasis was 1.99 to 2.34 mL / day / kg.

Average half-life ustekinumab in patients with psoriasis was approximately 3 weeks and in different studies varied from 15 to 32 days.

The concentration in the blood plasma depends on the patient's body weight. When administered in similar doses (45 mg or 90 mg) in patients weighing more than 100 kg ustekinumab mean concentration in the plasma was less than in patients weighing less than 100 kg.However, the average minimum concentration ustekinumab in blood plasma of patients body weight over 100 kg at a dose of 90 mg, was comparable to that in patients weighing less than 100 kg at a dose of 45 mg.

The apparent clearance and Vd were 0.465 l / day and 15.7 l respectively. Half-lifeustekinumab was approximately 3 weeks. The apparent clearance was influenced by the body weight of patients, while in patients with a greater body weight, its magnitude was greater. 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 patients with diabetes mellitus, the apparent apparent clearance was on average 29% higher than in healthy patients.

Indications:

Treatment of plaque psoriasis of moderate or severe severity.

ICD-10

XII.L40-L45.L40.9 Psoriasis, unspecified

XII.L40-L45.L40.8 Other psoriasis

XII.L40-L45.L40.4 Psoriasis teardeep

XII.L40-L45.L40.1 Generalized pustular psoriasis

XII.L40-L45.L40 Psoriasis

Contraindications:

Hypersensitivity, severe infectious diseases in the acute phase, incl. tuberculosis; malignant neoplasms; children under 18 years of age, pregnancy, breast-feeding.

Carefully:

Elderly age, renal and hepatic insufficiency.

Pregnancy and lactation:

Category of recommendations FDA H.

Contraindicated in pregnancy and lactation.

Dosing and Administration:

Enter the SC.

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

For patients with a body weight of more than 100 kg, the recommended dose is 90 mg.

If the therapy is ineffective for 28 weeks, it is recommended to consider the utility of ustekinumab.

If the clinical effect is not sufficiently pronounced, a dose adjustment according to a special scheme should be performed.

Side effects:

The most serious side effects are: malignant neoplasms and serious infections.

Most often (> 10%): nasopharyngitis and upper respiratory tract infections.

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

From the respiratory system: often - pain in the throat and larynx, nasal congestion.

From the digestive system: often diarrhea.

From the skin and subcutaneous tissues: often - itching.

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

Allergic reactions: less than 2% - rash and hives.

Common reactions: often fatigue.

Local reactions: often fatigue; sometimes - reactions at the injection site (pain, swelling, itching, tightness, bleeding, hemorrhage, irritation).

Immunogenicity: 5% - the formation of antibodies to ustekinumab, which usually had a low titer.

Overdose:Not described.

Interaction:Not described.

Special instructions:

Before starting the test, the patient should be tested for tuberculosis. In the presence of latent or active tuberculosis (including in the anamnesis), it is necessary to begin its treatment before the application of utekinumab. Also, it is necessary to begin treatment of tuberculosis in patients who have not had sufficient effect from the previous treatment. During the treatment with usekinumab and after this, patients should be closely monitored to identify signs and symptoms of active tuberculosis.

With the development of anaphylactic and other serious allergic reactions, the use of ustekinumab should be stopped immediately and appropriate treatment prescribed.

During the treatment period it is not recommended to use vaccines containing weakened infectious agents (viral or bacterial) diseases, as well as 15 weeks before the vaccination (after the last dose of ustekinumab) and 2 weeks after vaccination. Together with ustekinumab, vaccines containing inactivated microorganisms can be used.

The safety and efficacy of ustekinumab 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.

Instructions

Ustekinumab (Ustekinumabum)