STELARA
Active material: Ustekinumab
When ATH: L04AC05
CCF: Immunosuppressive drugs. Interleukin receptor antagonist
ICD-10 codes (testimony): L40
When CSF: 14.02.02
Manufacturer: JOHNSON & JOHNSON LTD (Russia)
Pharmaceutical form, composition and packaging
The solution for the p / to the introduction colorless to pale yellow, opalescent; It may comprise a single transparent particles protein.
| 1 fl. (0.5 ml) | |
| Ustekinumab | 45 mg |
Excipients: sucrose, L-histidine (incl. L-histidine hydrochloride monohydrate), polysorbate 80, water d / and.
0.5 ml – glass bottles with capacity 2 ml (1) – packs cardboard.
The solution for the p / to the introduction colorless to pale yellow, opalescent; It may comprise a single transparent particles protein.
| 1 fl. (1 ml) | |
| Ustekinumab | 90 mg |
Excipients: sucrose, L-histidine (incl. L-histidine hydrochloride monohydrate), polysorbate 80, water d / and.
1 ml – glass bottles with capacity 2 ml (1) – packs cardboard.
Pharmacological action
Interleukin inhibitors. Ustekinumab is a fully human monoclonal antibody class IgG1k with molecular weight of about 148600 Dalton, produced by recombinant cell line and passing a multi-stage cleaning, including inachtiwatia and removing viral particles. Ustekinumab has high affinity and specificity to the subunit of interleukins valve (IL) human IL-12 and IL-23. The drug blocks the biological activity of IL-12 and IL-23, preventing them from binding to receptor IL-12R-β1, jekspressiruemym on the surface of immune cells. Ustekinumab cannot communicate with IL-12 and IL-23, already associated with receptor IL-12R-β1. Therefore, the drug is unlikely to affect the complement- or antibody-dependent cell cytotoxicity, Bearing these receptors.
IL-12 and IL-23 are geterodimernymi cytokines, that Antigen-activated sekretirujutsja prezentirujushhimi cells, in particular, macrophages and dendritnymi cells. IL-12 and IL-23 involved in immune reactions, by facilitating the activation of NK cells (natural killer cells) and differentiation and activation of CD4+-T-cells. However, when diseases, associated with impaired immune system (such as psoriasis), There may be a violation of the regulation of IL-12 and IL-23. Ustekinumab blocks the effects of IL-12 and IL-23 to activate immune cells, in particular, called these cytokines intracellular signaling and secretion of cytokines. Thus, considered, that interrupts the ustekinumab cascade reactions signal transfer and secretion of cytokines, which play a key role in the development of psoriasis.
The drug Stelara® leads to a significant weakening of the histologic manifestations of psoriasis, including hyperplasia and proliferatiou cells of the epidermis. These data are consistent with clinical efficiency. Ustekinumab does not significantly affect the ratio of circulating immune cells in the blood, including memory cells and non-activated t cells, as well as on the concentration of cytokines in the blood.
Analysis of mRNA, biopsy of skin samples from the pockets of psoriasis initially and through 2 week of treatment, showed, that use of the drug Stelara® lead to a decrease in gene expression, coding its molecular targets – IL-12 and IL-23, as well as genes, encoding inflammatory cytokine and Chemokine – monocitarnyj hemotaksicheskij factor (MPW)-1, tumor necrosis factor (TNF)-alpha, Interferon-gamma – inducibel'nyj protein (IP)-10 and IL-8. These data are consistent with a significant clinical effect of treatment.
The clinical effect (improvement on the scale of assessment and severity PASI psoriasis area and severity index/psoriasis/), apparently, depends on the concentration of plasma ustekinumaba. In patients with the best result on the scale of PASI ustekinumaba the median concentration in plasma was higher, than patients with less clinical effect. Generally, the proportion of patients, which improvement scale PASI reached 75%, increased with increasing concentrations of plasma ustekinumaba.
Pharmacokinetics
Absorption
After a single s / c injection dose 90 mg healthy volunteers mean Tmax in plasma was 8.5 d. In psoriasis, this quantity of the drug at doses 45 mg or 90 mg was comparable to that in healthy volunteers. The absolute bioavailability of ustekinumab following a single s / c administration to patients with psoriasis was 57.2%.
Distribution
Mean value (V)d ustekinumaba in Terminal phase excretion after a single on/in the introduction of psoriasis patients was 57-83 ml / kg.
Systemic exposure ustekinumab (FROMmax и AUC ) in patients with psoriasis increases proportionally entered dose after a single on / in a dose in the range of 0.09 mg/kg up to 4.5 mg / kg, and after a single s / c injection of doses ranging from 24 mg 240 mg.
Changing the concentration ustekinumab plasma over time after single or repeated injections of multiple drug was substantially predictable. Css ustekinumaba in plasma achieved to 28 week when the proposed mode of therapy (second injection 4 weeks after the first application, then every 12 weeks). The average Css the drug is 0.21-0.26 ug / ml for a dose 45 mg 0.47-0.49 ug / ml for a dose 90 mg.
Cumulation of the drug in the serum were observed in treatment during the duration 12 weeks.
Metabolism
Pathway ustekinumab is unknown.
Deduction
The average systemic clearance ustekinumaba after a single on/in the introduction patients with psoriasis was 1.99 to 2.34 ml / day / kg.
Average T1/2 ustekinumaba in patients with psoriasis was approximately 3 week and in various studies ranged from 15 to 32 d.
Pharmacokinetics in special clinical situations
The concentration of drug in plasma depends on the body weight of the patient. With the introduction of the same doses (45 mg or 90 mg) for patients weighing more than 100 kg average concentration of ustekinumab in plasma was lower, than in patients weighing less than 100 kg. However, the average minimum concentration of ustekinumaba in plasma patients weighing more than 100 kg, administered 90 mg, was comparable to that in patients weighing less than 100 kg, administered 45 mg.
Population pharmacokinetic analysis. The apparent clearance and Vd were 0.465 l/d day and 15.7 l, respectively. T1/2 about ustekinumaba 3 of the week. Paul, age and belonging to a different race does not affect the apparent clearance ustekinumaba. The apparent clearance of the drug influence body weight patients, While patients with greater body mass its magnitude was larger. Average apparent clearance in patients weighing more than 100 kg was approximately 55% higher than those in patients with lower body weight. Vd for patients weighing more than 100 kg was approximately 37% higher than those in patients with lower body weight.
The analysis examined the impact of existing diseases (diabetes at present or in history, arterial hypertension, hyperlipidemia) on the pharmacokinetics of the drug. In patients with diabetes mellitus value apparent clearance was on average 29% higher, than in healthy patients.
Data on the pharmacokinetics of the drug in patients with renal or hepatic impairment is not.
Population pharmacokinetic analysis in patients older 65 years showed no effect of age on the magnitude of the apparent clearance and Vd.
Safety and efficacy of ustekinumab in children has not been studied.
The use of alcohol and tobacco will not affect the farmakokinetiku ustekinumaba.
Testimony
-treatment of patients over 18 years with moderate to severe plaque psoriasis.
Dosage regimen
The Drug Stelara® designed for p/to the injections older patients 18 years.
The recommended dose is 45 mg. A second injection makes 4 weeks after the first application, then every 12 weeks.
Patients weighing more than 100 kg the drug is recommended in a dose 90 mg.
With the ineffectiveness of therapy for 28 weeks to consider the feasibility of drug.
Dose adjustment. Patients, in which the clinical efficacy of the drug when used every 12 weeks expressed insufficient, You should increase the dose to 90 mg every 12 weeks. If such a dosing regime is not effective, dose 90 mg should be administered every 8 weeks.
The resumption of treatment under the proposed scheme – second injection through 4 weeks after the first application, and then every 12 weeks – It was also effectively, as for the first time conducted therapy.
In elderly patients over the age of 65 years There were no differences in safety and efficacy of the drug, compared to younger patients. During clinical studies found no effect of age on the ground or Vd product.
A study of the drug in patients with renal or hepatic insufficiency has not been.
Rules of administration
Before the introduction of the drug should carefully examine the contents of the bottle. The solution should be opalescent colorless to pale yellow, It may comprise a single transparent particles protein. This appearance is normal for protein solutions. If you change the color, turbidity or the presence of solid particles a solution can not be used. Ustekinumab contains no preservatives, so that any unused balance of the drug vial and syringe can not be used.
The drug should not be mixed with other liquids for injection. If the dose 90 mg used 2 vials 45 mg, should make 2 sequential injection. When the second injection should be made immediately after the first. Injections should be done in different areas. Do not shake the drug. Prolonged vigorous shaking may damage the drug. Do not use the drug, if shaken.
Recommended places for injections are the upper part of the thighs or abdomen approximately 5 cm from the navel. You can also use the buttocks or shoulder. Avoid injections in the area, psoriatic.
Side effect
The most serious side effects: serious infections and malignancies.
The most common side effects (>10%) in controlled and uncontrolled clinical trials of the drug in psoriasis were nasopharyngitis and upper respiratory tract infection. Most of these events were moderately severe and did not require discontinuation of treatment.
Determination of the frequency of adverse reactions: Often (>1/10), often (>1/100,<1/10), sometimes (>1/1000, <1/100), rarely (>/10 000, <1/1000), rarely (<1/10 000), including isolated cases.
Infection: Often – upper respiratory tract infection, nazofaringit; often – viral upper respiratory tract infection, inflammation of the subcutaneous fat.
In controlled trials in patients with psoriasis, the frequency of infection and serious infection when using the drug Stelara® and placebo was the same (the frequency of infection – respectively 1.39 and 1.21 per work-year of treatment, the frequency of serious infections – respectively 0.01 (5/407) and 0.02 (3/177) per work-year of treatment).
During the controlled and uncontrolled clinical studies the frequency of infections in applying the drug Stelara® was 1.24 (24/2251) per work-year of treatment. Cases of serious infection included inflammation of subcutaneous fat, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia and urinary tract infections.
CNS: often – dizziness, headache, depression.
The respiratory system: often – sore throat and larynx, nasal congestion.
From the digestive system: often – diarrhea.
Skin and subcutaneous tissue disorders: often – itch.
On the part of the musculoskeletal system: often – myalgia, backache.
Allergic reactions: less 2% – hives and urticaria.
General disorders and administration site reactions: often – fatigue, erythema at the injection site; sometimes – injection site reactions (pain, swelling, itch, packing, bleeding, hemorrhage, irritation).
Malignant tumors
In placebo-controlled clinical trials in patients with psoriasis, the incidence of malignant tumors (excluding non-melanoma form of skin cancer) patients, receiving ustekinumab and placebo, are, respectively, 0.25 (1/406) and 0.57 (1/177) case of 100 person / year. The incidence of other, than melanoma, forms of cancer, in applying the drug Stelara® and placebo respectively 0.74 (3/406) and 1.13 (2/176) case of 100 person / year. Registered development of breast cancer, bowel, Head and Neck, kidney, prostate and thyroid.
The incidence of malignant tumors in patients, receiving the drug Stelara®, It was comparable to the incidence of tumors in the general population.
The incidence of non-melanoma skin cancer patients, receiving the drug Stelara®, was 0.80 accidents 100 person / year (18/2245).
Immunogennost'
Approximately 5% patients, receiving the drug Stelara®, formed antibodies to ustekinumab, which typically have a low titer. The apparent correlation between the formation of antibodies and the presence of injection site reactions has been detected. In the presence of antibodies to ustekinumab patients are more likely to have lower efficacy of the drug, although the presence of antibodies does not preclude achievement of clinical effect.
Contraindications
— severe infectious diseases in the acute phase, incl. tuberculosis;
- Malignant neoplasms;
- Pregnancy;
- Lactation;
- Childhood and adolescence up 18 years;
- Hypersensitivity to the drug.
FROM caution should be used in patients with chronic or recurrent parasitic and infectious diseases virus, fungal or bacterial origin; malignant tumors in history; in elderly patients.
Pregnancy and lactation
Do not use this drug during pregnancy and lactation (breast-feeding).
There are no adequate and well-controlled studies in pregnant women has not been. Unknown, whether the application of ustekinumab in pregnant women result in adverse effects on the fetus or affect reproductive function.
Women of childbearing age You should use effective contraception during and 15 weeks after treatment.
Because many drugs and immunoglobulins stand out with breast milk, and because the drug Stelara® can cause adverse reactions in infants, If necessary, use during lactation should decide the issue of termination of breastfeeding.
IN experimental studies the drug was administered to animals in a dose, which in 45 times the recommended clinical dose for a person, while there was no evidence of teratogenicity effects, congenital anomalies or underdevelopment. However, animal studies are not always applicable to humans.
Studies in monkeys have shown, that ustekinumab is excreted in breast milk.
Cautions
Ustekinumab is a selective immunosuppressant and may increase the risk of infections and reactivation of infection, located in the latent phase.
In clinical studies in the application of the drug Stelara® experienced serious bacterial, fungal and viral infections. Ustekinumab should not be prescribed to patients with clinically significant, active infection. The drug should be used with caution in patients with chronic infections or the presence of recurrent infections in history.
Before applying the product should conduct testing for the presence of TB patient. Ustekinumab should not be used in patients with active tuberculosis. In the presence of latent or active tuberculosis (incl. history) It should start treatment before applying the drug Stelara®. You should also start to treatment of tuberculosis patients, have enough effect from previous treatment not confirmed. During treatment ustekinumabom and after that, you should carefully monitor patients for signs and symptoms of active tuberculosis.
Patients should be warned about the need for treatment to a doctor when symptoms, to suggest infection. When developing a serious infection the drug Stelara® should be abolished, the patient must be under the supervision of medical personnel. Do not apply until the end of ustekinumab treatment of infection.
The Drug Stelara® is a selective immunodepressantom. Immunosuppressive drugs may increase the risk of malignant tumors. In some patients,, receiving ustekinumab in clinical trials, observed the occurrence of malignancies (Skin and nekozhnyh forms).
With the development of anaphylactic or other serious allergic reactions use ustekinumab should be discontinued immediately and appropriate treatment.
During drug treatment Stelara® It is not recommended to apply the vaccines, containing weakened pathogens infectious (viral or bacterial) Diseases, as well as between 15 weeks before the vaccination (After taking the last dose of the drug Stelara®) and 2 weeks after vaccination.
Together with ustekinumab may be used vaccine, inactivated microorganisms.
Safety and efficacy of the drug Stelara® in combination with immunodepressivnymi drugs and phototherapy have not studied. Caution should be exercised when considering the simultaneous use of other immunosuppressants and ustekinumab, as well as the transition from other antipsoriatic treatment biologic therapy ustekinumab.
Effects on ability to drive vehicles and management mechanisms
Studies of the influence of the drug Stelara® on the ability to drive vehicles and other potentially hazardous activities were launched.
Overdose
During the clinical trials patients once in/in the injected medication in doses up to 4.5 mg/kg without the development of toxicity dozolimitirujushhej.
Treatment: It is recommended that you monitor the status of patients to detect symptoms of side effects and their development should immediately begin appropriate symptomatic therapy.
Drug Interactions
Special study of drug interaction drug Stelara® not carried out.
Do not use vaccine, containing weakened pathogens of infectious diseases, simultaneously with ustekinumab.
When the drug Stelara® and such drugs, how paracetamol (acetaminophen), Ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine and hydrochlorothiazide interactions have not been identified.
The safety and effectiveness of joint use of the drug Stelara® with other immunodepressantami (methotrexate, cyclosporine) or biological drugs for the treatment of psoriasis is not known.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children, protected from light, in its original packaging at a temperature from 2° to 8° c; Do not freeze, do not shake. Shelf life – 12 months.
