Ustekinumab

When ATH:
L04AC05

Pharmacological action

Pharmacological action – immunosuppressive.

Pharmacokinetics

Absorption. Tmax following a single s / c administration 90 mg ustekinumab in healthy volunteers was 8,5 day. In psoriasis, this quantity of the drug at doses 45 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. The average value of the volume distribution of ustekinumab in the terminal phase elimination after a single on / in the patients with psoriasis ranged from 57 to 83 ml / kg.

Metabolism. Pathway ustekinumab is unknown.

Deduction. The average value of systemic clearance ustekinumab following a single on / in the patients with psoriasis ranged from 1,99 to 2,34 ml / day / kg.

T1 / 2 ustekinumab in patients with psoriasis was about 3 Sun, and various studies ranged from 15 to 32 days.

Linearity. Systemic exposure ustekinumab (Сmax and AUC) in patients with psoriasis increases proportionally entered dose after a single on / in a dose in the range of 0,09 to 4,5 mg / kg, and after a single s / c injection of doses ranging from 24 to 240 mg.

Changing the concentration ustekinumab plasma over time after single or repeated injections of multiple drug was substantially predictable. The equilibrium concentration of ustekinumab plasma levels achieved in 28 weeks with the proposed mode of therapy (second injection 4 weeks after the first application, then every 12 Sun). Average, the equilibrium concentration of the drug is 0,21-0,26 g / ml for the dose 45 0,47-0,49 mg / ml - a dose 90 mg. Accumulation of the drug in the blood serum were observed during treatment duration 12 Sun.

Effect of patient body weight on the pharmacokinetics of the drug. The concentration of drug in plasma depends on the body weight of the patient. At the same dosage (45 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. But, ustekinumab average minimum concentration in plasma of patients with body weight more 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 (CL/F) and volume of distribution (V/F) were 0,465 l / h and d 15,7 l, respectively. T1 / 2 of the drug was approximately 3 Sun. Paul, age and belonging to a particular race did not affect CL / F ustekinumab. On CL / F drugs affect the body weight of patients, wherein patients with higher body weight value CL / F was greater. Middle CL / F in patients with body weight more 100 kg was approximately 55% higher than those in patients with lower body weight. V / F in 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 CL / F was an average of 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 value of CL / F and V / F.

Alcohol and tobacco use did not affect the pharmacokinetics of ustekinumab.

Testimony

For the treatment of older patients 18 years with moderate to severe plaque psoriasis.

Dosage regimen

P /, older patients 18 years.

The recommended dose - 45 mg. A second injection makes 4 weeks after the first application, then every 12 Sun.

In patients weighing more than 100 kg is recommended to use the drug in a dose 90 mg.

With the ineffectiveness of therapy for 28 weeks is recommended to consider the advisability of the drug.

Dose adjustment. Patients, in which the clinical efficacy of the drug when used every 12 Weeks expressed enough, should increase the dose to 90 mg every 12 Sun. If such a dosing regime is not effective, dose 90 mg should be administered every 8 Sun.

The resumption of treatment. The resumption of the treatment on the proposed scheme - second injection through a 4 weeks after the first application, and then every 12 Weeks - it was as effective, as for the first time conducted therapy.

Instructions for administration of the drug

Before the introduction of the drug, inspect the contents of the vial. 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. In this second injection must be made immediately after the first. Injections should be done in different areas. Do not shake the medication. Prolonged vigorous shaking may damage the drug. Do not use the drug, if shaken.

Recommend places for injection are the upper thigh or stomach area (about 5 cm from the navel). You can also use the buttocks or shoulder. Avoid injections in the area, psoriatic.

Use in elderly patients (senior 65 years). In clinical studies found no effect of age on the clearance and volume of distribution of the drug. Studies of the drug showed no differences in the safety and efficacy of the drug for elderly patients over 65 years compared with younger patients.

Use in children. Safety and efficacy of ustekinumab in children has not been studied.

Use in renal and liver failure. Studies of the drug in patients with renal or hepatic insufficiency has not been.

Side effect

The most serious adverse events were malignancies and serious infections.

The most common adverse events (>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.

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

Infection: very often - upper respiratory tract infection, nazofaringit; often - viral upper respiratory tract infection, inflammation of the subcutaneous fat.

In controlled trials in patients with psoriasis incidence of infection, incl. severe infection when using the drug Ustekinumab and placebo were similar (The rate of infection - 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) cases per person / year of treatment).

In controlled and uncontrolled clinical studies the frequency of infection when using the drug was Ustekinumab 1,24 (24/2251) cases per person / year of treatment. The incidence of severe infection include inflammation of subcutaneous fat, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia and urinary tract infections.

CNS: often - dizziness, headache, depression.

The respiratory system: often - a sore throat and larynx, nasal congestion.

On the part of the digestive tract: often - diarrhea.

Skin and subcutaneous tissue disorders: often - itching, hives.

On the part of the musculoskeletal system: Private - myalgia, backache.

General disorders and administration site reactions: often - fatigue, erythema at the injection site; infrequently - 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, cancers when using the drug and placebo was Ustekinumab 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 Ustekinumab, It was comparable to the incidence of tumors in the general population.

The incidence of non-melanoma skin cancer patients, receiving the drug Ustekinumab, was 0,8 (18/2245) case of 100 person / year.

Hypersensitivity reactions: in clinical studies rashes and urticaria have been observed in less than 2% patients.

Immunogenicity: approximately 5% patients, receiving the drug Ustekinumab, 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

• hypersensitivity to ustekinumab or any subsidiary of the drug substance;
• childhood (to 18 years);
• serious infectious diseases in the acute phase, incl. tuberculosis;
• malignant neoplasms (cm. "Cautions");
• pregnancy;
• lactation.

Carefully:

• chronic or recurrent parasitic and viral infections, fungal or bacterial origin;
• a history of malignancy;
• advanced age.

Pregnancy and lactation

During the study animals dosed with the drug, in 45 times the recommended clinical dose for humans, while there was no evidence of teratogenicity effects, congenital anomalies or developmental delay. However, animal studies are not always applicable to humans.

Unknown, whether the application of ustekinumab in pregnant women result in adverse effects on the fetus or affect reproductive function. There are no adequate and well-controlled studies in pregnant women has not been.

It is recommended to avoid using the drug during pregnancy and use effective contraceptive methods during and for 15 weeks after treatment.

Studies in monkeys have shown, that ustekinumab is excreted in breast milk. Unknown, whether the drug is absorbed systemically after ingestion of a newborn. Because many drugs and immunoglobulins are excreted in breast milk in lactating women because the drug Ustekinumab may cause adverse reactions in infants, should decide to discontinue breast-feeding while taking this drug, or the abolition of ustekinumab therapy.

Cautions

Infection. Ustekinumab is a selective immunosuppressant and may increase the risk of infections and reactivation of infection, located in the latent phase.

In clinical studies with the use of the drug in patients Ustekinumab observed serious bacterial, fungal and viral infections. Ustekinumab should not be used in patients with clinically significant, active infection. Caution should be exercised when using the drug in patients with chronic infections or the presence of recurrent infections history.

Before the start of the drug should be to test the patient for TB. Do not use ustekinumab in patients with active tuberculosis. In the presence of latent or active tuberculosis (incl. history) it should start treatment before use of the drug Ustekinumab. You should also start treatment for TB patients, in which a sufficient effect of its previous treatment is not certified. During treatment ustekinumab and then should be carefully observed for patients for signs and symptoms of active tuberculosis.

Patients should be warned of the need to see a doctor when the signs and symptoms, to suggest infection. With the development of severe infections Ustekinumab use of the drug should be abolished, the patient must be under the supervision of medical personnel. Do not apply until the end of ustekinumab treatment of infection.

Malignancies. The drug Ustekinumab is a selective immunosuppressant. 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).

Hypersensitivity reactions. With the development of anaphylactic or other serious allergic reactions use ustekinumab should be discontinued immediately and appropriate treatment.

Vaccination. During treatment with Ustekinumab is not recommended vaccines, containing weakened pathogens infectious (viral or bacterial) Diseases. Use of the drug is not recommended during 15 Weeks before vaccination (after receiving the last dose Ustekinumab) and for 2 weeks after vaccination.

Together with ustekinumab may be used vaccine, inactivated microorganisms.

Soputstvuyushtaya immunosupressivnaya therapy. The safety and efficacy of the drug Ustekinumab in combination with immunosuppressive drugs and phototherapy has not been 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 and use machines. Research was conducted.

Drug Interactions

Specific drug interaction studies have not been conducted.

Do not use vaccine, containing weakened pathogens of infectious diseases, simultaneously with ustekinumab.

In a joint application of the drug and these preparations Ustekinumab, how paracetamol (acetaminophen), Ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine and hydrochlorothiazide interactions have not been identified.

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