Ranvek, 15 mg 28 pcs.

Selective immunosuppressants

Pharmacological properties

Pharmacodynamics

Mechanism of action

Janus kinases (JAKs) are important intracellular enzymes that are involved in cytokine or growth factor signaling and are also involved in a wide range of cellular processes, including inflammatory responses, hematopoiesis and immune surveillance. The Janus kinase family of enzymes is represented by four JAK proteins, JAK1, JAK2, JAK3, and TYK2, which work in pairs to phosphorylate and activate signal transporter proteins and activators of transcription (STAT). The phosphorylation process, in turn, modulates gene expression and cell function. JAK1 plays an important role in cytokine signaling of inflammation, while JAK2 is important for erythrocyte maturation, JAK3 is involved in immune surveillance and regulation of lymphocyte function.

Upadacitinib is a selective reversible inhibitor of JAK1. Upadicitinib is a more potent inhibitor of JAK1 compared to JAK2 and JAK3. In activity studies on cell cultures to predict pharmacodynamic response in vivo, upadacitinib showed 50-70 times higher selectivity for JAK1 than for JAK2 and more than 100 times higher selectivity for JAK3.

Pharmacodynamic effects

Inhibition of IL-6-induced STATS phosphorylation and inhibition of IL-7-induced STAT5 phosphorylation
Administration of upadacitinib (in immediate-release dosage form) in healthy volunteers resulted in dose- and concentration-dependent inhibition of IL-6-induced (JAK1/JAK2) phosphorylation of STAT3 and IL-7-induced (JAK1/JAK3) phosphorylation of STAT5 in blood. Maximum inhibition was observed 1 hour after drug administration with a return of phosphorylation values to values close to baseline at the end of drug administration.

Lymphocytes

A slight transient increase in mean absolute lymphocyte counts from baseline up to 36 weeks was observed during treatment with upadecitinib. Lymphocyte counts gradually returned to baseline or near baseline with continued treatment.

The immunoglobulins

In the control period, there was a slight decrease in blood IgG and IgM concentrations compared to baseline during treatment with upadacitinib; however, the mean values at baseline and at all visits were in the normal range.

High-sensitivity C-reactive protein

In the first week of therapy with upadatinib, there was a significant decrease in high-sensitivity C-reactive protein concentration compared to baseline; this effect persisted throughout the treatment period.

Cardioelectrophysiology

The effect of upadecitinib on QTc interval length was evaluated in patients who received single and multiple doses of upadecitinib. Upadacitinib does not cause prolongation of the QTc interval at therapeutic or higher plasma concentrations.

Pharmacokinetics

In the therapeutic dose range, the plasma concentration of upadecitinib is proportional to the dose. The drug reaches equilibrium plasma concentrations within 4 days with slight accumulation after administration once daily for several days. The pharmacokinetic properties of RANVEC are shown in Table 1.

Table 1. Pharmacokinetic properties of the drug RANVEC

Special patient groups

Body weight, sex, race, age

Body weight, sex, race, ethnicity, and age had no clinically significant effect on upadacitinib plasma concentrations.

Patients with impaired renal function

Patients with impaired renal function have no clinically significant effect on the plasma concentration of upadecitinib. Value of AUC of upadacytinib was 18%, 33% and 44% higher in patients with mild, moderate and severe renal dysfunction, respectively, compared to that in patients with normal renal function. The Cmax value of upadecitinib in patients with normal renal function was similar to that in patients with impaired renal function.

Patients with impaired hepatic function

Mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment has no clinically significant effect on the plasma concentration of upadecitinib. The AUC of upadecitinib was 28% and 24% higher in patients with mild and moderate hepatic impairment, respectively, compared to that in patients with normal hepatic function.

The Cmax value of upadecitinib remained unchanged in patients with mild hepatic impairment and was increased by 43% in patients with moderate hepatic impairment compared to normal hepatic function. The effect of upadecitinib in patients with severe (Child-Pugh grade C) hepatic impairment has not been studied.

Interaction with other medicinal products

The in vitro metabolism of upadatinib is mediated by cytochrome CYP3A with minimal involvement of cytochrome CYP2D6. The effect of co-administration with other drugs on the plasma concentration of upadacitinib is shown in Table 2.

Table 2. Results of a study of the pharmacokinetics of upadacitinib when co-administered with other drugs

Methotrexate, OATP1B inhibitors and drugs that alter pH (e.g., antacids or proton pump inhibitors) have no effect on plasma levels of upadacitinib. The metabolic phenotype associated with CYP2D6 activity has no effect on the pharmacokinetics of upadacitinib, which means that CYP2D6 inhibitors have no clinically significant effect on the plasma concentration of upadacitinib.

The effect of upadacitinib on plasma concentrations of other drugs is shown in Table 3.

Table 3. Changes in the pharmacokinetics of co-administered drugs in the presence of upadacitinib

Summary of clinical trials

The efficacy and safety of RANVEC at a dose of 15 mg once daily was evaluated in five randomized, double-blind, multicenter phase 3 studies in adult patients with moderate to highly active rheumatoid arthritis.

The drug RANVEC was compared with placebo in the SELECT-COMPARE, SELECT-NEXT and SELECT-BEYOND trials; methotrexate in the SELECT-EARLY and SELECT-MONOTHERAPY trials; and adalimumab in the SELECT-COMPARE trial.

The study population included the following patients:

– methotrexate-naïve (SELECT-EARLY);
– with inadequate response to methotrexate therapy (SELECT-MONOTHERAPY and SELECT-COMPARE);
– with inadequate response to traditional baseline anti-inflammatory drugs (BVDs) (SELECT-NEXT);
– with inadequate response to at least one genetically engineered biologic drug (GEBP) or intolerance (SELECT-BEYOND).

In all studies, significantly more patients who received RANVEC at a dose of 15 mg achieved ACR20, ACR50 and ACR70 responses after 12 weeks compared to control groups (placebo, methotrexate and adalimumab), except for ACR70 in the SELECT-BEYOND study.
There was a rapid onset of treatment effect across all parameters, with a significant difference in ACR20 noted at week 1, followed by an increase over 12 weeks.

Sustained response to treatment (in combination with methotrexate or as monotherapy) by ACR20/50/70 parameters was observed for at least 1 year. Treatment with RANVEC at a dose of 15 mg in monotherapy or in combination with conventional DMARDs resulted in statistically significant improvements in individual ACR scale components, including number of painful, swollen joints, patient and physician assessment of general health, HAQ-DI, pain score, and high-sensitivity C-reactive protein levels compared to placebo or methotrexate.

All studies reported significantly higher remission rates on the DAS28-CPB index <2.6 in the RANVEC 15-mg treatment group compared to control groups.

In all studies, treatment with RANVEC at a dose of 15 mg resulted in a significant reduction in the duration and severity of morning stiffness compared to placebo and methotrexate.

The 15-mg dose of RANVEC significantly slowed the progression of structural joint damage compared to placebo at weeks 26 and 48 in the SELECT-COMPARE trial, and to monotherapy compared to methotrexate at week 24 in the SELECT-EARLY trial. The proportion of patients without radiological progression (mTSS change ≤0) with treatment with RANVEC 15 mg was significantly higher compared with placebo at weeks 26 and 48 and compared with methotrexate at week 24.

Indications

Treatment of moderate to severe rheumatoid arthritis in adult patients.

Active ingredient

Upadecitinib

Composition

Active ingredient:

Upadacytinib hemihydrate (in terms of anhydrous Upadacytinib) – 15.4 (15.0) mg;

Excipients: microcrystalline cellulose, hypromellose 2208, 3550 mPas, mannitol, tartaric acid, colloidal silicon dioxide, magnesium stearate;

Opadry® II Purple film coating: polyvinyl alcohol, macrogol 3350, talc, titanium dioxide, iron oxide black, iron oxide red E172.

How to take, the dosage

To be taken orally.

The tablet should be swallowed whole without chewing, breaking or crushing.

The recommended dose

The recommended dose of RANVEC is 15 mg once daily regardless of meals.
RANVEC may be used as monotherapy or in combination with methotrexate or other traditional DMARDs.
It is not recommended to initiate therapy with RANVEC in patients with an absolute lymphocyte count of less than 500 cells/mm³, an absolute neutrophil count of less than 1000 cells/mm³ or with a hemoglobin level less than 8 g/dL.

Missed doses of RANVEC should be taken as soon as possible if the drug is missed.
The next scheduled dose should be taken as planned.

Stopping RANVEC must be stopped if the patient develops a severe infection until the infection can be controlled.

The therapy may need to be discontinued due to abnormal laboratory values (see Table 4).

Table 4. Recommended discontinuation of therapy due to abnormal laboratory values

Special patient groups

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Patients with impaired renal function

The excretion of upadacitinib is largely by extrarenal clearance.

Patients with mild, moderate or severe renal dysfunction do not require dose adjustments. Studies on the use of RANVEC in patients with end-stage renal disease have not been conducted. It is assumed that hemodialysis has no clinically significant effect on the plasma concentration of upadecitinib.

Patients with hepatic impairment

Patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment do not require dose adjustment.

The use of RANVEC is not recommended in patients with severe (Child-Pugh class C) hepatic impairment.

The use in elderly patients

Of the 4381 patients treated in the five phase 3 clinical trials, a total of 906 patients with rheumatoid arthritis were aged 65 years or older, including 146 patients aged 75 years or older. No differences in efficacy were observed between elderly and younger patients. However, side effects were observed more frequently in the elderly.

Children

There are no data on the safety and efficacy of RANVEC in children and adolescents under 18 years of age.

Interaction

Powerful CYP3A inhibitors

When co-administering RANVEC with powerful CYP3A inhibitors (e.g., ketoconazole) an increase in plasma concentrations of upadecitinib is observed. RANVEC should be used with caution in patients receiving long-term treatment with potent CYP3A inhibitors.

Powerful CYP3A inducers

When coadministration of RANVEC with potent CYP3A inducers (such as rifampicin), a decrease in plasma upadacitinib concentration is observed. Co-administration may lead to a decrease in the therapeutic effect of RANVEC. Patients should be monitored for changes in health status when co-administering RANVEC with potent CYP3A inducers.

Special Instructions

Serious infections

There is evidence of severe and sometimes fatal infections in patients with rheumatoid arthritis who have taken RANVEC. The most common severe infections that have been observed with RANVEC include pneumonia and phlegmon (see section Side effects). Opportunistic infections such as tuberculosis, multidermatoma shingles, oral/esophageal candidiasis, and cryptococcosis have been reported with RANVEC.

The drug RANVEC should not be used to treat patients with severe active infections, including localized infections. The risks and benefits of therapy should be considered before starting RANVEC in patients:

– with chronic or recurrent infection;
– who have been in contact with a patient with tuberculosis;
– with a history of severe or opportunistic infection;
– who have lived or traveled in areas with an increased risk of tuberculosis or endemic mycosis;
– with comorbidities that increase the risk of infection.

Patients should be closely monitored for signs or symptoms of infection during and after therapy with RANVEC. If a patient develops a severe or opportunistic infection, the drug should be discontinued. If the patient develops a new infectious disease during RANVEC therapy, a complete diagnostic evaluation suitable for immunocompromised patients should be promptly performed and an appropriate therapy should be initiated. The patient should be closely monitored and RANVEC should be discontinued if the patient does not respond to anti-infective therapy. Resumption of RANVEC is possible after ensuring complete control of the infectious disease.

Tuberculosis

Patients should be evaluated for the presence of tuberculosis before starting therapy with RANVEC. Therapy with RANVEC should not be administered to patients with an active form of tuberculosis. If patients have a previously untreated latent form of tuberculosis, the use of anti-tuberculosis therapy should be considered before starting therapy with RANVEC.

Patients should be closely monitored for signs and symptoms of tuberculosis, including patients who test negative for latent tuberculosis before initiating therapy.

Reactivation of viral infection

In clinical trials, cases of reactivation of viral infections (e.g., herpes zoster) have been noted (see section Side effects). If a patient develops herpes zoster, consideration should be given to temporarily interrupting therapy with RANVEC until the episode resolves.

Patients should be screened for viral hepatitis before and during therapy with RANVEC and patients should be monitored for viral reactivation in accordance with clinical guidelines. Patients who test positive for hepatitis C virus antigen antibodies or hepatitis C virus RNA content have been excluded from clinical trials. Patients who tested positive for hepatitis B surface antigen antibodies or hepatitis B virus DNA were excluded from clinical trials. If hepatitis B DNA is detected while taking RANVEC, a liver specialist should be consulted.

Vaccination

There are no data on the reaction of patients taking the drug to vaccination with live or inactivated vaccines. The use of live attenuated vaccines during or immediately prior to therapy with RANVEC is not recommended. Before using the drug, it is recommended that all patients be fully immunized according to current immunization recommendations, including prophylactic vaccination against herpes zoster.

Malignant neoplasms

Patients with rheumatoid arthritis have an increased risk of developing malignant neoplasms, including lymphoma. Immunosuppressant therapy may increase the risk of malignancies, including lymphoma. The effect of RANVEC therapy on the development of malignancies has not been established.

In clinical trials of RANVEC, the development of malignancies has been observed (see section Side effects). The benefits and risks of RANVEC should be evaluated before initiating therapy in patients with diagnosed malignancies other than successfully treated NMRCC, and before continuing therapy with RANVEC in patients who developed a malignancy during therapy.

Nemelanocytic skin cancer

Patients treated with RANVEC have had cases of NMRCC. Regular skin exams are recommended for patients at increased risk of developing skin cancer.

Laboratory indices

Neutropenia: therapy with RANVEC was accompanied by an increased incidence of neutropenia (ACN less than 1000 cells/mm³). A direct correlation between neutrophil count and the occurrence of severe infections has not been established.

Lymphopenia: in clinical trials of RANVEC there were cases of decrease of ACL to values less than 500 cells/mm³. No association has been established between reduction of lymphocyte counts to the lower limit of normal with the development of severe infection.

Anemia: in clinical trials of RANVEC there have been cases of decrease of hemoglobin levels to 8 g/dL or lower.

Most of the changes in laboratory values mentioned above were transient and reached normal when therapy was temporarily interrupted.

The appropriateness of RANVEC should be evaluated initially and then according to the usual management of patients. Treatment should not be initiated or should be temporarily interrupted in patients who meet the criteria in Table 4 (see Administration and Dosage).

Lipids

Therapy with RANVEC has been associated with increased lipid concentrations, including total cholesterol, low-density lipoproteins (LDL) and high-density lipoproteins (HDL) (see section Side effects). With statin therapy, elevated LDL levels decreased to the values observed before the start of treatment. The effect of the observed increase in lipid concentrations on the incidence of cardiovascular disease and cardiovascular mortality has not been established.

Patients should be monitored 12 weeks after initiation of therapy and thereafter according to clinical guidelines for hyperlipidemia.

Elevation of hepatic enzyme activity

Therapy with RANVEC was accompanied by an increased incidence of increased hepatic enzyme levels compared to placebo administration.

The appropriateness of RANVEC should be evaluated initially and then according to the usual management of patients.

It is recommended that the cause of elevated liver enzymes be investigated immediately to identify possible cases of drug-induced liver damage.

If elevated ALT or ACT activity is observed during routine management of a patient and drug-induced liver damage is suspected, therapy with RANVEC should be discontinued until this diagnosis is excluded.

Immunosuppressants

. Co-administration of RANVEC with other immunosuppressants such as azathioprine, cyclosporine, tacrolimus, GIBP or other JAK inhibitors has not been studied in clinical trials and therefore is not recommended because risks associated with additive immunosuppressive effects cannot be excluded.

Influence on driving and operating machinery

The drug RANVEC has no effect on driving and operating machinery.

Contraindications

• Hypersensitivity to the drug components
• Pregnancy and breastfeeding
• Children under 18 years (effectiveness and safety have not been studied).

Cautions

• Cautious use of RANVEC in patients receiving long-term treatment with potent CYP3A inhibitors.
• No co-administration of RANVEC with other strong immunosuppressants such as azathioprine, cyclosporine, tacrolimus and GIBP or other JAK inhibitors is recommended.
• The use of RANVEC should be avoided in patients with active severe infections, including localized infections.
  

Side effects

Clinical trial experience

As clinical trials are conducted in different settings, the incidence of adverse events observed in clinical trials of a drug cannot be directly compared to those in clinical trials of another drug and may not reflect the rates observed in practice.

A total of 4,443 patients with rheumatoid arthritis received therapy with upadacitinib in clinical trials, corresponding to 5,263 patient-years. Of all patients, 2,972 had been taking the drug for at least one year. In the phase 3 studies, 2,630 patients received at least 1 dose of the 15-mg drug, of which 1,607 patients took the drug for at least one year.

Data from three placebo-controlled studies (1,035 patients who took 15 mg of the drug once daily and 1,042 patients who took placebo) were pooled to evaluate the safety of the 15 mg dose of the drug compared with placebo for 12 to 14 weeks from the start of therapy.

Table 5. Frequency of adverse reactions (≥ 1%) in patients with rheumatoid arthritis treated with RANVEC at a dose of 15 mg in placebo-controlled trials

Other adverse reactions reported in less than 1% of patients in the group receiving RANVEC 15 mg and with a higher incidence than in the placebo group included pneumonia, herpes zoster, herpes simplex (including oral herpes), and oral candidiasis.

Description of individual adverse reactions

Infections

. In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional DMARDs, the rate of infections over 12-14 weeks was 27.4% in the group of patients taking RANVEC at a dose of 15 mg compared to 20.9% in the placebo group. In controlled trials with methotrexate as a comparison drug, the 12-14 week infection rate in the 15 mg RANVEC monotherapy group was 19.5% compared to 24.0% in the methotrexate group. The overall incidence of developing infections during long-term therapy in the group of patients receiving RANVEC 15 mg in all five phase 3 clinical trials (2,630 patients) was 93.7 cases per 100 patient-years.

In placebo-controlled clinical trials where patients in the groups were receiving concomitant therapy with traditional DMARDs, the incidence of severe infections over 12-14 weeks was 1.2% in the group of patients taking RANVEC 15 mg compared with 0.6% in the placebo group. In controlled trials with methotrexate as a comparison drug, the 12-14 week rate of infections in the RANVEC monotherapy group at a dose of 15 mg was 0.6% compared to 0.4% in the methotrexate group.

The overall incidence of serious infections during long-term therapy in the group of patients taking RANVEC 15 mg in all five phase 3 clinical trials was 3.8 cases per 100 patient-years. The most common serious infections were pneumonia and phlegmon. The incidence of serious infections did not increase with long-term use of the drug.

Tuberculosis

In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional DAAs, no cases of active tuberculosis were observed in either group. In studies where methotrexate was used as a comparison drug, no cases of tuberculosis were observed in both the RANVEC monotherapy group at a dose of 15 mg and in the methotrexate group for 12-14 weeks of follow-up. Overall incidence of active tuberculosis during long-term treatment in the RANVEC drug group in the dose of 15 mg in all five clinical phase 3 trials was 0.1 case per 100 patient-years.

Opportunistic infections (excluding tuberculosis)

In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional DAAs, the incidence of opportunistic infections over 12-14 weeks was 0.5% in the group of patients taking RANVEC at a dose of 15 mg compared to 0.3% in the placebo group. In studies using methotrexate as a comparison drug in the RANVEC monotherapy group at a dose of 15 mg no cases of opportunistic infections were noted during 12-14 weeks of follow-up. The incidence of these infections in the methotrexate group was 0.2%. Overall incidence of opportunistic infections during long-term treatment in the group of patients treated with RANVEC at the dose of 15 mg, in all five clinical trials of phase 3 was 0.6 cases per 100 patient-years.

Malignant neoplasms

. In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional DMARDs, the incidence of malignancies, excluding non-melanocytic skin cancer (NMSC), in the group of patients receiving RANVEC at the 15 mg dose was <0.1% compared to <0.1% in the placebo group over 12-14 weeks of follow-up. In controlled trials with methotrexate as a comparison drug, the incidence of malignancy at 12-14 weeks of follow-up in the RANVEC monotherapy group at a dose of 15 mg was 0.6% compared to 0.2% in the methotrexate group. The overall incidence of malignancies during long-term treatment in the group of patients receiving RANVEC at a dose of 15 mg, excluding NMRK, in the clinical trial program was 0.8 per 100 patient-years.

Gastrointestinal hollow organ perforation

. In placebo-controlled clinical trials in which patients in the groups received concomitant therapy with traditional DMARDs, the incidence of gastrointestinal hollow-tract perforation was 0.2% in the RANVEC 15-mg dose compared to 0% in the placebo group. In controlled trials with methotrexate as a reference drug over 12-14 weeks no cases of gastrointestinal perforation were observed in the RANVEC monotherapy group at a dose of 15 mg and in the methotrexate group. Overall incidence of gastrointestinal perforation during long-term therapy in the group of patients treated with RANVEC in the dose of 15 mg in all five clinical trials of phase 3 amounted to 0.08 cases per 100 patient-years.

Thrombosis

. In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional BPVP, there were 2 cases (0.2%) of venous thromboembolism (pulmonary embolism or deep vein thrombosis) in the patient group taking RANVEC at the 15 mg dose, compared with 1 case (0.1%) in the placebo group. In controlled trials with methotrexate as a comparative medicine during 12-14 weeks 1 case of venous thromboembolism (0.2%) was reported in RANVEC monotherapy group in 15 mg dose, and no cases in methotrexate group. Overall incidence of venous thromboembolism during long-term treatment in the group of patients treated with RANVEC in the dose of 15 mg in all five clinical phase 3 trials was 0.6 cases per 100 patient-years.

Laboratory abnormalities

Elevated hepatic transaminase activity

. In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional BPVs, within 12-14 weeks, increases in alanine transaminase (ALT) and aspartate transaminase (ACT) activity to values more than 3 times the upper limit of normal (ULN) according to at least one measurement was observed in 2.1% and 1.5% of patients taking RANVEC at a dose of 15 mg, compared to 1.5% and 0.7% of patients in the placebo group. Most cases of increased hepatic transaminase activity were transient and had no clinical manifestations.

In studies using methotrexate as a reference drug over a time period of 12-14 weeks, increases in ALT and ACT activity to values more than 3 times greater than GGN based on at least one measurement were observed in 0.8% and 0.4% of patients in the RANVEC group taking the 15 mg dose, compared with 1.9% and 0.9% of patients in the methotrexate group.

The frequency and severity of increases in ALT/AST activity did not increase over time, including during extended studies.

Elevation of lipids

Therapy with RANVEC at a dose of 15 mg was accompanied by an increase in blood lipid levels, including total cholesterol, triglycerides, LDL and HDL. LDL/HDL ratio did not change. The increase in baseline LDL and HDL cholesterol levels reached a maximum by week 8 and remained stable thereafter. In controlled trials lasting up to 12-14 weeks, the following abnormalities were noted in the group of patients taking RANVEC at a dose of 15 mg:

– Mean LDL cholesterol levels increased by 0.38 mmol/L.
– Mean HDL cholesterol levels increased by 0.21 mmol/L.
– The ratio of mean LDL / HDL levels remained stable.
– Mean triglycerides increased by 0.15 mmol/L.

Creatine phosphokinase (CPK)

In placebo-controlled clinical trials where patients in groups receiving concomitant therapy with traditional DMARDs lasting up to 12-14 weeks, increased CPK levels were observed. After 12-14 weeks, elevation of CPK to >5×VGN levels was observed in 1.0% and 0.3% of patients in the groups of patients receiving RANVEC at a dose of 15 mg and placebo, respectively. Most cases of elevation to the >5×VGN level were temporary and did not require discontinuation of therapy. Mean CPK levels increased after 4 weeks and remained stable thereafter, including during longer therapy.

Neutropenia

In placebo-controlled clinical trials where patients in groups receiving concomitant therapy with traditional DAAs lasting up to 12-14 weeks, there was a decrease in neutrophil count to below 1000 cells/mm3 on at least one measurement in 1.1% and <0.1% of patients in the groups receiving RANVEC at a dose of 15 mg and placebo, respectively. In clinical trials, therapy was discontinued when the ACH decreased to a level of <500 cells/mm3. The nature and frequency of the decrease in neutrophil counts remained stable at lower levels relative to the beginning of the study, including during longer therapy.

Lymphopenia

In placebo-controlled studies lasting up to 12-14 weeks, there was a decrease in lymphocyte counts to below 500 cells/mm³ on at least one measurement in 0.9% and 0.7% of patients in the groups receiving RANVEC at the 15 mg dose and placebo, respectively.

In placebo-controlled clinical trials where patients in the groups received concomitant therapy with traditional RANVEC up to 12-14 weeks, there was a decrease in hemoglobin levels to values below 8 g/dL on at least one measurement in <0.1% of patients in both groups: those taking RANVEC at a dose of 15 mg and the placebo group.

Overdose

In clinical trials, the maximum dose of upadacitinib was equivalent to 60 mg as measured by the daily AUC when administered once daily in a sustained-release formulation. Observed adverse events were comparable to those observed with lower doses.

No specific toxicity was detected.

About 90% of the administered dose of upadacitinib (in the dose range evaluated in the clinical studies) was expected to be eliminated within 24 hours. In the event of overdose, it is recommended that the patient be monitored for signs and symptoms of adverse events.

Patients who develop adverse reactions should be given appropriate treatment.

Pregnancy use

Pregnancy

The data on the use of upadecitinib in pregnant women are limited. The data are insufficient to inform about the risks of birth defects and miscarriage associated with the use of this drug.

According to animal studies, upadecitinib may affect fetal development.

In embryofetal toxicity studies of the drug in rats and rabbits, upadacitinib had teratogenic effects when animals received upadacitinib during organogenesis at a dose 1.6 and 15 times the clinical dose (15 mg) for rats and rabbits, respectively.

Further, according to the results of a study of pre- and postnatal development in rats, the use of upadacitinib had no toxic effects on females and cubs.

The estimated risk of major birth defects and miscarriage in pregnant women is unknown. There remains a risk of birth defects, miscarriage or other adverse effects during any pregnancy.

Clinical considerations

The risk to the mother and/or embryo/fetus associated with the disease

Published data suggest that increased disease activity is associated with the risk of adverse pregnancy outcomes in women with rheumatoid arthritis. Adverse pregnancy outcomes include premature delivery (before 37 weeks’ gestation), low birth weight (less than 2500 g), and low birth weight for gestational age at birth.

The data from animal studies

. Studies in rats and rabbits demonstrated the teratogenicity of upadacitinib when administered to animals at doses 1.6 and 15 times the clinical dose of 15 mg (oral doses to maternal individuals were 4 mg/kg/day and 25 mg/kg/day, respectively, and were calculated based on AUC values).

In two studies of embryofetal development in rats, the drug was administered to animals during organogenesis from day 6 to day 17 of gestation. Upacitinib demonstrated teratogenicity in rats at all but the lowest dose of 1.5 mg/kg/day studied.

At doses of 4, 5, 25 and 75 mg/kg/day, administration of upadacitinib resulted in an increased incidence of humerus and scapular bone deformities. In addition, administration of 75 mg/kg/day resulted in an increased frequency of development of forelimb and hindlimb bone deformities. In addition, at doses of 25 and 75 mg/kg/day there was an increase in the incidence of rib deformities and skeletal development disorders, which was also associated with the use of upadacitinib.

In a study of embryofetal development in rabbits, the drug was administered to animals during organogenesis from day 7 to day 19 of gestation. Upacitinib demonstrated teratogenicity at a dose of 25 mg/kg/day. Among the developmental abnormalities observed in rabbits associated with the use of the drug at a dose of 25 mg/kg/day, there was an increase in the frequency of postimplantation fetal death, an increase in the overall frequency and frequency of early fetal resorption, a decrease in fetal body weight, and an increase in the frequency of heart defects. In addition, in the group of animals receiving the dose of 25 mg/kg/day a toxic effect of the drug on female animals was observed, expressed in a decrease in animal body weight and food intake, as well as an increase in the frequency of spontaneous abortions.

In a study of pre- and postnatal development in rats, the development of offspring was evaluated when maternal animals were exposed to the drug from implantation and continuing through lactation until cessation of lactation of infant feeding. Since the development of abnormalities caused by the drug at a given time may be delayed, observations were continued until the offspring became sexually mature. The drug was administered to the maternal specimens from the 6th day of gestation to the 20th day of lactation. At no dose level did upadacytinib affect behavioral and reproductive endpoints in the mothers and offspring.

Breastfeeding Period

It is not known whether upadacytinib or its metabolites are excreted with human breast milk. Available data from studies of pharmacodynamics and toxic effects of the drug in animals have shown excretion of upadacitinib in milk.

The risk to newborns and infants cannot be excluded.

The drug RANVEC should not be used during breastfeeding.

Data from animal studies

After administration to lactating female rats, the concentration of upadecitinib in milk was approximately 30 times higher than that of upadecitinib in the blood plasma of the mother. About 97% of the substance excreted with milk was the parent drug.

Females and males of reproductive potential

Contraception
In animal studies of embryofetal development, upadacitinib had teratogenic effects in rats and rabbits.

Women with preserved childbearing function should use reliable contraceptive methods during administration of RANVEC and for at least 4 weeks after completion of treatment.

Fertility

Studies in animals have shown no adverse effects of upadacitinib on reproductive function in males and females of reproductive potential.