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

Active substancePembolizumabPembolizumab

Similar drugsTo uncover

Kitruda®

concentrate d / infusion

MSD FARMASYUTIKALS, LLC Russia

Dosage form: & nbspTOoncentrat for solution for infusion.

Composition:

1 bottle contains:

active substance: pembolizumab 100.0 mg;

Excipients: L-cystidine 1.2 mg; L-histidine hydrochloride monohydrate 6.8 mg; nolisorbate-80 0.8 mg; sucrose 280 mg; water for injection up to 4.0 ml,

Description:

Transparent or opalescent from colorless to light yellow color solution.

Pharmacotherapeutic group:antitumor agent - antibodies monoclonal

ATX: & nbsp

L.01.X.C.18 Pembolizumab

Pharmacodynamics:

Pembrolisumab is a human monoclonal antibody that selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. Pembrolisumab is an immunoglobulin isotype IgG4 kappa with a molecular mass of about 149 kDa.

Mechanism of action

PD-1 is the receptor of the immune control point, which limits the activity of T-lymphocytes in peripheral tissues. Tumor cells can use the metabolic pathway involving PD-1 for inhibition of active T-cell immunological surveillance.

Pembolizumab is a high affinity antibody to PD-I receptor, which has a double blocking effect on the ligands of the metabolic pathway involving PD-1, including PD-L1 and PD-L2 tumor or antigen-presenting cells.As a result of inhibition of receptor binding PD-1 with its ligands pembolizumab Reactivates tumor-specific cytotoxic T-lymphocytes in the microenvironment of the tumor and. thus, reactivates the antitumor immunity.

Pharmacodynamics

In the peripheral blood of patients who received pembolizumab 2 mg / kg every 3 weeks or 10 mg / kg every 2 or 3 weeks, there was an increase in the percentage of activated (i.e. HLA-DR+) Cd4+ and Cd8+ T cells after treatment with all doses and regimens without increasing the total number of circulating T-lymphocytes.

Pharmacokinetics:

The pharmacokinetics of pembolizumab was studied in studies involving 2195 patients with metastatic or inoperable melanoma, non-small cell lung cancer (NSCLC) or other malignant tumors that received the drug at dosages of 1 to 10 mg / kg every 2 or 3 weeks.

Suction

The drug Kitruda^® is administered intravenously, so pembolizumab immediately and completely becomes bioavailable.

Distribution

In accordance with the limited extravascular distribution, the volume of pembolizumab distribution in the equilibrium state is insignificant (about 7 L, the coefficient of variation (CV): 19%). Like other antibodies, pembolizumab does not bind to plasma proteins in a specific way.

Metabolism

Pembolizumab is catabolized by non-specific routes, the metabolism of the drug is not affected by its clearance.

Excretion

The systemic clearance of pembolizumab is approximately 0.2 l / day (CV: 37%); and the final half-life (T_1/2) is approximately 27 days (CV: 38%). Exposure of pembolizumab, expressed as the maximum concentration (C_m_Oh) or the area under the curve "concentration-time" (AUC), increased proportionally to the dose within the effective dose range. Upon repeated administration, it was shown that the clearance of pembolizumab is independent of time, and systemic accumulation is approximately 2.2 times higher when administered every 3 weeks. Near-equilibrium concentrations of pembolizumab were achieved at week 19: the mean minimum concentration (C_min) at week 19 was approximately 26 μg / ml with a dosage regimen of 2 mg / kg every 3 weeks.

Pharmacokinetics in specific patient groups

The effect of different covariates on the pharmacokinetics of pembolizumab was evaluated in population pharmacokinetic analysis. The clearance of pembolizumab increased with increasing body weight.At the same time, the resulting differences in exposure are adequately controlled when calculating the dose for administration (mg / kg). The following factors did not have a clinically significant effect on the clearance of pembolizumab: age (15 to 94 years), sex, race, mild to moderate renal insufficiency, mild liver failure, tumor mass.

Renal insufficiency

The effect of renal insufficiency on the clearance of pembolizumab was evaluated in a population pharmacokinetic analysis in patients with mild (60 <glomerular filtration rate (GFR) <90 ml / min / 1.73 m², 937 patients) or moderate (30 ≤ GFR <60 ml / min / 1.73 m², 201 patients) with renal failure compared to patients with normal renal function (GFR ≥ 90 ml / min / 1.73 m², 1027 patients). There were no clinically significant differences in the clearance of pembolizumab between patients with mild or moderate renal failure and with normal renal function. In patients with severe renal insufficiency (15 ≤ GFR <30 ml / min / 1.73 m²) studies on the use of pembolizumab were not conducted.

Liver failure

The effect of liver dysfunction on the clearance of pembolizumab was assessed in a population pharmacokinetic analysis in patients with hepatic insufficiency of mild severity (the concentration of total bilirubin (OB) is from 1.0 to 1.5 times higher than the upper limit of the norm (VGN) or activity aspartate aminotransferase (ACT) higher VLN: 269 patients) when compared with patients with normal liver function (concentration of OB and activity ACT ≤ VGN; 1871 patients). There were no clinically significant differences in the clearance of pembolizumab between patients with mild hepatic insufficiency and normal liver function. In patients with moderate hepatic insufficiency (OB concentration 1.5 to 3 times higher than UGN and any value of ACT activity) or severe (concentration OB> 3 times higher than UGN and any value of ACT activity), the severity of the study on the use of pembolizumab was not performed.

Indications:

Melanoma

Kitruda® is indicated for the treatment of adult patients with inoperable or metastatic melanoma.

Non-small cell lung cancer

Kitruda® is indicated for the treatment of patients with advanced non-small cell lung cancer who have confirmed expression PD-L1 tumor cells and in which progression of the disease is observed during or after therapy with platinum drugs. In patients with mutations in the epidermal growth factor gene (EGFR) or anaplastic lymphoma kinase (ALK) there should be progression of the disease after treatment with specific drugs in the presence of these mutations before they are prescribed treatment with Kitrud®.

Contraindications:

- Hypersensitivity to pembolizumab or other components of the drug.

- Severe degree of renal failure.

- The average and severe degree of hepatic insufficiency.

- Age to 18 years.

- Pregnancy.

- The period of breastfeeding.

Pregnancy and lactation:

Pregnancy

There are no data on the use of pembolizumab in pregnant women. Special studies to study the effect of pembolizumab on reproductive function in animals have not been carried out, however in mice pregnancy models it has been shown that blockade of the signal system PD-L1 leads to a decrease in the mother's tolerance to the fetus and an increased threat of fetal death. These results indicate the possible risk (on the basis of the mechanism of action) of adverse effects on the fetus, including an increase in the incidence of miscarriages or stillbirths, with the use of pembolizumab during pregnancy. It is known that the human IgG4 (immunoglobulin) passes through the placental barrier, therefore, pembolizumab can penetrate the placenta from mother to fetus. Women of childbearing age should use reliable contraceptive methods during treatment with pembolizumab and for at least 4 months after the introduction of the last infusion of pembolizumab.

Breastfeeding period

There is no data on the secretion of pembolizumab in breast milk. Pembolizumab contraindicated during breastfeeding.

Impact on fertility

There are no clinical data on the possible effects of pembolizumab on reproductive function. Despite the fact that separate studies of the toxic effect of pembolizumab on reproductive function and intrauterine development have not been carried out, no significant effect on the reproductive organs of male and female monkeys was observed in a one-month and six-month toxicity studies of repeated doses.

Dosing and Administration:

Treatment should be started and carried out under the supervision of qualified and experienced oncologists.

For the treatment of NSCLC with Kituda®, patients should be selected on the basis of the presence of positive expression PD-L1 (quantitative index ≥ 1%).

Dose

The recommended dose of Kitrud® is 2 mg / kg. The drug is administered intravenously (IV) in the form of infusion for 30 minutes every 3 weeks. Treatment with Kitruda is carried out until the disease progresses or the development of unacceptable toxicity. There were atypical responses (ie initial short-term increase in tumor size or small new foci during the first few months, followed by a decrease in tumor size). It is recommended to continue treatment of clinically stable patients with initial signs of disease progression until the confirmation of disease progression.

Temporary or complete cancellation of treatment

Recommendations for the temporary or complete withdrawal of Kitrud® are described below (see also "Specific guidance").

Use of the Citrus® preparation should be temporarily discontinued in the event of the following immunological adverse reactions, including:

- pneumonitis - 2 (moderate) severity (according to classification The National Cancer Institute of the United States (NCI-CTCAE, edition 4));

- Colitis - 2 or 3 (moderate or severe) severity;

- nephritis - 2 (moderate) severity;

- endocrinopathy - 3 or 4 (severe or life-threatening) severity;

- hepatitis, followed by:

increased activity of ACT or ALT (3 to 5 times higher than UGN) or OB concentration (1.5 to 3 times higher than ULN).

The use of the Citrus® preparation should be resumed in patients with a decrease in undesirable reactions to 0-1 severity.

The use of Kitrud® should be discontinued in the following cases:

- If it is not possible to reduce the dose of corticosteroids ≤ 10 mg of prednisone or analogue per day for 12 weeks:

- If the toxicity associated with treatment does not decrease to 0-1 severity within 12 weeks after the administration of the last dose of Citrada®;

- In case of repeated development of any undesirable phenomenon of a severe degree;

- In case of undesired reactions, including:

undesirable reactions 4 (life-threatening) severity, with the exception of endocrinopathies, which improve to 2 degrees of severity or lower and are controlled by substitution therapy; o Immuno-mediated pneumonitis 3 or 4 (severe or life threatening) severity or recurrent 2 (moderate) severity:
immuno-mediated jade 3 or 4 (severe or life threatening) severity;
immuno-mediated hepatitis, accompanied by: increased activity of ACT or ALT (> 5 times higher than UGN) or OB concentration (> 3 times higher than UGN); in patients with liver metastases who started treatment with a moderate (2) increase in ALT or ACT, if the ALT or ACT increase is ≥50% relative to baseline values is held ≥ 1 week;
Infusion reactions 3 or 4 (severe or life-threatening) severity.

Special patient groups

Elderly patients (≥65 years of age)

There were no reported differences in safety or efficacy between elderly patients (≥65 years of age) and younger patients (<65 years). Correction of dose in elderly patients is not required.

Patients with impaired renal function

Patients with mild to moderate renal insufficiency do not need dose adjustment. Treatment with Citrus® was not studied in patients with severe renal failure.

Patients with impaired hepatic function

Patients with mild degrees of hepatic insufficiency do not need dose adjustment. Treatment with Citrus® was not studied in patients with moderate or severe hepatic impairment.

Melanoma of the eye

There are limited data on the safety and efficacy of Kitruda in patients with melanoma of the eye.

Children

The effectiveness and safety of Kitruda in children under the age of 18 years is not established. No data available.

Mode of application

The drug Kitruda® should be administered intravenously in the form of infusion for 30 minutes.

INSTRUCTION FOR PREPARATION AND INTRODUCTION OF SOLUTION FOR INFUSIONS

Preparation and Administration

- The bottle with the drug should be stored in a dark place. Do not freeze. Do not shake.

- It is necessary to bring the temperature of the vial with the Kituda® preparation to room temperature.

- The vial with the drug, prior to dilution, may be outside the refrigerator (at a temperature of not more than 25 ° C) for 24 hours.

- Drugs for parenteral administration before use should be visually checked for foreign particles and discoloration of the solution. The Kitreda® preparation is a clear or opalescent solution from colorless to light yellow in color. In the case of foreign matter, the vial with the drug can not be used.

- It is necessary to collect the required volume (up to 4 ml, 100 mg) of Kitrud® and Transfer to an infusion bag containing 0.9% sodium chloride solution or 5% glucose solution (dextrose) to prepare a diluted solution with a final concentration of 1 to 10 mg / ml. Stir the diluted solution, carefully turning the infusion bag.

- Prepared infusion solution should not be frozen.

- The drug does not contain preservatives. The diluted drug should be used immediately. If diluted solution is not used immediately after preparation, it can be stored at room temperature for a total of up to 6 hours. The diluted solution may be stored in the refrigerator at a temperature of 2 to 8 ° C, while the total time from the preparation of the diluted solution to the infusion should not exceed 24 hours. After removal from the refrigerator and before use, the vials and / or infusion bags must be brought to room temperature.

- The infusion solution is administered intravenously for 30 minutes through an intravenous system using a sterile, pyrogen-free, low-binding protein filter with a pore diameter of 0.2 to 5 microns, embedded or attached to the infusion system.

- Do not administer other medications through the same infusion system through which the Citrus® drug is administered.

- You should discard any unused amount of the drug left in the vial.

Side effects:

The safety of Kitruda® has been studied in the treatment of inoperable or metastatic melanoma in two controlled, randomized trials (KEYNOTE-002 and KEYNOTE-006), and in the treatment of inoperable or metastatic melanoma and metastatic NSCLC in an uncontrolled open-label study (KEYNOTE-001). A total of 1,567 patients with melanoma (699 previously treated with ipilimumab and 868 previously untreated with ipilimumab) and 550 patients with NSCLC received treatment. Safety of application is described for the general population of 2117 patients (studied among groups of 3 dosages: 2 mg / kg every 3 weeks and 10 mg / kg every 2 or 3 weeks). The median duration of treatment was 4.6 months (range from 1 to 28.3 months), including 906 patients treated for ≥6 months, and 203 patients who received treatment for ≥1 year.

The administration of the Citrus® preparation was canceled due to unwanted reactions, associated with treatment, in 4% of patients. Treatment-related serious adverse events (PCOS) reported within 90 days after the last administration of the drug were observed in 9% of patients receiving the Citrus® preparation. Among these treatment-related and identified in more than 5 patients (out of 2117) pneumonitis (n = 24), colitis (n = 19), diarrhea (n = 16), fever (n = 8), adrenal insufficiency (n = 6) and autoimmune hepatitis (n = 6).

Immuno-mediated undesirable reactions (see "Special instructions"):

Immuno-mediated adverse reactions are presented based on data from 2117 patients with melanoma and NSCLC. The safety profile was generally similar for patients with melanoma and NSCLC. In Table 1, according to the degree of severity, the frequency of occurrence of immuno-mediated adverse reactions that were observed in patients treated with Citrus®

Table 1: Immuno-mediated undesirable reactions

	Kitruda® 2 mg / kg every 3 weeks or 10 mg / kg every 2 or 3 weeks, n=2117
Unwanted reaction	All severity, (%)	2 degree of severity, (%)	3 degree of severity, (%)	4 degree of severity, (%)	5 degree of severity, (%)
Hypothyroidism	7.8	5,9	0,1	0	0
Hyperthyroidism	2,9	0,6	0,1	0	0
Pneumonitis	2,4	0,9	0,6	0,1	<0,1
Colitis	1,7	0,4	1,0	0,1	0
Hepatitis	0.8	0,1	0,5	0,1	0
Hypophysitis	0,7	0,2	0,3	<0,1	0
Nephritis	0,3	0,1	0,1	<0,1	0
Type 1 diabetes mellitus	0,1	<0,1	<0.1	<0,1	0

Other undesirable phenomena

Table 2 summarizes the adverse events that have been observed in at least 10% of patients with melanoma who received Kitruda® in the KEYNOTE-006 clinical trial. The most common adverse events (noted in at least 20% of patients) were fatigue and rash.

Table 2: Some of the adverse events observed in ≥10% of patients treated with Kitruda® (KEYNOTE-006)

	Kitruda® 10 mg / kg every 2 or 3 weeks, n=555		Ipilimumab n=256
Unwanted phenomena	All severity levels², (%)	3-4 degree of severity, (%)	All degrees of severity, (%)	3-4 degree of severity, (%)
General disorders and disorders at the site of administration
Fatigue	28	0,9	28	3,1
Violations from one hundredroskin and subcutaneous tissues
Rash³	24	0,2	23	1,2
Vitiligo⁴	13	0	2	0
Disturbances from musculoskeletal and connective tissue
Arthralgia	18	0,4	10	1,2
Backache	12	0,9	7	0,8
Disturbances from the respiratory system, chest and mediastinal organs
Cough	17	0	7	0,4
Dyspnea	11	0.9	7	0,8
Violations from one hundredrometabolism and nutrition
Decrease appetite	16	0,5	14	0,8
Disturbances from the nervous system
Headache	14	0,2	14	0,8

1 - undesirable phenomena observed with the same or greater frequency of occurrence in comparison with the group of ipilimumab.

2 - severity according to the classification of the National Cancer Institute (NCI-CTCAE, edition 4).

3 - includes a rash, erythematous rash, vesicular rash, generalized rash, macular rash, maculopapular rash, papular rash, itching rash and exfoliative rash.

4 - including hypopigmentation of the skin.

Table 3: Separate¹ abnormalities from laboratory indicators that deteriorated from baseline, observed in ≥20% of patients with melanoma treated with Kitrud^® (KEYNOTE-006)

	Kitruda® 10 mg / kg every 2 or 3 weeks		Inilimumab
Laboratory index²	All severity levels³, (%)	3-4 degree of severity, (%)	All degrees of severity, (%)	3-4 degree of severity, (%)
Biochemical indicators
Hyperglycaemia	45	4,2	45	3.8
Hypertriglyceridemia	43	2.6	31	1,1
Hyponatremia	28	4.6	26	7
Increased activity ACT	27	2.6	25	2,5
Hypercholesterolemia	20	1.2	13	0
Hematologic disorders
Anemia	35	3.8	33	4,0
Lymphopenia	33	7	25	6

1 - undesirable phenomena observed with the same or greater frequency of occurrence in comparison with the group of ipilimumab.

2 - each violation of the laboratory indicator is based on the number of patients,in which the initial data were known and at least one value measured during the study: Kitruda^® (520 to 546 patients) and ipilimumab (237 to 247 patients): hypertriglyceridemia: Citrus® n= 429 and ipilimumab n= 183; hypercholesterolemia: Citrus® n= 484 and ipilimumab n=205.

3 - gradation according to the classification of the National Cancer Institute of the USA (NCI-CTCAE, edition 4).

Table 4 summarizes the adverse events that occurred in at least 10% of patients with melanoma who received Kitruda® therapy in KEYNOTE-002. The most common adverse events (noted in at least 20% of patients) were itching, rash, constipation and diarrhea.

Table 4: Separate¹ adverse events observed in ≥10% of patients with melanoma treated with Citrud® (KEYNOTE-002)

	Kitruda® 2 mg / kg or 10 mg / kg every 3 weeks, n=357		Chemotherapy² n=171
Unwanted reaction	All severity levels³, (%)	3-4 degrees of severity, (%)	All degrees of severity, (%)	3-4 degrees of severity, (%)
General disorders and disorders at the site of administration
Fever	14	0,3	9	0,6
Asthenia	10	2,0	9	1.8
Disturbances from the skin and subcutaneous tissues
Itching	28	0	8	0
Rash⁴	24	0,6	8	0
Disorders from the gastrointestinal tract
Constipation	22	0,3	20	2,3
Diarrhea	20	0.8	20	2.3
Abdominal pain	13	1,7	8	1,2
Disturbances from the respiratory system, chest and mediastinal organs
Cough	18	0	16	0
Disturbances from musculoskeletal and connective tissue
Arthralgia	14	0,6	10	1,2

1 - undesirable phenomena observed with the same or greater frequency of occurrence in comparison with the chemotherapy group.

2 - chemotherapy: dacarbazine. temozolomide. carboplagin with paclitaxel. pacligaxel or carboplatin.

3 - severity according to the classification of the National Cancer Institute of the United States (NCI-CTCAE, edition 4).

4 - includes rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash and itching rash.

Table 5: Selected¹ abnormalities from laboratory indicators worsening from baseline, observed in ≥20% of patients with melanoma treated with Kitruda® (KEYNOTE-002)

	Kitruda® 2 mg / kg or 10 mg / kg every 3 weeks		Chemotherapy
Laboratory index²	All severity levels³, (%)	3-4 degree of severity, (%)	All degrees of severity, (%)	3-4 degree of severity, (%)
Biochemical indicators
Hyperglycaemia	49	6	44	6
Hypoalbuminemia	37	1,9	33	0,6
Hyponatremia	37	7	24	3,8
Hypertriglyceridemia	33	0	32	0,9
Increase in activity of alkaline phosphatase	26	3,1	18	1,9
Increased activity ACT	24	2,2	16	0,6
Reduction of bicarbonate concentration	22	0,4	13	0
Hypocalcemia	21	0,3	18	1,9
Increased ALT activity	21	1.8	16	0,6

1 - undesirable phenomena observed with the same or greater frequency of occurrence in comparison with the troupe of chemotherapy.

2 - each violation of the laboratory indicator is based on the number of patients who knew the baseline data and at least one measured during the study: Kitruda (320 to 325 patients) and chemotherapy (154 to 161 patients); hypertriglyceridemia: Citrus^®n= 247 and chemotherapy n= 116; decrease in bicarbonate concentration: Citrus® n = 263 and chemotherapy n = 123.

3 - gradation according to the classification of the National Cancer Institute of the USA (NC1-CTCAE, edition 4).

In general, the safety profile was similar between all doses and between patients who had previously received or were not receiving treatment with ipilimumab.

Table 6 summarizes the adverse events that occurred in at least 10% of patients with NSCLC receiving therapy with Kirtrud^® at KEYNOTE-001. The most common adverse events (noted in at least 20% of patients) were fatigue, decreased appetite, dyspnea, and cough.

Table 6: Adverse events observed in ≥10% of patients with NSCLC treated with Citrada® (KEYNO TE-001)

	Kitruda® 2 mg / kg every 3 weeks or 10 mg / kg every 2 or 3 weeks, N=550
Unwanted phenomenon	All degrees of severity, (%)	3 degree of severity¹, (%)
General disorders and disorders at the site of administration
Fatigue²	44	4
Fever	12	1
Peripheral edema	10	0
Disorders from the metabolism and nutrition
Decreased appetite	25	1
Disturbances from the respiratory system, chest and mediastinal organs
Dyspnea	23	4
Cough³	29	<1
Disorders from the gastrointestinal tract
Nausea	18	1
Diarrhea	15	1
Constipation	15	<1
Vomiting	12	1
Disturbances from musculoskeletal and connective tissue
Arthralgia	15	1
Backache	10	2
Violations of the blood and lymphatic system
Anemia	12	2
Disturbances from the skin and subcutaneous tissues
Itching	12	0
Rash⁴	18	<1

1 - none of the adverse events reported in ≥10% of patients reported any 4 or 5 degree of severity.

2 - includes the terms fatigue and asthenia.

3 - includes the terms cough, productive cough and hemoptysis.

4 - includes terms dermatitis, acneiform dermatitis, erythema multiforme, drug rash, rash, generalized rash, itching rash, macular / maculopapular rash, papular rash.

Table 7: Disorders from laboratory indicators that deteriorated from baseline, observed in ≥20% of patients with NSCLC treated with Kitruda® (KEYNOTE-001)

	Kitruda® n = 550
Laboratory indicator	All degrees of severity, (%)	3-4 degree of severity, (%)
Biochemical indicators
Hyperglycaemia	48	3*
Hyponatremia	38	6
Hypoalbuminemia	32	1
Increase activity of alkaline phosphatase	26	1
Hypetiglyceridemia	23	0
Increased activity ACT	20	1
Hypercholesterolemia	20	1¹
Hematologic disorders
Anemia	36	2¹

1 - violations of 4 degrees of severity in this table are limited to hyperglycaemia (n = 4), hypercholesterolemia (n = 3) and anemia (n = 1).

Overdose:

There is no information about an overdose of Kitreda®. The maximum tolerated dose for Kitrud^® not installed. In clinical trials in patients who received pembolizumab in a dose of up to 10 mg / kg, the safety profile was comparable to that of patients who received pembolizumab in a dose of 2 mg / kg.

In case of an overdose, patients should be closely monitored for signs and symptoms of adverse reactions and appropriate symptomatic treatment should be prescribed.

Interaction:

Special studies of the pharmacokinetic interaction of the Kitrud preparation^® with other medications were not performed.

Because the pembolizumab is excreted from the circulation by catabolism, then metabolic drug interactions should not be expected.

Use of systemic corticosteroids or immunosuppressants should be avoided prior to the initiation of therapy with Kitudra®, taking into account their possible effects on the pharmacodynamic activity and efficacy of the Citrada® preparation. Nevertheless, systemic corticosteroids or other immunosuppressants can be used after the start of treatment with pembolizumab for the treatment of immuno-mediated adverse reactions (see "Specific guidance").

Special instructions:

Immuno-mediated undesirable reactions

Immunosupplemented undesirable reactions were observed in patients receiving the Citruda® preparation. Most immuno-mediated adverse reactions observed in clinical trials were reversible and controlled by temporary discontinuation of Citrad ®, the use of corticosteroids and / or symptomatic therapy.

If suspicion of immuno-mediated adverse reactions is required, a thorough evaluation is required to confirm the etiology and exclude other possible causes. Based on the severity of the unwanted reaction, it is necessary to temporarily stop taking Citrada® and prescribe corticosteroids (see below).

From the moment of improvement to I degree of severity or less, begin a gradual reduction in the dose of corticosteroids and continue the gradual decrease for at least 1 month.

According to limited data obtained in clinical studies, in patients in whom immuno-mediated adverse reactions can not be controlled by the use of corticosteroids, the possibility of prescribing other systemic immunosuppressants may be considered.

Renewal of the preparation of the Citrus® preparation is possible if the severity of the undesired reaction remains I degree of severity or less. In the event of another episode of adverse severity, it is necessary to completely stop the use of the Citrude® preparation (see "Dosage and Administration" and "Side-Effects").

Immunosuppressed pneumonitis

Patients who received the Citrus® preparation reported cases of pneumonitis (including fatal cases). It is necessary to conduct active monitoring of patients with signs and symptoms of pneumonitis. If a pneumonig is suspected, an X-ray examination should be performed to exclude other causes.

Corticosteroid therapy is prescribed for pneumonitis of 2 degrees of severity or higher (initial dose of 1-2 mg / kg / day of prednisone or an analogue, followed by a gradual decrease in dose). Temporarily cancel the use of Kitrud® with pneumonitis 2 (moderate) severity and completely abolish the administration of Kitrud® at 3 (severe) or 4 (life-threatening) severity of pneumonitis or relapse of pneumonitis 2 (moderate) severity (see "Method of administration and dose ").

Immuno-mediated colitis

Patients who received the Citrus® preparation reported cases of developing colitis (see "Side effect"). It is necessary to actively monitor patients for signs and symptoms of colitis and exclude other causes of its development. Therapy with corticosteroids is prescribed at 2 degrees of severity or higher (initial dose of 1-2 mg / kg / day of prednisone or an analogue, followed by a gradual decrease in dose).Temporarily cancel the reception of the drug Kirtruda at 2 (moderate) or 3 (severe) severity of colitis and the use of the drug Kitrud^® completely abolished with colitis 4 (life-threatening) severity (see "Method of administration and dose").

Immunopreparated hepatitis

Patients who received the Citrus® preparation reported cases of hepatitis (see "Side effect"). It is necessary to monitor patients with respect to the dynamics of liver functional parameters (at the beginning of treatment, periodically during therapy, and also on the basis of clinical evaluation) and the symptoms of hepatitis and exclude other causes.

Therapy with corticosteroids is prescribed for hepatitis of 2 severity (initial dose 0.5-1 mg / kg / day of prednisone (or similar) followed by a gradual decrease in dose) and for hepatitis of 3 severity or higher (1-2 mg / kg / day prednisone (or the like) followed by a gradual decrease in the dose). Temporarily or completely cancel the reception of the Citrus® preparation in accordance with the level of increase in the activity of liver enzymes (see "Method of administration and dose").

Immuno-mediated nephritis

In patients who received the drug Kitruda^®, reported cases of development of nephritis (see "Side effect"). Patients should be monitored in to change the function of the kidneys and exclude other causes.

Therapy with corticosteroids is prescribed for the development of adverse events of 2 degrees of severity and higher (initial dose of 1-2 mg / kg / prednisone fowl (or similar) followed by a gradual decrease in dose).

Temporarily cancel the drug Kitruda^® in the case of development of 2 (moderate) severity of nephritis, and completely reject the use of the Citruda ® preparation at 3 (severe) or 4 (life-threatening) severity of nephritis (see "Method of administration and dose").

Immunopreparated endocrinopathies

Patients who received the Citrus® preparation reported cases of development of the hypophysitis (see "Side effect"). Patients should be monitored in the signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and exclude other causes.

In case of manifestation of secondary adrenal insufficiency, corticosteroid therapy or other hormone replacement therapy is prescribed in accordance with the clinical evaluation.

Temporarily cancel the reception of the drug Kitruda in case of 2 (moderate) severity of the hypophysitis. completely cancel the use of the drug Kitruda^® at 3 (severe) or 4 (life-threatening) severity of the hypophysitis (see "Method of administration and dose").

Patients who received the Citrus® preparation reported cases of type I diabetes, including cases of diabetic ketoacidosis. Patients should be monitored for hyperglycemia or other signs and symptoms of diabetes mellitus. In type 1 diabetes, insulin is prescribed, and in cases of severe hyperglycemia, the administration of Kitruda® is temporarily canceled until control of the metabolism is achieved.

Patients who received the Citrus® preparation were informed of thyroid disorders, they can develop at any time during the treatment. Therefore, patients should be monitored for changes in thyroid function (at the beginning of treatment, periodically during therapy, and also on the basis of clinical evaluation) and clinical signs and symptoms of thyroid dysfunction.Treatment of hypothyroidism can be carried out through replacement therapy without interruption of treatment and without the use of corticosteroids. With hyperthyroidism, symptomatic treatment is possible. Temporarily or completely canceled at reception Kitruda® preparation 3 (severe) or 4 (life-threatening) degree gipergireoza gravity (cm. "Dosage and Administration").

Patients with 3 (severe) or 4 (life-threatening) endocrinopathy severity while improving severity to 2 or below, and the control means of hormone replacement therapy may be considered a continuation of application Kitruda® preparation.

Other immuno-mediated undesirable reactions

The following additional clinically significant immune-mediated adverse reactions were observed in less than 1% of patients (unless another frequency) treated with drug in studies Kitruda® KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006: uveitis, myositis, Guillain-Barre syndrome, pancreatitis and severe skin reactions (1.1%).

Infusion reactions

Severe infusion reactions were reported in 3 (0.1%) of 2117 patients treated with the drug in clinical trials Kitruda® KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006. If the severity of the infusion reaction is severe, infusion should be discontinued and Kiturda® should be discontinued completely (see "Dosage and Administration"). In patients with mild or moderate severity of infusion reactions, the possibility of continuing the administration of Kitrud® under the close supervision of an oncologist may be considered; premedication through antipyretic and antihistamines.

Effect on the ability to drive transp. cf. and fur:The Kitreda® preparation may have little effect on the ability to drive and work with machinery. Reported fatigue after the introduction of pembolizumab (see "Side effect").

Form release / dosage:Concentrate for the preparation of a solution for infusions, 25 mg / ml.

Packaging:

By 4.0 ml of the drug in a bottle of colorless glass type I (Hebrew Farm, US Pharm.), Sealed with a stopper of chlorobutyl rubber, crimped with an aluminum cap and protected with a plastic cover.

In the case of secondary packaging at Schering-Plau, NV Lapo, Belgium:

1 bottle with instructions for use in a cardboard pack. In order to control the first opening on the cardboard pack, stick self-adhesive stickers.

In the case of secondary packaging at ZAO ORTAT, Russia:

For 1 bottle in a cardboard pallet together with instructions for use in a cardboard bundle. In order to control the first opening on the cardboard pack, stick self-adhesive stickers.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C. Do not freeze. Do not shake.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003972

Date of registration:18.11.2016

Expiration Date:18.11.2021

The owner of the registration certificate:MSD FARMASYUTIKALS, LLC MSD FARMASYUTIKALS, LLC Russia

Manufacturer: & nbsp

ORTAT, CJSC Russia

SCHERING-PLOUGH LABO, N.V. Belgium

Representation: & nbspMSD Pharmaceuticals Ltd.MSD Pharmaceuticals Ltd.

Information update date: & nbsp14.12.2016

Illustrated instructions

Instructions

Kitruda® (KEYTRUDA®)