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

Active substanceIxazomibIxazomib

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Millennium Pharmaceuticals Incorporated USA

Dosage form: & nbspcapsules

Composition:

One capsule with a dosage of 2.3 mg contains:

active substance: Ixazomibe citrate 3.29 mg corresponds to Ixazomibe 2.3 mg; Excipients: cellulose microcrystalline 65.66 mg, talc 0.70 mg, magnesium stearate 0.35 mg;

shell capsules: gelatin 36.83 mg, titanium dioxide 1.14 mg, iron dye oxide red 0.03 mg, black ink 10A2¹ trace amounts.

One capsule with a dosage of 3 mg contains:

active ingredient: Ixazomibe citrate 4.3 mg corresponds to Ixazomibe 3 mg; Excipients: cellulose microcrystalline 64.65 mg, talc 0.70 mg, magnesium stearate 0.35 mg;

shell capsules: gelatin 37.07 mg, titanium dioxide 0.89 mg, iron dye oxide black 0.05 mg, black ink 10A2¹ trace amounts.

One capsule with a dosage of 4 mg contains:

active substance: Ixazomibe citrate 5.7 mg corresponds to Ixazomibe 4 mg; Excipients: cellulose microcrystalline 107.5 mg, talc 1.20 mg, magnesium stearate 0.60 mg;

shell capsules: gelatin 46.53 mg, titanium dioxide 1.13 mg, iron dye oxide red 0.03 mg, iron dye oxide yellow 0.32 mg, black ink 10A2¹ trace amounts.

¹Ink black 10A2 contain: shellac, propylene glycol, potassium hydroxide, iron oxide black dye.

Description:

Dosage of 2.3 mg: Hard gelatin capsules No. 4, capsule case light pink, cap capsule light pink, with inscriptions "Takeda" on the cap of the capsule and "2.3 mg" on the capsule body, printed with black ink:

Dosage 3 mg: hard gelatin capsules No. 4. capsule body light gray, cap capsule light gray, with inscriptions "Takeda" on the cap of the capsule and "3 mg" on the capsule body, printed with black ink:

Dosage 4 mg: hard gelatin capsules No. 3, capsule case light orange, cap capsule light orange, with inscriptions "Takeda" on the cap of the capsule and "4 mg" On the capsule body, applied in black ink.

The contents of the capsules are white to yellowish white powder.

Pharmacotherapeutic group:Antitumor agent

ATX: & nbsp

L.01.X.X.50 Ixazomib

Pharmacodynamics:

Ixazomib is a reversible proteasome inhibitor. Ixazomib predominantly binds and inhibits the chymotrypsin-like activity of the beta-5 subunit 20S proteasomes.

Ixazomib causes apoptosis of cultured in vitro cell lines of multiple myeloma. Ixazomib exhibited cytotoxicity in vitro for myeloma cells taken from patients with developed relapses after multiple cycles of therapy, including bortezomib. lenalidomide and dexamethasone. The combination of Ixazomib and Lenalidomide demonstrated a synergistic cytotoxic effect on the multiple myeloma cell lines. In conditions in vivo Ixazomib showed antitumor effect on the model of tumor xenograft of multiple myeloma of mice.

Cardioelectrophysiology

Ninlaro® did not extend the interval QTc at exposures corresponding to clinical, according to pharmacokinetic-pharmacodynamic analysis of 245 patients.

Pharmacokinetics:

Suction

After oral administration, the median time to reach the maximum concentration of ixazomib in plasma was one hour. The value of absolute bioavailability after oral administration was 58% based on the results of a population analysis of pharmacokinetics. AUC Ixazomibe increases dose-dependent manner in the dose range from 0.2 to 10.6 mg. The study of the effect of food intake, conducted in patients who received a single dose of 4 mg of Ixazomib,that foods high in fat lowered AUC Ixazomib by 28% and C_Max (maximum concentration) by 69%.

Distribution

Ixazomib binds 99% to plasma proteins and is distributed to erythrocytes with a blood-plasma ratio of 10. The volume of distribution in the equilibrium state is 543 liters.

Excretion

According to the results of the population analysis of pharmacokinetics, the system clearance was about 1.9 l / h with a variability of individual values of 44%. The half-life in the final phase (T_1/2) of ixazomibe was 9.5 days. After weekly oral administration, the accumulation ratio was determined to be twofold.

Metabolism

After oral administration of a dose with a radioisotope label Ixazomib represented 70% of all radioactive material associated with the drug in plasma. The main mechanism of excretion of Ixazomib is considered metabolism under the action of multiple enzymes CYP and not-CYP proteins. At clinically significant levels of Ixazomib concentration studies in vitro using cytochrome P450 isoenzymes derived from human complementary DNA,that there is no specific isoenzyme CYP, predominantly involved in the metabolism of Ixazomib. At concentrations higher than clinical, Ixazomib was metabolized under the influence of many isoforms CYP with estimated participation interests: 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2С19 (5%) and 2С9 (<1%).

Allocation

After oral administration of a single dose ¹⁴C-Ixazomibe in 5 patients with a common malignant tumor 62% of the incoming radioactivity was excreted in the urine and 22% with feces. Unchanged Ixazomib, excreted in the urine, was <3.5% of the administered dose.

Special patient groups

Age, gender, ethnicity

There was no clinically significant effect of age (in the range of 23-91 years), sex, body surface area (range 1.2-2.7 m²) or race for Ixazomib clearance based on a population analysis of pharmacokinetics.

Dysfunction of the liver

The pharmacokinetics of ixazomib was similar in patients with normal liver function and in patients with mild liver function disorders (total bilirubin ≤ VLD [upper limit of the norm] and ACT > VLN, or total bilirubin> 1-1.5 x VLN and any value ACT) based on a population analysis of pharmacokinetics.Pharmacokinetic data have been described in patients with normal liver function when taking Ixazomib in a dose of 4 mg (N=12), with moderate violations of the liver at a dose of 2.3 mg (total bilirubin> 1.5-3 x VPN, N=13) or severe impairment of liver function at a dose of 1.5 mg (total bilirubin> 3 x VPN, N=18). Normalized for the dose average values AUC were 20% higher in patients with moderate or severe impairment of liver function compared to patients with normal liver function.

Renal impairment

The pharmacokinetics of ixazomib was similar in patients with normal renal function and in patients with mild to moderate-to-moderate function disorders (creatinine clearance ≥ 30 mL / min) based on a population-based pharmacokinetics analysis. Pharmacokinetic data were described with a dose of ixazomib 3 mg in patients with normal renal function (creatinine clearance ≥ 90 mL / min, N=18), severe impairment of kidney function (creatinine clearance <30 ml / min, N=14) or with end-stage renal disease requiring dialysis (N=6). Mean values AUC were 39% higher in patients with severe renal dysfunction or with end-stage renal disease requiring dialysis compared to patients with normal function of the kidneys.The concentrations of Ixazomib before dialysis, during and after dialysis were similar, suggesting that Ixazomib is not displayed during dialysis.

Indications:

The drug Ninlaro® is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received at least one previous therapy line before.

Contraindications:

Hypersensitivity to the components of the drug, pregnancy, the period of breastfeeding, children under 18 years of age.

Carefully:Precautions for use

Thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, peripheral edema, skin reactions, hepatotoxicity, embryophototoxicity.

Pregnancy and lactation:

Pregnancy

A brief description of the risk

The mechanism of action of Ninlaro® and data from studies of reproductive toxicity in animals indicate that Ninlaro® can have a harmful effect on the fetus when used in pregnant women. No clinical data are available regarding the potential effects of Ninlaro® on pregnancy or on the development of an embryo or fetus. Ixazomib caused embryophototoxicity in pregnant rats and rabbits in doses that lead to an effect slightly higher than that observed in patients receiving the recommended doses. A woman should be informed of the potential hazard to the fetus and avoid pregnancy during the period of Ninlaro® use.

In the general US population, the estimated risk of severe congenital defects or miscarriage in clinically established pregnancies is 2-4% and 15-20%, respectively.

Data

Data obtained in animal studies

In the study of embryo-fetal development in pregnant rabbits, the fetus experienced an increase in the incidence of abnormal development / changes in the skeleton (fusion of the caudal vertebrae, change in the number of lumbar vertebrae and full complementary ribs) at doses that were toxic to the female (≥ 0.3 mg / kg). Levels of exposure to a dose of 0.3 mg / kg in rabbits were 1.9 times higher than the average dose of exposure in humans with the recommended dose of 4 mg. In a study to determine the range of doses affecting embryo-fetal development of rats at doses that were toxic to the female, a decrease in fetal body mass was observed,the tendency to decrease the viability of the fetus and increase the frequency of postimplantation death of the fetus at doses of 0.6 mg / kg. The exposure levels in rats at doses of 0.6 mg / kg were 2.5 times higher than the average level of exposure in humans when the recommended doses were 4 mg.

Lactation

A brief description of the risk

There is no data on the isolation of Ninlaro® or its metabolites with breast milk and the effect of the drug on children who are breastfeeding or on the formation of breast milk. In view of the fact that the risk of developing serious adverse reactions in the child when using Ninlaro® is unknown, a woman should be recommended to stop breastfeeding during the treatment period and within 90 days after taking the last dose.

Women and men capable of childbearing

Contraception

Male and female patients who are capable of giving birth should use reliable contraception during the treatment period and within 90 days after it.

It is known that dexamethasone has a weak or moderate effect of inducing action on the isoenzyme CYP3A4, as well as other enzymes and carrier proteins. Because Ninlaro® is used in conjunction with dexamethasone, the risk of reducing the effectiveness of contraceptives should be considered.Women who use hormonal contraceptives should also use the barrier method of contraception.

Dosing and Administration:

Ninlaro® in combination with lenalidomide and dexamethasone

Ninlaro® is intended for oral administration.

Ninlaro® should be taken once a week, on the same day of the week, and approximately at the same time, during the first three weeks of a four-week cycle. Ninlaro® should be taken at least one hour before or at least two hours after ingestion. Capsule swallowed whole, washed down with water. Capsule should not be crushed, chewed or opened.

Dosing regimen

The recommended initial doses of Ninlaro® are 4 mg taken internally once a week at 1, 8 and 15 days of the 28-day treatment cycle.

The recommended initial doses of lenalidomide are 25 mg taken internally every day from 1 to 21 days of the 28-day treatment cycle.

The recommended initial doses of dexamethasone are 40 mg, used at 1, 8, 15 and 22 days of the 28-day treatment cycle.

Table. 1. Scheme of application of Ninlaro in combination with lenalidomide and dexamethasone

28-day cycle (4-week cycle)
	1 Week		2 weeks		3 week		4 week
	1 day	2-7 days	Day 8	9-14 days	Day 15	16-21 days	22 day	23-28 days
Ninlaro	V		V		V
Lenalidomide	V	V daily	V	V daily	V	V daily
Dexamethasone	V		V		V		V

V - taking the medicine

For more information on lenalidomide and dexamethasone, refer to the instructions for their medical use.

Before the start of a new cycle of therapy:

- The absolute number of neutrophils should be at least 1000 / mm³

- The number of platelets must be at least 75,000 / mm³

- Non-hematologic toxicity should generally be restored to the patient's initial condition, either to grade 1 or lower, at the doctor's discretion.

Treatment should continue until the disease progresses or the development of unacceptable toxicity.

Concomitant therapy

The necessity of the prophylactic administration of antiviral drugs in patients receiving Ninlaro® should be considered with a view to reducing the risk of reactivation of the herpes zoster virus (see "Side effect" section).

Delayed doses or missed doses

If the Ninlaro® capsule is delayed or missed, the drug should be taken only if the remaining scheduled dose remains ≥ 72 hours.The missed dose should not be taken less than 72 hours before the next scheduled dose. Do not take a double dose of the drug instead of the missed dose.

If vomiting occurs after taking the drug, do not take an additional dose. The patient should continue treatment with the drug at the next scheduled dose.

Instructions for changing the dose

The sequence of dose reduction of Ninlaro® is presented in Table 2. Recommendations for dose adjustment are given in Table 3.

Table. 2. Lowering the dose of Ninlaro® due to undesirable reactions

Recommended initial

dose*

The first dose reduction before

The second dose reduction before

Cancel

preparation

4 mg

3 mg

2.3 mg

* The recommended initial dose of 3 mg in patients with moderate or severe impairment of liver function, severe renal dysfunction, or end stage renal disease requiring dialysis.

An alternating approach to the variation of the dose of Ninlaro® and lenalidomide is recommended. thrombocytopenia, neutropenia and rash, as described in Table 3. Refer to instructions for the medical use of lenalidomide if a dose reduction is required lenalidomide.

Table 3.Indications for a change in the dose of Ninlaro® when used in combination with lenalidomide and dexamethasone

Hematological toxicity	Recommended actions
Thrombocytopenia (number of platelets)
The number of platelets is less than 30,000 / mm³	- Do not use Ninlaro® and lenalidomide, until the platelet count is at least 30,000 / mm³. - After normalization, the use of lenalidomide is continued at the next lower dose according to the instructions for its use and Ninlaro® is continued in its last dose. - If the platelet count falls again below 30,000 / mm³, do not use Ninlaro® and lenalidomide, until the platelet count is at least 30,000 / mm³ - After normalization, the use of Ninlaro® is continued at the next lower dose and lenalidomide is continued in its last dose. *
Neutropenia (absolute number of neutrophils)
Absolute number of neutrophils less than 500 / mm³	- Do not use Ninlaro® and lenalidomide. until the absolute number of neutrophils is at least 500 / mm³. Consider the feasibility of using G-CSF (granulocyte colony-stimulating factor) according to the instructions for medical use. - After normalization, the use of lenalidomide is continued at the next lower dose according to the instructions for its use and Ninlaro® is continued in its last dose. - If the absolute number of neutrophils again falls below 500 / mm³, do not use Ninlaro® and lenalidomide, until the absolute amount of neutrophils becomes at least 500 / mm³ - After normalization, the use of Ninlaro® is continued at the next lower dose and lenalidomide is continued in its last dose. *
Non-hematological toxicity	Recommended actions
Rash
Power^ţ 2 or 3	- Do not apply lenalidomideuntil the rash has decreased to 1 or lower. - After normalization, lenalidomide is continued at the next lower dose according to the instructions for its use. - If a rash of degree 2 or 3 appears, do not use Ninlaro® and lenalidomide. until the rash has decreased to 1 or lower. - After normalization, the use of Ninlaro® is continued at the next lower dose and lenalidomide is continued in its last dose. *
Degree 4	Cancel Treatment Scheme
Peripheral Neuropathy
Peripheral neuropathy degree 1 with pain or peripheral neuropathy degree 2	- Do not apply Ninlaro® until peripheral neuropathy decreases to a grade of 1 or lower without pain or to the patient's initial condition. - After normalization, the use of Ninlaro® in its last dose continues.
Peripheral neuropathy degree 2 with pain or peripheral neuropathy degree 3	- Do not use Ninlaro®. Toxicological effects, at the discretion of the physician, should generally be reduced to the initial state of the patient or grade 1 or lower before resuming the administration of Ninlaro®. - After normalization, the use of Ninlaro® in the next lower dose
Peripheral neuropathy degree 4	Cancel Treatment Scheme
Other non-hematological toxicity
Other types of non-hematological toxicity degree 3 or 4	- Do not use Ninlaro®. Toxicological effects, at the discretion of the physician, should generally be reduced to the initial state of the patient or grade 1 or lower before resuming Ninlaro® administration. - If the phenomenon is associated with Ninlaro®, after normalization, the use of Ninlaro® continues at the next lower dose

* In case of repeated manifestations of toxicity, it is recommended to use the scheme of sequential reception of lenalidomide and Ninlaro *.

ţ The grading is based on the Common Terminological Criteria for Undesirable Events of the National Institute of Oncology (STAAE, version 4.03)

Special patient groups

Patients of advanced age (65 years and older)

Results of population pharmacokinetic (PK) analysis in patients older than 65 years showed no need for dose adjustment of Ixazomib.

In studies of ixazomib, no clinically significant differences in the safety and efficacy of the drug in patients younger than 65 years of age and patients aged 65 years and older have been identified.

Impaired liver function

The initial dose of Ninlaro® is reduced to 3 mg in patients with moderate (total bilirubin higher than 1.5-3 x VLN [upper limit of the norm]) or severe (total bilirubin is higher than 3 x VLN) violations of the liver function.

Impaired renal function

The initial dose of Ninlaro® is reduced to 3 mg in patients with severe renal impairment (creatinine clearance less than 30 mL / min) or with end-stage renal disease requiring dialysis. Ninlaro® can not be removed by dialysis.Regarding the recommendations for lenalidomide dosing in patients with impaired renal function, refer to the instructions for its medical use.

Children and teens

The safety and efficacy of Ixazomib in children under the age of 18 years have not been established. No data available.

Side effects:

The following undesirable reactions are described in detail in the section "Special instructions":

- Thrombocytopenia

- Gastrointestinal toxicity

- Peripheral Neuropathy

- Peripheral edema

- Skin Reactions

- Hepatotoxicity

Experience in clinical trials

Because Ninlaro® is used in combination with lenalidomide and dexamethasone, information should be obtained about the undesirable reactions of these drugs in the instructions for medical use.

The safety assessment population in the Phase 3 baseline study included 720 patients with recurrent and / or treatment-resistant multiple myeloma who received Ninlaro® in combination with lenalidomide and dexamethasone (Scheme with Ninlaro *; N=360) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=360) and 115 patients from a double-blind, placebo-controlled study.

The most frequent adverse reactions (≥20%) that were recorded in 417 patients receiving Ninlaro and 418 patients receiving placebo were diarrhea (39% compared to 32%), thrombocytopenia (33% compared to 21%), neutropenia (33% compared with 30%), constipation (30% compared with 22%), peripheral neuropathy (25% compared to 20%), nausea (23% compared to 18%), peripheral edema (23% compared to 17%), vomiting (20% compared to 10%) and upper respiratory tract infection (21% compared to 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%).

Undesirable reactions to the drug are ordered according to the system-organ class and are consistent with terms of preferred use (in accordance with the Medical Dictionary for Regulatory Activities - MedDRA) (see Table 4). To describe the frequency of undesired reactions (HP) The classification is based on the recommendations of the Council of International Scientific and Medical Organizations - CIOMS: very often (≥ 1/10); often (≥ 1/100 to <1/10); infrequently (≥ 1/1000 to <1/100); rarely (≥ 1/10 000 to <1/1000); very rarely (<1/10 000); unknown (can not be calculated based on available data).

Table. 4.Undesirable reactions with the use of Ninlaro in combination with lenalidomide and dexamethasone (all degrees of severity, 3 degrees and 4 degrees)

Organ system class / Undesirable reactions	Undesirable reactions (all degrees of severity)	Undesirable reactions of the 3rd degree of severity	Undesirable reactions of the 4th degree of severity
Infectious and parasitic diseases
Upper respiratory tract infection	Often	Infrequently
Shingles Herpes	Often	Often
Disorders from the blood and lymphatic system
Thrombocytopenia *	Often	Often	Often
Neutropenia *	Often	Often	Often
Disturbances from the nervous system
Peripheral neuropathies *	Often	Often
Disorders from the gastrointestinal tract
Diarrhea	Often	Often
Constipation	Often	Infrequently
Nausea	Often	Often
Vomiting	Often	Infrequently
Disturbances from the skin and subcutaneous tissues
Rash*	Often	Often
Disturbances from musculoskeletal and connective tissue
Backache	Often	Infrequently
General disorders and disorders at the site of administration
Peripheral edema	Often	Often

* Represents a group of preferred terms.

Description of individual adverse reactions

Discontinuation of treatment

The development of each of these unwanted reactions required the elimination of one or more of the three drugs in ≤ 1% of patients in the Ninlaro® group.

Thrombocytopenia

In 3% of patients taking Ninlaro® and 1% of patients receiving placebo during treatment platelet count was ≤ 10000 / mm³. In less than 1% of patients in both groups, the number of platelets decreased during treatment to ≤ 5000 / mm³. The development of thrombocytopenia led to the cancellation of one or more of the three drugs in <1% of patients in Ninlaro® group and 1% of patients in the placebo group. Thrombocytopenia was not accompanied by an increase in the frequency or amount of hemorrhagic manifestations platelet transfusions.

Toxic effects from the gastrointestinal tract

Diarrhea led to the cancellation of one or more of the three drugs in 1% of patients in the group Ninlaro® and <1% of patients in the placebo group.

Rash

A rash was observed in 18% of patients in the Ninlaro® group compared with 10% of patients in the placebo group. Most often in both groups spotted-papular and macular eruptions were revealed.A grade 3 rash was reported in 2% of patients in the Ninlaro® group compared with 1% in the placebo group. The appearance of rashes led to the cancellation of one or more of the three drugs in <1% of patients in both groups.

Peripheral Neuropathy

Peripheral neuropathy occurred in 25% of patients in the Ninlaro® group compared with 20% of patients in the placebo group. Peripheral neuropathy of grade 3 was registered in 2% of patients in both groups. The most frequently developed peripheral sensory neuropathy (16% and 12% in the Ninlaro® group and placebo, respectively). Peripheral motor neuropathy was infrequent in both groups (<1%). The development of peripheral neuropathy led to the cancellation of one or more of the three drugs in 1% of patients in the Ninlaro® group compared with <1% of patients in the placebo group.

Visual disturbances

Visual disorders were described by many different terms of preferred use, in total their incidence was 24% in patients receiving the Ninlaro® regimen and 15% in patients receiving the placebo regimen. The most frequent adverse reactions were blurred vision (5% with Ninlaro® and 4% with (4% in the Ninlaro® regimen and 1% in the placebo regimen), conjunctivitis (5% in the Ninlaro® regimen and 1% in the placebo regimen), and cataracts (4% with the Ninlaro regimen) ® and 5% in the placebo regimen). Undesirable reactions of grade 3 were observed in 2% of patients in both groups.

Other undesirable reactions

However, the following serious adverse reactions have been reported in rare cases: the acute febrile ytetrophilic dermatosis (Sweet syndrome), Stevens-Johnson syndrome, transverse myelitis, reverse reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura .

In the baseline study of 3 phases (N=720) and a double-blind, placebo-controlled study (N=115) the undesirable reactions listed below occurred with the same frequency in the Ninlaro® group and placebo group: fatigue (26% vs 24%), decreased appetite (12% vs 9%), hypotension (4% in each group), heart failure (3% in each group), arrhythmia (12% vs. 11%), as well as impaired liver function, including changes in the level of hepatic enzymes (8% vs 6%).

The incidence of severe (grade 3-4) hypokalemia was higher in the Ninlaro® group (5%) than in the placebo group (<1%).

The development of fungal and viral pneumonia with a fatal outcome was recorded in patients who received the combination of Ninlaro®, lenalidomide and dexamethasone, rarely.

The patient should be informed of the need inform the doctor about all cases of undesirable reactions, including those not listed in this manual for medical use.

Overdose:

There is no specific antidote for use in an overdose of Ninlaro®. In case of overdosage, monitoring of the patient's condition, presence of undesirable reactions (see section "Side effect"), as well as symptomatic therapy.

Interaction:

Pharmacokinetic interactions

Powerful inductors CYP3A

The simultaneous use of Ninlaro® with powerful inducers should be avoided CYP3A (such as rifampin, phenytoin, carbamazepine and St. John's wort). The combined use of Ninlaro with rifampin lowers C_Max iksazomib by 54% and AUC on 74%.

Powerful inhibitors CYP3A

Joint use of Ninlaro with clarithromycin, a potent inhibitor CYP3A, did not lead to a clinically significant change in the presence of Ixazomib in the systemic circulation.

Powerful inhibitors CYP1A2

According to the population analysis of pharmacokinetics, simultaneous use of Ixazomib with powerful inhibitors of CYP1A2 did not lead to a clinically significant change in systemic exposure to Ixazomib.

Effect of Ninlaro® on other medicines

Ninlaro® is neither a reversible nor time-dependent inhibitor of isoforms CYP - 1A2, 2B6, 2C8, 2C9, 2C19. 2D6 or 3A4 / 5. Ixazomib did not induce activity CYP1A2, CYP2B6 and CYP3A4/5 or levels of the corresponding immunoreactive proteins. When Ninlaro® is used, drug interactions are not expected to develop by suppression or induction CYP.

Interactions related to vectors

Ixazomib is a low affinity substrate of glycoprotein-P. Ixazomib is not a substrate BCRP (protein resistance of breast cancer), MRP2 (protein 2 of multiple drug resistance) or hepatic OATP (transport polypeptides of organic anions). Ixazomib is not an inhibitor of glycoprotein-P, BCRP, MRP2, OATP1B1, OATP1B3, OCT (carrier of organic cations) type 2, OAT (carrier of organic anions) 1 and 3 types, MATEE (extrusion proteins of drugs and toxins) 1 or 2-K.When Ninlaro® is used, the development of drug interactions associated with vectors is not expected.

Oral contraceptives

With the simultaneous use of Ninlaro® with dexamethasone, which is a weak or moderate inducer CYP3A4, as well as other enzymes and carrier proteins, the risk of a decrease in the effectiveness of oral contraceptives should be considered. Women taking hormonal contraceptives should also use the barrier method of contraception.

Special instructions:

Thrombocytopenia

There are reports of thrombocytopenia with Ninlaro®, with the highest platelet count decrease observed between 14-21 days of each 28-day cycle, and recovering to baseline by the start of the next cycle of therapy. During treatment, 3% of patients in the Ninlaro® and 1% of patients in the placebo regimen had a platelet count of ≤ 10,000 / mm³. In less than 1% of patients, in the background of the use of both regimens, the number of platelets ≤ 5000 / mm³. The abolition of treatment due to thrombocytopenia occurred with similar frequency in both treatment regimens (<1% of patients with Ninlaro® and 2% of patients when using placebo abolished one or more of the three drugs used).The frequency of platelet transfusion was 6% for the Ninlaro® regimen and 5% for the placebo regimen.

The number of platelets is monitored at least monthly during treatment with Ninlaro®. It is recommended to consider more frequent control during the first three cycles of therapy. Thrombocytopenia is corrected by changes in the dose (see section "Method of administration and dose") and transfusion of platelet mass according to standard medical recommendations.

Gastrointestinal toxicity

Against the background of the use of Ninlaro®, diarrhea, constipation, nausea and vomiting, occasionally requiring the use of antidiarrheal, antiemetics and maintenance treatment, were noted. Diarrhea is described in 42% of patients in the Ninlaro® regimen and 36% of patients in the placebo regimen, constipation in 34% and 25% of patients, respectively, nausea in 26% and 21 % of patients, respectively, and vomiting in 22% and 11% of patients, respectively. Diarrhea led to the cancellation of one or more of the three medications used in 1% of patients with Ninlaro® and <1% of patients in placebo. For symptoms of grade 3 or 4, modify the dose (see p.See section "Dosing and Administration").

Peripheral Neuropathy

Most cases of adverse reactions in the form of peripheral neuropathy were grade 1 (18% for the Ninlaro® regimen and 14% for the placebo regimen) and grade 2 (8% for the Ninlaro® regimen and 5% for the placebo regimen) . Undesirable reactions in the form of peripheral neuropathy of grade 3 were observed in 2% of patients in both regimens; no undesired reactions of grade 4 or serious adverse reactions were noted.

The most frequently observed response was peripheral sensory neuropathy (19% and 14% with the Ninlaro® regimen and placebo, respectively). Peripheral motor neuropathy was observed in both regimens infrequently (<1%). Peripheral neuropathy led to the cancellation of one or more of the three drugs used in 1% of patients in both regimens. Patients should be monitored regularly for symptoms of neuropathy. Patients with newly diagnosed peripheral neuropathy or worsening of what is available may need a dose change (see "Dosage and Administration").

Peripheral edema

Peripheral edema was described in 25% and 18% of patients in the Ninlaro® and placebo regimen, respectively. Most cases of undesirable reactions in the form of peripheral edema were grade 1 (16% in the Ninlaro® regimen and 13% in the placebo regimen) and grade 2 (7% for the Ninlaro® regimen and 4% for the placebo regimen) .

Peripheral edema of grade 3 was observed in 2% and 1% of patients in the scheme with Ninlaro® and placebo, respectively. Peripheral edema of degree 4 was not observed. Cases of cancellation of treatment because of peripheral edema was not. The underlying cause should be evaluated and supportive treatment as necessary. For symptoms of grade 3 or 4, the dose of dexamethasone is adjusted according to the instructions for its medical use or the dose of Ninlaro® (see section "Method of administration and dose").

Skin Reactions

The rash is described in 19% of patients with the Ninlaro® regimen and 11% in the placebo regimen. Most cases of adverse reactions in the form of rashes were grade 1 (10% for the Ninlaro® regimen and 7% for the placebo regimen) or grade 2 (6% for the Ninlaro® 3% regimen with placebo).A grade 3 rash was noted in 3% of patients in the Ninlaro® regimen and 1% in the placebo regimen. Undesirable reactions in the form of a rash of grade 4 or serious adverse reactions in the form of a rash have not been noted. The most common type of rash in both regimens was a maculopapular and macular rash. The rash resulted in the cancellation of one or more of the three medications used in <1% of patients in both regimens. The rash is monitored by maintenance treatment or dose changes in the case of degree 2 or higher (see section "Method of administration and dose").

Hepatotoxicity

Medicinal liver damage, hepatocellular lesions, hepatic steatosis, cholestatic hepatitis and hepatotoxicity have been described in <1% of patients in each of the listed reactions that received Ninlaro®. There were violations of liver function (6% in the scheme of application with Ninlaro® and 5% of patients in the scheme of application with placebo).

The level of hepatic enzymes should be monitored regularly and the dose adjusted for symptoms of grade 3 or 4 (see "Dosage and Administration").

Embryophototoxicity

Based on knowledge of the mechanism of action and the results of animal studies, Ninlaro® can have a harmful effect on the fetus when used in pregnant women.Adequate and strictly controlled studies of the use of Ninlaro® in pregnant women are not available. Ixazomib caused embryophototoxicity in pregnant rats and rabbits in doses that lead to an effect slightly higher than that observed in patients receiving the recommended doses.

Women who are fertile should be advised to avoid pregnancy during the period of Ninlaro®. If Ninlaro® is used during pregnancy or if a woman becomes pregnant while Ninlaro® is being used, she should be informed of the potential hazard to the fetus. The use of reliable contraception during the period of Ninlaro® application and within 90 days after the last dose should be recommended for fertile women. Women using hormonal contraceptives should also additionally use the barrier method of contraception (see the section on "Application during pregnancy and during breastfeeding").

Ninlaro® is a cytotoxic drug. The rules for handling and disposal of cytotoxic drugs should be observed. Do not open or destroy capsules.Avoid direct contact with the contents of the capsule. In case of capsule failure, avoid direct contact of the contents of the capsule with the skin or eyes. If skin contact occurs, rinse thoroughly with soap and water. If contact occurs, rinse thoroughly with water.

Any unused amount of medicine or waste should be disposed of in accordance with local requirements.

Effect on the ability to drive transp. cf. and fur:

The drug Ninlaro® has little effect on the ability to drive vehicles and mechanisms. In clinical studies, fatigue and dizziness were observed. Patients should be advised to refrain from driving the car and managing the mechanisms when these symptoms are present.

Form release / dosage:

Capsules 2.3 mg, 3 mg and 4 mg.

Packaging:

1 capsule in a PVC Aluminum / Aluminum blister pasted into a folding cardboard cover. On 1 cardboard cover, together with the instruction, but the application is placed in a pack of cardboard (intermediate packaging). 3 cardboard packs (intermediate packages) are placed in a common cardboard box.On the protective sticker a holographic way is indicated by a logo "Takeda". and/Will

1 capsule in a PVC Aluminum / Aluminum blister pasted into a folding cardboard cover. On 1 cardboard cover, along with instructions for use, put in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C. Do not freeze. Store in the original package immediately before each capsule. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004500

Date of registration:19.10.2017

Expiration Date:19.10.2022

The owner of the registration certificate:Millennium Pharmaceuticals IncorporatedMillennium Pharmaceuticals Incorporated USA

Manufacturer: & nbsp

HAUPT PHARMA AMAREG, GmbH Germany

Representation: & nbspTakeda Pharmaceuticals Ltd.Takeda Pharmaceuticals Ltd.

Information update date: & nbsp26.10.2017

Illustrated instructions

Instructions

Ninlaro® (Ninlaro®)