Pleriksafor - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Other immunomodulators

Included in the formulation

Mozobail

solution PC

Genzyme Europe BV Netherlands

АТХ:

L.03.A.X.16 Pericrixfor

Pharmacodynamics:

Periciksafor is a biclamide derivative and is a selective reversible CXCR4 antagonist of the chemokine receptor, blocking it by binding to the cognate ligand, the stromal cell factor-lα (SDF-lα), also known as CXCL12. Plerixaphor-induced leukocytosis and an increase in circulating hematopoietic progenitor cells are thought to result from a disruption of the bond between CXCR4 and its cognate ligand, which results in the emergence of mature and pluripotent cells in the systemic circulation. CD34 + cells mobilized with plirixafor are functional and capable of engraftment, with a long-term potential for population recovery.

Pharmacokinetics:

Absorption

Periciksafor is rapidly absorbed after subcutaneous administration, the maximum concentrationis reached in about 30-60 minutes. After subcutaneous administration of preexaphora at a dose of 0.24 mg / kg, which was preceded by a preliminary treatment with granulocyte colony stimulating factor for 4 consecutive days, the maximum plasma pliencaphor concentration and mean system exposure were (887 ± 217) ng / ml and (4337 ± 922) ng · h / ml, respectively.

Distribution

Pleriksafor moderately binds to human plasma proteins (up to 58%). Apparent volume of distributionpleriksafora in people is 0.3 l / kg, this indicates that the drug is prone to distribution in the extravascular space, but not limited to them.

Metabolism

In experiments in vitro pleriksafor was not metabolized by human hepatic microsomes and human embryonic hepatocytes. Also in vitro it was shown that the preparation does not inhibit the main metabolizing isoenzymes of cytochrome P450 (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 / 5). In experiments in vitro with human hepatocytes pleriksafor did not induce isoenzymes CYP1A2, CYP2B6 and CYP3A4.

Elimination

The main way of eliminating pleriksafora is excretion through the kidneys. After the administration of preexaphor in a dose of 0.24 mg / kg to healthy volunteers with normal renal function, approximately 70% of the drug was excreted unchanged in the urine within the first 24 hours after administration. Half-lifefrom the plasma is 3-5 h.

Special patient groups

Patients with impaired renal function. In individuals with varying degrees of renal insufficiency pleriksafora clearance after a single dose (0.24 mg / kg) decreased; there was a positive correlation with creatinine clearance.The average indices of systemic exposure of plexixaphor in patients with mild (creatinine clearance 51-80 ml / min), moderate (creatinine clearance 31-50 ml / min) and severe (creatinine clearance ≤ 30 ml / min) were 5410, 6780 and 6990 ng · h / ml, respectively, which exceeds the exposure values observed with normal kidney function (5070 ng · h / ml). Renal failure did not affect the maximum concentration.

Indications:

To enhance the mobilization of hematopoietic stem cells in the peripheral bloodstream for the purpose of their collection and subsequent autotransplantation to patients with lymphoma and multiple myeloma combined with granulocyte colony-stimulating factor.

ICD-10

II.C81-C96.C85 Other and unspecified types of non-Hodgkin's lymphoma

II.C81-C96.C90.0 Multiple myeloma

Contraindications:

Hypersensitivity to plerixafor or any excipients of the drug; pregnancy and lactation; children and adolescents under the age of 18 (due to lack of experience).

Carefully:

In case of creatinine clearance ≤ 50 ml / min, the dose of plerixafor should be reduced by one third, to 0.16 mg / kg per day. Clinical data on the use of the adjusted dose of the drug are limited.The existing experience of clinical use of plerixafora does not allow giving recommendations on dosing of the drug with creatinine clearance <20 ml / min, as well as in patients on hemodialysis.

Given that the effect of the drug increases with increasing body weight, the dose of plriixafor should not exceed 27 mg per day if creatinine clearance is ≤ 50 ml / min.

In elderly patients with normal renal function, dose adjustment is not required. When creatinine clearance is ≤ 50 ml / min, it is recommended to change the dose of the drug. It should be remembered that with age, the likelihood of reducing renal function increases, so in elderly patients the dose of the drug should be selected with caution.

Pregnancy and lactation:

Data on the use of plerixafora in pregnant women is not enough. Studies in animals showed the presence of a teratogenic effect of the drug. The patient should be informed that the use of plerixafor during pregnancy can lead to congenital malformations. Use during pregnancy is only possible when the benefits of the application exceed the potential risk to the fetus.

Women of childbearing age need to use effective contraception during treatment.

Data on the possible penetration of plriixafor into breast milk are not available, so the risk for an infant can not be ruled out. During therapy, breastfeeding should be discontinued.

Dosing and Administration:

Subcutaneously.

Doses. The recommended dose of plerixafor is 0.24 mg / kg per day. The drug is administered subcutaneously 6 to 11 hours before the onset of apheresis. Before this, it is necessary to perform a preliminary treatment with a granulocyte colony-stimulating factor for 4 days.

To calculate the dose of plerixaphor, the mean body weight, measured within 1 week prior to the administration of the first dose of the drug, is used. The dose of the drug (in ml) is calculated by the formula: 0.012 × body weight (kg). Given that the effect of the drug with increasing body weight increases, the dose of plerixafor should not exceed 40 mg per day.

Recommended concomitant medications

In the baseline clinical trials supporting drug treatment, all patients received a granulocyte colony-stimulating factor at a dose of 10 μg / kg in the morning for 4 consecutive days prior to the first administration of plirixafor, and then every morning before the apheresis.

Use of the drug in specific patient groups

Impaired renal function. When the creatinine clearance is <50 ml / min, the dose of plercixafor should be reduced by one third, to 0.16 mg / kg per day. Clinical data on the use of the adjusted dose of the drug are limited. The experience of clinical use of plerixafor does not allow us to give recommendations on the dosage of the drug with creatinine clearance <20 ml / min, as well as in patients on hemodialysis. Given that the effect of the drug with increasing body weight increases, the dose of plriixafor should not exceed 27 mg per day if creatinine clearance <50 ml / min.

The creatinine clearance (in ml / min) for men is calculated by the formula: ((body weight, kg) x (140 - age, years)) / (72 x serum creatinine mg / dL).

Women: 0.85 × value, calculated by the formula for men.

Children. The experience of using the drug in children is limited. The safety and efficacy of the drug for treating children have not been evaluated in controlled clinical trials.

Patients of advanced age (more than 65 years). In elderly patients with normal renal function, dose adjustment is not required. When creatinine clearance <50 ml / min is recommended to change the dose of the drug.It should be remembered that with age, the likelihood of reducing renal function increases, so elderly patients dose of the drug should be selected with caution.

Side effects:

From the side immune system: infrequently - allergic reactions, hives, periorbital edema, dyspnea or hypoxia, anaphylactic reactions, including anaphylactic shock.

From the side mentality: often - insomnia.

From the side nervous system: often - headache, dizziness.

From the side GIT: very often - diarrhea, nausea; often - flatulence, abdominal pain, vomiting, bloating, dry mouth, discomfort in the epigastric region, constipation, dyspeptic phenomena, hypoesthesia of the oral mucosa.

From the side skin and subcutaneous tissues: often - hyperhidrosis, erythema.

From the side musculoskeletal and connective tissue: often - arthralgia, musculoskeletal pain.

General disorders and disorders in place of administration: very often - reactions at injection sites; often - fatigue, malaise.

In patients with cancer, the frequency of adverse reactions did not differ depending on the disease, age or sex.

Paresthesia: often observed in cancer patients after autotransplantation due to numerous medical procedures.

Overdose:

There were no cases of overdose. Given the limited data on the use of the drug at a dose exceeding the recommended dose to 0.48 mg / kg / day, it can be assumed that the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension and / or syncope may increase.

Interaction:

Studies to study the interactions of this drug have not been conducted. Tests performed in vitro showed that pleriksafor It is not metabolized by cytochrome P450 isoenzymes, nor does it inhibit or enhance their activity. According to research in vitro, pleriksafor is not a substrate or an inhibitor of P-glycoprotein.

The addition of rituximab to the mobilization regime (pleriksafor and granulocyte colony-stimulating factor) in clinical trials involving patients with non-Hodgkin's lymphoma did not affect the safety of the patient or the concentration of CD34 + cells.

Special instructions:

The drug should be prescribed and administered by a qualified oncologist and / or hematologist.Mobilization and apheresis of cells should be carried out in cooperation with an oncohematological center, which has sufficient experience in this field, where it is possible to properly control the level of hematopoietic progenitor cells.

Before administration, the bottle should be inspected. If the product contains mechanical inclusions or there are discolourings of the solution, it can not be introduced. The preparation containing pleriksafor, is a sterile drug that does not contain preservatives, therefore, in the process of recruitment of the contents of the vial into the syringe for hypodermic injections, it is necessary to observe aseptic rules.

Studies on the compatibility of the drug with other drugs have not been conducted, so do not mix it with other drugs in one syringe.

The drug remaining after the administration of the required dose should be destroyed.

Mobilization of tumor cells in patients with leukemia. Pericrixfor and granulocyte colony stimulating factor was prescribed for acute myeloid and plasmacytic leukemia as part of a program for the use of the study drug individually.In some cases, there was an increase in the number of circulating leukemia cells. Pericrixfor, designated for the mobilization of hematopoietic stem cells, can cause the mobilization of tumor cells and their subsequent entry into the apheresis product. therefore pleriksafor It is not recommended to be used in leukemia for the mobilization of hematopoietic stem cells and their subsequent collection.

Hematologic effects.

· Hyperleukocytosis. Pericrixfor, administered in combination with a granulocyte colony-stimulating factor, increases not only the population of hematopoietic stem cells, but also the number of circulating leukocytes. During the use of the drug should monitor the number of leukocytes. Each case of prescribing should be carefully evaluated for patients in whom the number of neutrophils in the peripheral blood exceeds 50,000 cells / μl.

· Thrombocytopenia. Thrombocytopenia is a known complication of apheresis and is observed in patients receiving the drug. The number of platelets must be monitored in all patients who receive pleriksafor and which is planned to conduct apheresis.

The possibility of mobilizing tumor cells in patients with lymphoma and multiple myeloma. The consequences of potential reinfusion of tumor cells have not been properly studied. When the drug is used in combination with granulocyte colony-stimulating factor (for mobilization of hematopoietic stem cells in lymphoma or multiple myeloma), tumor cells can be released from the bone marrow and subsequently picked up in leukophoresis.

The clinical significance of the possible risk of mobilizing tumor cells has not been fully determined. In clinical studies involving patients with non-Hodgkin's lymphoma and multiple myeloma, there was no mobilization of tumor cells with the use of plerixafor.

Allergic reactions. Mild and moderate allergic reactions were resolved spontaneously or supervised by appropriate therapy (eg, antihistamines, glucocorticosteroids, hydration, oxygen therapy). Serious hypersensitivity reactions, including anaphylactic reactions, some of which were life-threatening with clinically significant lowering of blood pressure and shock, were reported in patients receiving pleriksafor. It is recommended that patients be observed during and after administration of the drug for at least 30 minutes after each use of the drug. The potential risk of allergic reactions requires appropriate precautions.

Vazovagalnye reaction. After subcutaneous injections of the drug, vasovagal reactions, orthostatic hypotension and / or syncope can be noted. In connection with the possibility of developing such reactions, appropriate precautions must be observed. In general, these reactions developed within 1 h after application of the drug.

Splenomegaly. In pre-clinical studies, an increase in the absolute and relative mass of the spleen was associated with extramedullary hematopoiesis, with prolonged (2-4 weeks) daily administration of plerixaphor to rats (subcutaneous injections, the dose of the drug exceeded the dose recommended for humans 4 times).

In clinical studies, the effect of pleriksafore on the size of the spleen was not specifically evaluated. Thus, it is impossible to completely exclude the possibility of enlarging the spleen on the background of taking plriixafor and the granulocyte colony-stimulating factor.In very rare cases, the appointment of a granulocyte colony-stimulating factor leads to rupture of the spleen. This should be remembered when patients receiving the drug in combination with a granulocyte colony-stimulating factor complain of pain in the left hypochondrium and / or in the shoulder or shoulder area.

Control of laboratory indicators. In patients receiving the drug and passing apheresis, it is necessary to control the number of leukocytes and blood platelets.

Since some patients have dizziness, fatigue, or vasovagal reactions, care must be taken when driving vehicles and engaging in other potentially hazardous activities. When these undesirable phenomena appear, one should refrain from performing these activities.

Instructions

Pericrixfor (Plerixaforum)