Universal reference book for medicines
Product name: ABRAXANE ®

Active substance: human albumin, paclitaxel

Type: Antitumor preparation

Manufacturer: CELGENE INTERNATIONAL (Switzerland) manufactured by FRESENIUS KABI USA (USA), which issues quality control ABRAXIS BIOSCIENCE (USA)
Composition, form of production and packaging
Lyophilizate for the preparation of a suspension for infusions
in the form of a lyophilized powder or a porous mass of white or white with a yellowish hue;
after dissolving: a translucent homogeneous suspension of white or white with a yellowish tinge.
1 f.

paclitaxel 100 mg

human albumin 900 mg

100 mg - bottles (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Antitumor drug.
The mechanism of action of paclitaxel is based on its ability to stimulate the assembly of microtubules of the mitotic spindle from dimer molecules of tubulin and to stabilize the microtubules, suppressing their depolymerization. This leads to the suppression of the normal dynamic reorganization of the microtubular network in the interphase of mitosis, and also causes the formation of abnormal microtubule congestions throughout the entire cell cycle and the appearance of multiple star-shaped clusters (asters) in the mitosis phase.
Abraxan contains nanodispersed paclitaxel stabilized with albumin, with a nanoparticle size of approximately 130 nm, in which paclitaxel is in a non-crystalline (amorphous) state.
After iv administration, the nanoparticles dissociate rapidly to form soluble complexes of paclitaxel bound to albumin, the approximate size of which is 10 nm. It is known that albumin regulates the processes of transendothelial transport of plasma components, and in vitro studies it was demonstrated that the presence of albumin in the preparation of Abraxan stimulates the transport of paclitaxel through the endothelial cell layer. It has been hypothesized that transendothelial transport is mediated by the gp-60 albumin transporter, and an increase in paclitaxel accumulation in the tumor is noted due to the presence of an albumin-binding protein, an acid secreted protein rich in cysteine ​​(SPARC).
PHARMACOKINETICS

The pharmacokinetics (PK) of paclitaxel has been studied in clinical studies with 30-minute and 180-minute infusions of the drug Abraxan in doses ranging from 80 to 375 mg / m 2 .
The AUC values ​​for paclitaxel increased linearly, from 2653 ng h / ml to 16736 ng h / ml, in the dose range of 80 to 300 mg / m 2 .
In a study involving patients with advanced solid tumors, the parameters of paclitaxel FC after iv administration of the 260 mg / m 2 drug Abraxan were compared for 30 min to the PK parameters after administration of paclitaxel based on a 175 mg / 3 hours.
Based on the results of the analysis without taking into account the compartments, clearance of paclitaxel (43%) and its V d (53%) was higher with the administration of the drug Abraxan than with paclitaxel based on the solvent. There was no difference in the terminal T 1/2 .
In a study of repeated intravenous administration of the drug Abraxan in a dose of 260 mg / m 2 to 12 patients, the intra-individual variability of systemic exposure to paclitaxel (AUC) was 19% (range = 3.21% -27.70%).
Signs of cumulation of paclitaxel during several courses of therapy were not recorded.
Distribution

After the administration of the drug Abraksan to patients with solid tumors, paclitaxel was evenly distributed in blood cells and plasma.
Binding to plasma proteins - 94%.
The binding of paclitaxel to proteins was assessed by ultrafiltration as part of a comparison study for the same patient.
The proportion of free paclitaxel was significantly higher with Abraxan (6.2%) than with solvent-based paclitaxel (2.3%). This provided significantly higher exposure values ​​for the unbound fraction of paclitaxel when the drug Abraxan was administered than for solvent-based paclitaxel, even at comparable total exposure values. This phenomenon is probably due to the lack of binding of paclitaxel to Cremophor EL micelles, which is observed with the use of solvent-based paclitaxel. According to published studies in which in vitro The association of paclitaxel (in concentrations from 0.1 to 50 μg / ml) with human plasma proteins was assessed, the presence of cimetidine, ranitidine, dexamethasone or diphenhydramine had no effect on the association of paclitaxel with plasma proteins.
Taking into account the results of the population analysis of PK data, the total volume of distribution is approximately 1741 l;
a large V d indicates an intensive extravascular distribution and / or binding of paclitaxel to tissue proteins.
Metabolism and excretion

In vitro studies using liver microsomes and sections of human tissues, it has been shown that paclitaxel is metabolized predominantly to the formation of 6? -hydroxy paclitaxel, as well as two additional metabolites present in smaller amounts (3'-p-hydroxypaclitaxel and 6? -3'- n-dihydroxy paclitaxel).
The formation of these hydroxylated metabolites is catalyzed by isoenzymes of the cytochrome CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4, respectively.
In patients with metastatic breast cancer after intravenous drip of the drug Abraxan for 30 minutes at a dose of 260 mg / m 2, the average cumulative excretion in the urine of the unchanged active substance corresponded to 4% of the total administered dose of the drug;
less than 1% of the administered dose accounted for the excreted with urine metabolites 6? -hydroxypaclitaxel and 3? -n-hydroxypaklitaxel, indicating a significant extrarenal clearance of the drug. Paclitaxel is predominantly eliminated by hepatic metabolism and excretion with bile.
When the drug is administered at a therapeutic dose of 80 to 300 mg / m 2 , the average plasma clearance of paclitaxel varies from 13 to 30 L / h / m 2 , and the mean terminal T 1/2 varies from 13 to 27 h.

Pharmacokinetics in special clinical cases

Violation of the function of the liver.
The results of clinical trials demonstrated that mild liver failure (total bilirubin> 1 to? 1.5? VGN) had no clinically significant effect on paclitaxel FC parameters. In patients with moderate hepatic impairment (total bilirubin> 1.5 to? 3? VGN) and severe severity (total bilirubin> 3 to? 5? VGN), a decrease in the maximum elimination rate of paclitaxel by 22-26% and an increase in the mean AUC of paclitaxel about 20%. Hepatic insufficiency did not affect the average value of C max of paclitaxel. In addition, the elimination of paclitaxel was inversely correlated with the indices of total bilirubin, and directly proportional to the albumin concentration in the blood plasma.
Pharmacokinetic / pharmacodynamic modeling showed no correlation between liver function (baseline albumin or total bilirubin) and neutropenia, taking into account the exposure of the drug Abraxan.

FK analysis was not performed in patients with common bilirubin> 5? VNG or patients with metastatic pancreatic adenocarcinoma.

Impaired renal function.
Renal failure of mild or moderate degree (QC from? 30 to <90 ml / min) had no clinically significant effect on the maximum elimination rate and systemic exposure (AUC and C max ) of paclitaxel. There is insufficient pharmacokinetic data for patients with severe renal insufficiency, and data are not available for patients with terminal renal failure.
Elderly patients.
The population analysis of the FC Abraxan included data from patients aged 24 to 85 years. His results showed that age does not significantly affect the maximum elimination rate and systemic exposure (AUC and C max ) of paclitaxel.
Pharmacokinetic / pharmacodynamic modeling using data from 125 patients with advanced solid tumors showed that patients aged ≥65 years may be more prone to developing neutropenia during the first cycle of therapy, although age did not affect the exposure of paclitaxel in plasma.

Other internal factors.
Population analysis of the FC of the drug Abraksan demonstrated that sex, race (Mongoloid versus europoid) and type of solid tumors do not have a clinically significant effect on systemic exposure (AUC and C max ) of paclitaxel. AUC paclitaxel in patients with a body weight of 50 kg is approximately 25% lower than in patients with a body weight of 75 kg. The clinical significance of this data is unknown.
INDICATIONS

- Therapy of the second and subsequent lines in patients with metastatic breast cancer refractory to standard anthracycline-containing combination chemotherapy (or in the presence of contraindications), as well as relapse of the disease within 6 months after completion of adjuvant chemotherapy;

- in combination with gemcitabine - as first-line therapy in adult patients with metastatic pancreatic adenocarcinoma.

DOSING MODE

Abraxan should be administered only under the supervision of a qualified oncologist in units intended for the treatment of cytotoxic drugs.
The drug should not be replaced or used together with other dosage forms of paclitaxel.
Mammary cancer

Abraxane is injected intravenously into the drip for 30 minutes at a dose of 260 mg / m 2 once every 3 weeks.

Change in the dose of the drug in the treatment of breast cancer

With the development of severe neutropenia (the number of neutrophils less than 500 / μl for 1 week or more) or severe sensory neuropathy, it is necessary to reduce the dose of Abraxane to 220 mg / m 2 in all subsequent courses of therapy.

With the repeated development of severe neutropenia or severe sensory neuropathy, it is necessary to reduce the dose to 180 mg / m 2 .

Abraxane should not be used until the amount of neutrophils is restored to a level above 1500 / μL, and the number of platelets to a level above 100,000 / mm 3 .
In patients with sensory neuropathy of grade 3, treatment should be suspended until the neuropathy is reduced to grade 1 or grade 2, followed by a reduction in the dose of the drug Abraxan for all subsequent courses of therapy.
Adenocarcinoma of the pancreas

Abraxane in combination with gemcitabine is administered iv.
Abraxane in a dose of 125 mg / m 2 is administered for 30 minutes on days 1, 8 and 15 of each 28-day cycle. Gemcitabine at the recommended dose of 1000 mg / m 2 is administered within 30 minutes immediately after the completion of the administration of the drug Abraxan, on days 1, 8 and 15 of each 28-day cycle.
Dose change in the treatment of pancreatic adenocarcinoma

Table 1. Decrease in the dose of drugs in patients with pancreatic adenocarcinoma

Dose Dose of the drug Abraxane (mg / m 2 ) Gemcitabine dose (mg / m 2 )

Total dose 125 1000

First dose reduction 100 800

Second dose reduction 75 600

If additional dose reduction is required Discontinue treatment Discontinue treatment

Table 2. Changes in dose for neutropenia and / or thrombocytopenia at the beginning or in the middle of the cycle in patients with pancreatic adenocarcinoma

Day of cycle Absolute number of neutrophils (cells / mm 3 ) Number of platelets (cells / mm 3 ) Dose of drug Abraxan Dose of gemcitabine

Day 1 <1500 OR <100 000 Suspend therapy before recovery

Day 8-500, but <1000 OR ? 50 000, but <75 000 Lower doses per level

<500 OR <50 000 Suspend therapy

Day 15: IF doses of drugs intended for use on Day 8 have not been changed:

Day 15 ? 500, but <1000 OR ?
50 000, but <75 000 Enter the drugs at a dose intended for Day 8, then introduce a colony-stimulating factor OR Lower the dose of drugs one level from the dose of Day 8
<500 OR <50 000 Suspend therapy

Day 15: IF doses of drugs intended for use on Day 8 have been lowered:

Day 15 ? 1000 And ? 75 000 Reuse the drugs in doses of Day 1, then introduce a colony-stimulating factor OR Enter the drugs in doses, as on Day 8

? 500, but <1000 OR ? 50 000, but <75 000 Enter the drugs at a dose intended for Day 8, then introduce a colony-stimulating factor OR Lower the dose of drugs one level from the dose of Day 8

<500 OR <50 000 Suspend therapy

Day 15: IF the Day 8 therapy was suspended:

Day 15 ? 1000 And ?
75 000 Reuse drugs at Day 1 doses, then introduce a colony-stimulating factor OR Decrease doses of drugs one level from the doses of Day 1
? 500 but <1000 OR ?
50 000, but <75 000 Decrease doses of drugs at one level, then introduce a colony-stimulating factor OR Decrease doses of drugs at two levels from the doses of Day 1
<500 OR <50 000 Suspend therapy

Table 3. Change in the dose of drugs with the development of other unwanted drug reactions (NLR) in patients with pancreatic adenocarcinoma

NLR Dose of the drug Abraxan Dose of gemcitabine

Febrile neutropenia: 3 or 4 degrees Suspend the administration of the drugs until the fever disappears and the number of neutrophils reaches? 1500;
resume therapy with the next lower dose level a
Peripheral neuropathy: 3 or 4 degrees Suspend the introduction of the drug to reduce the severity of neuropathy to? 1 degree;
resume therapy with the next lower dose level a. Administer the drug at the same dose.
Toxicity from the skin and subcutaneous tissues: 2 or 3 degrees Lower the dose of drugs to the next lower dose level a ;
discontinue therapy if NLR persists.
Toxicity from the digestive tract: mucositis or type 3 diarrhea Suspend the administration of the drugs until the condition improves to?
1 degree; resume therapy with the next lower dose level a
a - see table 1 for dose reduction

Special patient groups

Patients with hepatic insufficiency of mild severity (total bilirubin> 1 to? 1.5? VGN and AST? 10? VGN) do not need a dose change, regardless of the indication.
Use the same doses of the drug as in patients with normal liver function.
In patients with metastatic breast cancer with hepatic insufficiency of moderate and severe severity (total bilirubin> 1.5 to? 5? VGN and AST? 10? VGN) it is recommended to lower the dose by 20%.
This reduced dose can be increased to a normal therapeutic dose (as in patients with normal liver function) if the patient has had a good first two cycles of therapy.
For patients with pancreatic metastatic pancreatic adenocarcinoma and impaired liver function of moderate or severe severity, there is insufficient data, which does not allow us to develop recommendations for changing the dose of the drug Abraxan.

For patients with a concentration of total bilirubin> 5? VGN and ACT activity> 10? VGN , regardless of the indications, data for developing recommendations on the dosage regimen is not enough.

For patients with mild or moderate renal insufficiency (QA from? 30 to <90 ml / min), a change in the starting dose of Abraxan is not required.
There is insufficient data to develop recommendations for dosing regimens for patients with severe and terminal (QC <30 mL / min) stages of renal failure .
The safety and efficacy of the drug Abraxan in children and adolescents under the age of 18 years have not been studied.
Data on the use of the drug
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