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

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 intravenous administration, the nanoparticles rapidly dissociate to form soluble complexes of paclitaxel bound to albumin, the approximate size of which is 10 nm.

It is known that albumen regulates the process of transendothelial transfer of plasma components, and in studies in vitro it was demonstrated that the presence of albumin in the preparation of Abraxan stimulates the transport of paclitacosel through the endothelial cell layer. It has been hypothesized that transendogelial transport is mediated by the gp-60 albumin transporter, and there is an increase in cumulation of paclitaxel in the tumor 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 a 30-minute and 180-minute infusion of the drug Abraxan in doses from 80 to 375 mg / m². The area under the concentration-time curve (AUC) for paclitaxel increased linearly, from 2653 ng / h / ml to 16736 ng / h / ml, in the dose range of 80 to 300 mg / m².

In a study involving patients with advanced solid tumors, the parameters of paclitaxel FC after intravenous administration of the drug Abraxan at a dose of 260 mg / m² for 30 minutes was compared with the parameters of PK after administration of paclitaxel on a solvent basis at a dose of 175 mg / m²for 3 hours. Based on the results of the analysis excluding compartments, the clearance of paclitaxel (43%) and the volume of its distribution (53%) was higher with the administration of the drug Abraxan than with paclitaxel on a solvent basis. There were no differences in the terminal half-life period.

During the study of multiple intravenous administration of the drug Abraxan in a dose of 260 mg / m² 12 patients with intra-individual variability of systemic exposures of paclitaxel (AUC) was 19% (range of values = 3.21% -27.70%). Symptoms of cumulating paclitaxel in several courses of therapy are not registered.

Distribution

After the administration of the drug Abraksan to patients with solid tumors paclitaxel was evenly distributed in blood and plasma cells and was 94% bound to plasma proteins.

The binding of paclitaxel to proteins was assessed by ultrafiltration as part of a comparison study in one total patient. The proportion of free paclitaxel was significantly higher with Abraxane (6.2%) than with paclitaxel based on a solvent (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 micelles Cremophor EL, which is observed with the use of solvent-based paclitaxel. According to published studies, in which in vitro The association of paclitaxel (at concentrations of 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 the PC data,the total volume of distribution is approximately 1,741 liters; a large volume of distribution indicates an intensive extravascular distribution and / or binding of paclitaxel to tissue proteins.

Metabolism and excretion

In studies in vitro using liver microsomes and sections of human tissues, it was shown that paclitaxel is metabolized predominantly with the formation of 6α-hydroxypaclitaxel, as well as two additional metabolites present in smaller k(3'-n-hydroxypaclitaxel and 6α-3'-n-dihydroxy paclitaxel). The formation of these hydroxylated metabolites is catalyzed by cytochrome P450 isoenzymes 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 / m² the average cumulative urinary excretion of unchanged active substance was 4% of the total administered dose of the drug; Metabolites 6α-hydroxypaclitaxel and 3'-n-hydroxyacylnaxel were excreted less than 1% of the administered dose, which indicates a significant extrarenal clearance of the drug. Paclitaxel predominantly eliminated by hepatic metabolism and excretion with bile.

When the drug is administered at a therapeutic dose of 80 to 300 mg / m², the average plasma clearance of paclitaxel varies from 13 to 30 l / h / m², and the average terminal half-life varies from 13 to 27 hours.

Impaired liver function

Results of clinical trials demonstrated, that hepatic insufficiency of mild degree (total bilirubin> 1 to ≤1.5 x upper limit of norm, VGN) had no clinically significant effect on the parameters of paclitaxel FC.

In patients with moderate hepatic insufficiency (total bilirubin> 1.5 to ≤3 x VGN) and severe severity (total bilirubin> 3 to ≤5 x HNG), the maximum elimination rate of paclitaxel was reduced by 22% -26% and the mean meanings AUC paclitaxel by about 20%.

Hepatic failure did not affect the average value of C_max 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 general bilirubin> 5 x VGN or patients with metastatic pancreatic adenocarcinoma (see section "Method of administration and dose").

Impaired renal function

Renal failure of mild or moderate degree (creatinine clearance from ≥30 to <90 ml / min) had no clinically significant effect on the maximum elimination rate and systemic exposure (AUC and C_m_Oh) 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 the age of ns had a significant effect on the maximum elimination rate and systemic exposure (AUC and C_m_Oh) paclitaxel.

Pharmacokinetic / pharmacodynamic modeling using data from 125 patients with advanced solid tumors showed that patients ≥65 years of age 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_m_Oh) 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 a combination chemotherapy (or in the presence of contraindications), as well as a relapse of the disease within 6 months after the completion of adjuvant chemotherapy.

The drug Abraksan in combination with gemcitabine is indicated as first-line therapy in adult patients with metastatic pancreatic adenocarcinoma.

Contraindications:

Hypersensitivity (to paclitaxel and human albumin), neutropenia (less than 500 / μL), severe liver dysfunction, pregnancy, lactation period, children under 18 years of age (lack of sufficient safety and efficacy data).

Carefully:

With oppression of bone marrow hematopoiesis (including after chemotherapy or radiation therapy), mild and moderate severity of liver function disorders, heart and lung diseases, previous therapy with anthracyclines, neuropathy, acute infectious diseases.

Pregnancy and lactation:

Pregnancy

There are only limited data on the use of paclitaxel in pregnant women. It is assumed that when administered during pregnancy paclitaxel causes severe birth defects. In animal studies, the reproductive toxicity of the drug is indicated. The use of the drug Abraxan during pregnancy is contraindicated. Women of childbearing age should use reliable methods of contraception.

Breastfeeding period

It is not known whether the paclitaxel in breast milk. Given the potential serious adverse reactions in children are breastfed, Abraxane is contraindicated in lactating women.Women who are treated with Abraxan should stop breastfeeding.

Fertility

In studies in vivo determined that paclitaxel has genotoxic, teratogenic, embryo and fetotoxic effects, and also reduces reproductive function in both males (atrophy / degeneration of the testes) and in females (decrease in the number of cases pregnancy and an increase in the number of deaths of embryos).

Dosing and Administration:

The drug Abraxan should be administered only under the supervision of a qualified oncologist in units designed to treat cytotoxic drugs. It should not be replaced or used together with other dosage forms of paclitaxel.

Mammary cancer

The drug Abraksan is administered intravenously drip for 30 minutes at a dose of 260 mg / m² 1 time in 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 the drug Abraxan to 220 mg / m² 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 / m². The drug Abraxan should not be used until the amount of neutrophils is restored to a level above 1500 / μL, and the amount of platelets to a level above 100,000 / μL. In patients with sensory neuropathy of grade 3, treatment should be suspended until the severity of neuropathy is reduced to grade 1 or 2, followed by a decrease in the dose of Abraxan for all subsequent courses of therapy.

Adenocarcinoma of the pancreas

The drug Abraksan in combination with gemcitabine is administered intravenously. The drug Abraksan in a dose of 125 mg / m² administered for 30 minutes at 1.8 and 15 days of each 28-day cycle. Gemcitabine in the recommended dose of 1,000 mg / m² injected within 30 minutes immediately after the completion of the administration of the drug Abraxan, on the 1.8 and 15 days 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 Abraxan (mg / m²)	The dose of gemcitabine (mg / m²)
The total dose	125	1000
First dose reduction	100	800
Second dose reduction	75	600
If an additional dose reduction is required	Stop treatment	Stop treatment

Table 2: Dose change for neutropenia and / or thrombocytopenia at the beginning or middle of the cycle in patients with pancreatic adenocarcinoma

Day cycle	Absolute number of neutrophils (cells / mm)³)		Number of platelets (cells / mm)³)	Dose of the drug Abraxan	The dose of gemcitabine
Day 1	< 1500	or	< 100,000	Suspend therapy before recovery
Day 8	≥ 500, but <1000	or	≥ 50,000, but <75,000	Reduce doses by one 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 in a dose intended for Day 8, then introduce a colony-stimulating factor or Lower the dose of drugs at 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	Re-use 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	Introduce the drugs in a dose intended for Day 8. Then introduce a colony-stimulating factor or Lower the dose of drugs at 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	Re-use the drugs in doses of Day 1, then introduce a colony-stimulating factor or Lower doses of drugs at one level from the doses of Day 1
	≥ 500, but <1000	or	≥ 50,000, but <75,000	Lower doses of drugs at one level, then introduce a colony-stimulating factor or Lower 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	The 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	Enter the drug in 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 gastrointestinal tract: mucositis or grade 3 diarrhea	Suspend the administration of drugs until the condition improves to ≤ 1 degree; resume therapy with the next lower dose level^a

^aSee Table 1 for dose reduction

Special patient groups

Patients with hepatic impairment

Patients with mild hepatic insufficiency (total bilirubin> 1 to ≤1.5 x VGN and aspartate aminotransferase (ACT) ≤ 10 x VLN) 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 x VGN and ACT <10 x VLN), 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 suffered the first two cycles of therapy (see "Special instructions" and "Pharmacokinetics").

For patients with metastatic pancreatic adenocarcinoma and impaired liver function of moderate or severe severity, there is insufficient data, which does not allow the development of recommendations for changing the dose of the drug Abraxan (see "Special instructions" and "Pharmacokinetics").

For patients with common bilirubin> 5 x VGN and ACT> 10 x VGN. irrespective of the indications given for the development of recommendations on the dosage regimen is not enough (see "Special instructions" and "Pharmacokinetics").

Patients with impaired renal function

For patients with mild or moderate renal insufficiency (creatinine clearance 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 (creatinine clearance <30 mL / min) stages of renal failure (see section "Pharmacokinetics").

Children and teens

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 Abraksan in patients of childhood in breast cancer or pancreatic adenocarcinoma are absent.

Elderly patients (over 65 years of age)

For patients aged 65 years and over, an additional dose reduction in addition to that recommended for all patients is not provided.

It is necessary to carefully assess the condition of the patient with pancreatic adenocarcinoma aged 75 years and older before prescribing therapy (see section "Special instructions").

The analysis of armakokinetic / pharmacodynamic modeling data for 125 patients with common solid tumors shows that the risk of developing neutropenia during the first two cycles of therapy may be higher in patients aged 65 years and older.

PREPARATION OF THE PREPARATION FOR INTRAVENOUS INTEGRATION

The reconstituted suspension of the drug Abraxan is administered intravenously, by means of an infusion system with a built-in filter having a pore diameter of 15 μm.

With the aseptic requirements, prepare a suspension for infusion as follows:

1. Remove the protective cap from the bottle, wipe the plug with alcohol solution.

2. Using a sterile syringe slowly (for at least 1 minute), 20 ml of a 0.9% solution of sodium chloride for injection into the vial is inserted. The needle of the syringe should be directed in such a way that the solution flows down the inner wall of the vial.

3. To prevent pricing, AVOID the ingestion of 0.9% solution of sodium chloride directly on the lyophilizate.

4. After the entire solution of sodium chloride is introduced into the vial, leave it for at least 5 minutes to evenly absorb the solution with lyophilizate.

5. Gently rotating and (or) turning the bottle for at least 2 minutes, achieve complete and uniform distribution of lyophilizate in the volume of the introduced sodium chloride solution to form a homogeneous suspension. Do not foam.

6. When forming foam or agglomerates, leave the vial for at least 15 minutes before the foam settles completely. If necessary, repeat the above procedure until the agglomerates disappear completely.

7. Ready-to-use preparation is a homogeneous translucent suspension of white or white with a yellowish hue of color without visible mechanical inclusions. Some sedimentation of the reconstituted suspension is allowed. In the presence of sediment before the introduction of the drug should be again, gently flipping the bottle, to achieve uniformity of the suspension. Before administration, it is necessary to inspect the suspension for the presence in itany visible mechanical particles. If such particles are found, the introduction of a reconstituted suspension is not permissible.

8. Each ml of the resulting suspension contains 5 mg of albumin-stabilized nanodispersed paclitaxel (no additional dilution is required before administration of additional dilution). The total volume of the suspension for infusion is calculated as follows: infusion volume (ml) = total dose (mg) / 5 (mg / ml).

9. Ready suspension of the drug Abraksan in the required volume, corresponding to the calculated dose of the drug, transfer into an empty sterile infusion bag of PVC (PVC) or PVC-free. Application for recovery and injection Abraxane medical device (in particular, a package for syringes and infusion), in the manufacture of which is used as a lubricant silicone oil may lead to the formation of protein "threads." Therefore, to eliminate the possibility of ingress protein "threads" in the bloodstream, the drug infusion Abraxane be carried out using the high-pass filter with a pore size of 15 microns. Such a filter removes these particles without altering the physical and chemical characteristics of the reconstituted drug suspension.

Applying a filter with a pore size of less than 15 μm can lead to clogging and blockage.

Given the possibility of getting the drug into the circulatory tissues, it is necessary to closely monitor the administration of the drug, promptly identifying possible symptoms of infiltration at the site of intravenous injection.

Limiting the time of administration of the drug Abraxan up to 30 min. in accordance with the recommendations, reduces the likelihood of developing unwanted reactions together infusion.

Storage of the finished suspension in vials

Apply immediately after dilution, if necessary, the finished suspension can be stored in the refrigerator at a temperature of 2-8 ° C for not more than 8 hours. Store r protected from bright light. Dispose of unused product according to local requirements.

Storage of the finished suspension in infusion packets

Ready to administer the drug should be used immediately after dilution. If necessary, the finished suspension in the infusion bag can be stored at room temperature (not above 25 ° C) under normal illumination conditions and applied no later than 8 hours after dilution.

Side effects:

The most frequent and clinically relevant NLDs developing Mr.a background of the drug Abraxane, were neutropenia, peripheral neuropathy, arthralgia / myalgia, and disorders of the gastrointestinal tract.

The following describes the NAL registered on the background of treatment with Abraxane - as monotherapy and in combination with gemcitabine - all the possible indications.

To assess the incidence of ADRs of the drug, the following terms are used in this manual: very common (≥1 / 10), often (<1/10 - ≥1 / 100), uncommon (<1/100 -≥1 / 1000), rarely ( <1/1000 - ≥1 / 10000), very rarely (<1/10000).

Breast cancer (monotherapy Pwith the drug Abraxan)

Infectious and parasitic diseases

Often: infection, urinary tract infection, folliculitis, infections of the upper respiratory tract, candidiasis, sinusitis;

Infrequently: oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, pneumonia, infection associated with the catheter, fungal infection, herpes zoster, infectious complications in the site of injection, sepsis², neutropenic sepsis².

Benign, malignant and unspecified neoplasms (including castes and polyps)

Infrequently: metastatic pain, necrosis of the tumor.

Violations of the blood and lymphatic system

Often: neutropenia, anemia, leukopenia, thrombocytopenia, lymphopenia, oppression of bone marrow hematopoiesis;

Often: febrile neutropenia;

Rarely: pancytopenia.

Immune system disorders

Infrequently¹: hypersensitivity reactions;

Rarely: severe hypersensitivity reactions.

Disorders from the metabolism and nutrition

Often: anorexia;

Often: dehydration, decreased appetite, hypokalemia;

Infrequently: hypophosphatemia, fluid retention, hypoalbumism, nolidipsia, hyperglycemia, hypokalemia, hypocalcemia, hypoglycemia, hyponatremia.

Disorders of the psyche

Often: insomnia, depression, anxiety;

Infrequently: anxiety.

Disturbances from the nervous system

Often: peripheral neuropathy, neuropathy, hypoesthesia, paresthesia;

Often: peripheral sensory neuropathy, headache, dysgeusia. dizziness, peripheral motor neuropathy, ataxia, sensory disorders, increased drowsiness;

Infrequently: polyneuropathy, decreased reflexes / areflexia, dyskinesia, neuralgia, loss of sensitivity, fainting, postural dizziness, neurogenic pain, tremor.

Disturbances on the part of the organ of sight

Often: increased lacrimation, blurred vision, dry eye syndrome, dry keratoconjunctivitis, madarose;

Infrequently: eye irritation, eye pain, visual impairment, decreased visual acuity, conjunctivitis, visual disturbances, itchy eyes, keratitis;

Rarely: cystoid macular edema².

Hearing disorders and labyrinthine disorders

Often: vertigo;

Infrequently: pain in the ears, tinnitus.

Heart Disease

Often: tachycardia, arrhythmia, supraventricular tachycardia;

Rarely: bradycardia, cardiac arrest, left ventricular dysfunction, congestive heart failure, atrioventricular block².

Vascular disorders

Often: "tides" of blood, increased blood pressure (BP), lymphatic edema;

Infrequently: a decrease in blood pressure; "cold" limbs, orthostatic hypotension;

Rarely: thrombosis.

Disturbances from the respiratory system, chest and mediastinal organs

Often: interstitial pneumonitis³, shortness of breath, nosebleeds, pharyngo-laryngeal pains, cough, rhinitis, rhinorrhea;

Infrequently: cough with phlegm, dyspnoea with physical exertion,swelling of the mucosa of the paranasal sinuses, weakened breathing, pleural effusion, allergic rhinitis, hoarseness, dryness / congestion of the nose, wheezing, thromboembolism / embolism of the pulmonary artery.

Disorders from the gastrointestinal tract

Often: nausea, diarrhea, vomiting, constipation, stomatitis;

Often: abdominal pain, bloating, epigastric pain, dyspepsia, gastroesophageal reflux, hypoesthesia of the oral mucosa;

Infrequently: dysphagia, flatulence, glossalgia, dry mouth, pain in the gums, loose stools, esophagitis, lower abdominal pain, ulcerous lesions of the oral mucosa, mouth pain, rectal bleeding.

Disturbances from the liver and bile ducts

Infrequently: hepatomegaly.

Disturbances from the skin and subcutaneous tissues

Often: alopecia, skin rash;

Often: nail damage, itching, dry skin, erythema, lesions of nail plates (changes in pigmentation or discoloration of the nail bed), onycholysis (exfoliation of nails), hyperpigmentation of the skin, changes in nails;

Infrequently: soreness of the nail bed, rashes, pain in the skin,photosensitivity reactions, skin pigmentation disorders, itching rash, skin diseases, excessive sweating, onychomadez (complete nail loss), erythematous rash, generalized rash, dermatitis, night sweats, maculopapular rash, vitiligo, hypotrichosis, discomfort in the nails, general itching , damage to skin, face swelling:

Rarely: Stevens-Johnson Syndrome², toxic epidermal necrolysis².

Disturbances from musculoskeletal and connective tissue

Often: arthralgia, myalgia;

Often: pain in the limbs, pain at bones, back pain, muscle cramps, pain in the distal parts of the limbs;

Infrequently: pain in the chest, muscle weakness, neck pain, pain in the chest groin, muscle spasms, musculoskeletal pain, side pain, discomfort in the extremities.

Disorders from the kidneys and urinary tract

Infrequently: dysuria, pollakiuria, hematuria, nocturia, polyuria, incontinence.

Violations of the genitals and mammary gland

Infrequently: pain in the mammary gland.

General disorders and disorders at the site of administration

Often: fatigue, asthenia, fever;

Often: peripheral edema, mucosal inflammation, pain, chills, swelling, weakness, decreased performance, chest pain, flu-like syndrome, malaise, drowsiness, hyperthermia;

Infrequently: feeling of discomfort in the chest, gait disturbance, swelling, reactions at the injection site;

Rarely: extravasation.

Laboratory and instrumental data

Often: weight loss, increased activity of alanineaminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase, gamma-glutamintransferase (GGT), decrease in erythrocyte count, decrease in hematocrit, increase in body temperature:

Infrequently: increased blood pressure, weight gain, hyperbilirubinemia; increased serum creatinine concentration, hyperphosphatemia, hyperglycemia, hyponatremia, an increase lactate dehydrogenase activity (LDH).

Injuries, intoxication and complications of manipulation

Infrequently: bruises;

Rarely: anamnestic radiation phenomenon, radiation pneumonitis³.

¹ -frequency of hypersensitivity reactions was determined on the basis of one definitely associated with the drug Abraxan case in a population of 789 patients.

² - according to the post-registration report for the drug Abraksan.

³ - frequency of pneumonitis is calculated on the basis of generalized data 1310 patients who participated in clinical trials of the drug Abraksan, which was prescribed as a monotherapy in breast cancer and other indications (see section "Special instructions").

Adenocarcinoma of the pancreas (drug Abraxane in combination with gemcitabine)

Infectious and parasitic diseases

Often: sepsis, pneumonia, candidiasis of the oral cavity

Violations of the blood and lymphatic system

Often: neutropenia, anemia, thrombocytopenia;

Often: pancytopenia;

Infrequently: thrombotic thrombocytopenic purpura

Disorders from the metabolism and nutrition

Often: dehydration, decreased appetite, hypokalemia.

Disorders of the psyche

Often: insomnia, depression;

Infrequently: anxiety.

Disturbances from the nervous system

Often: peripheral neuropathy, dysgeusia, headache, dizziness;

Infrequently: paralysis of the facial nerve.

Disturbances on the part of the organ of sight

Often: increased tear;

Infrequently: cystoid macular edema.

Heart Disease

Often: congestive heart failure, tachycardia;

Vascular disorders

Often: decrease and increase of blood pressure;

Disturbances from the respiratory system, organs of the chest and mediastinum

Often: shortness of breath, nosebleeds, cough;

Often: pneumonitis, nasal congestion;

Infrequently: Dryness of pharynx / nose.

Disorders from the gastrointestinal tract

Often: nausea, diarrhea, vomiting, constipation, abdominal pain, epigastric pain;

Often: stomatitis, intestinal obstruction, colitis, dryness of the oral mucosa.

Disturbances from the liver and bile ducts

Often: cholangitis.

Disturbances from the skin and subcutaneous tissues

Often: alopecia, skin rash;

Often: itching, dry skin, nail diseases, "hot flashes".

Disturbances from musculoskeletal and connective tissue

Often: pain in the extremities, arthralgia, myalgia;

Often: muscle weakness, pain in the bones.

Disorders from the kidneys and urinary tract

Often: acute renal failure

Infrequently: hemolytic-uremic syndrome.

General disorders and disorders at the site of administration

Often: fatigue, peripheral edema, fever body, asthenia, chills;

Often: reactions at the injection site.

Laboratory and instrumental data

Often: weight loss, increased ALT activity;

Often: increased activity ACT, hyperbilirubinemia, increased creatinine concentration in the blood plasma.

Description of individual adverse reactions

Violations of the blood and lymphatic system

Table 4 provides information on the frequency and severity of changes in hematologic test parameters in patients who received the drug Abraxan in combination with gemcitabine or one gemcitabine.

Table 4. Pathological changes in hematological tests in patients with pancreatic adenocarcinoma

	The drug Abraksan (125 mg / m²) / Gemcitabine		Gemcitabine
	1-4 power (%)	3-4 power (%)	1-4 power (%)	3-4 power (%)
Anemia^{a, b}	97	13	96	12
Neutropenia^{a, b}	73	38	58	27
Thrombocytopenia^{b, c}	74	13	70	9
^a - evaluated the data of 405 patients on the background of treatment with a combination Abraxane / gemcitabine. ^b- evaluated the data of 388 patients on the background of treatment with gemcitabine ^from- evaluated the data of 404 patients on the background of treatment with the combination Abraksan / gemcitabine.

Post-registration application experience

During the post-registration study of the drug Abraksan, cases of paralysis of the cranial nerves, voice vocal cord paresis and rare cases of severe hypersensitivity reactions were described.

There were also rare cases of visual acuity reduction due to cystoid edema of the retinal yellow spot on the background of therapy with the drug Abraksan. It is necessary to abrogate Abraxan when diagnosing cystoid edema of the retina yellow spot.

In some patients who received pre- capecitabine, cases of palmar-plantar erythrodysthesis are noted. Because. that reports of such complications came spontaneously in the clinical use of the drug, their true frequency and cause-and-effect relationship can not be determined.

Overdose:

The specific antidote of paclitaxel is unknown. In case of an overdose of the drug, Abraksan is given symptomatic treatment and careful monitoring of the patient.

Treatment should be directed to the main predictable complications (missosuppression, mucositis and peripheral neuropathy).

Interaction:

Special studies of the interaction of paclitaxel with other drugs have not been conducted.

Due to the fact that the metabolism of paclitaxel is partially mediated by isoenzymes CYP2C8 and CYP3A4 cytochrome P450 systems, caution should be taken with the preparation of Abraxane along with inhibitors of these isoenzymes (including ketoconazole and others antifungal agents - derivatives of imidazole, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) or inducers of these isoenzymes (including rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine).

Paclitaxel and gemcitabine have different metabolic pathways. The clearance of paclitaxel is due, mainly, to the metabolism catalyzed by isoenzymes CYP2C8 and CYP3A4, followed by excretion with bile; gemcitabine is inactivated by cytidine deaminase followed by excretion in the urine. Studies of the pharmacokinetic interaction of the drug Abraxan and gemcitabine in humans have not been conducted.

The drug Abraksan is indicated as a monotherapy for breast cancer, or in combination with gemcitabine for the treatment of pancreatic adenocarcinoma (see section "Indications for use").

The drug Abraxan should not be combined with other antitumour agents.

Special instructions:

The drug Abraxan should be administered only under the supervision of a doctor who has experience with antitumor drugs, and in the presence of the conditions necessary for the relief of possible complications.

This drug should not be mixed with other drugs, except listed in the section "Preparation of the drug for intravenous administration. "

Contraception in men and women

Women of childbearing age should apply reliable methods of contraception during treatment and within 1 month after stopping treatment with Abruxan.

Men who receive the drug Abraxan should not participate in the conception of the child during the course of therapy, and also within 6 months after the end.

Hypersensitivity

In rare cases, severe hypersensitivity reactions were noted, including, very rarely, anaphylactic reactions with a fatal outcome. When a patient develops symptoms of hypersensitivity, the drug should be immediately discontinued without the possibility of subsequent resumption.Patients should be prescribed symptomatic therapy.

Hematological toxicity

Suppression of bone marrow function (mainly neutropenia) during treatment with drug Abraxan is observed frequently. Neutropenia is dose-dependent and is the main factor limiting the dose of the drug.

During treatment with Abraxan, regular monitoring of the peripheral blood pattern is necessary.

Repeated courses of the drug Abraxan should be carried out only with recovery of neutrophils more than 1500 / μl, and platelets above 100,000 / μL (see section "Method of administration and dose").

Neuropathy

In the treatment with the drug Abraksan, sensory neuropathy often develops, although its severe forms are not diagnosed infrequently. In the case of sensory neuropathy 1 or 2 severity, as a rule, there is no need to reduce the dose of the drug. With the development of pronounced sensory neuropathy (3 degrees of severity) against the background monotherapy drug Abraksan should suspend the treatment to alleviate symptoms to 1-2 degrees and reduce the dose of the drug Abraxan in all subsequent courses. With the development of sensory neuropathy ≥3 degrees in the background combined therapy with the drug Abraxan and gemcitabine, it is necessary to postpone the introduction of the drug Abraxan, continuing the therapy with gemcitabine at a constant dose. Therapy with Abraxan in a reduced dose is resumed after a decrease in the severity of peripheral neuropathy to 0 or 1 degree (see section "Method of administration and dose").

Sepsis

Sepsis was recorded in 5% of patients who received the drug Abraxan in combination with gemcitabine. regardless of whether they have neutropenia. Complications of pancreatic cancer, especially obstruction of the bile duct and the presence of a biliary stent, were the main risk factors for the development of sepsis. When the patient's body temperature increases (regardless of the amount of neutrophils), it is necessary to start therapy with broad-spectrum antibiotics. With the development of febrile neutropenia, the administration of the drug Abraksan and gemcitabine should be postponed until the body temperature is normalized and the absolute amount of neutrophils is restored ≥ 1500 cells / mm³, and then resume treatment with both drugs in a reduced dose (see section "Method of administration and dose").

Pneumonitis

Pneumonitis was registered in 4% of patients who received the drug Abraxane in combination with gemcitabine. Of the 17 cases of pneumonitis 2, they ended lethal. Careful observation of patients is needed to timely detect signs and symptoms of pneumonitis. After excluding the infectious etiology of the disease and confirming the diagnosis of pneumonitis, it is necessary to cancel the treatment with the drug Abraxan and gemcitabine (without the possibility of its renewal), and immediately begin the appropriate treatment and supportive activities (see section "Method of administration and dose".

Hepatotoxicity

Since patients with impaired liver function are more likely to manifest toxicity of paclitaxel, the drug Abraxan should be used with caution. In connection with a higher risk of toxic reactions, especially myelosuppression, in patients with impaired liver function, it is necessary to constantly monitor the blood picture for the timely detection of symptoms of severe myelosuppression.

The drug Abraxan should not be used in patients who have a bilirubin concentration> 5 x VGN or ACT > 10 x VGN.In addition, the drug Abraksan is not recommended for patients with metastatic pancreatic adenocarcinoma if they have moderate and severe hepatic insufficiency (total bilirubin> 1.5 x VGN and ACT <10 x VGN), (see section "Pharmacokinetics").

Cardiotoxicity

In patients who received the drug Abraksan, single cases of congestive heart failure and left ventricular dysfunction were reported.

Moreover, most patients had a history of heart disease or cardiotoxic drugs, such as anthracyclines.

Thus, patients receiving the drug Abraxan should be under the constant supervision of a physician to monitor the development of heart failure.

Metastases in the central nervous system (CNS)

Efficacy and safety of the drug Abraxan in patients with metastases at CNS is not defined. Usually metastases at CNS is poorly controlled by systemic chemotherapy.

Gastrointestinal Symptomamika

When Abraksan appears on the background of treatment with nausea, vomiting and diarrhea, conventional antiemetic and antidiarrheal agents can be used in patients.

Elderly patients (over 75 years of age)

Patients aged 75 years and older did not benefit from combination therapy with Abraxane and gemcitabine compared with gemcitabine alone.

In patients of very old age (≥75 years), the combination of the drug Abraksan and gemcitabine showed an increase in the incidence of serious NLR, as well as NLR, leading to early completion of therapy, including hematological toxicity, peripheral neuropathy, decreased appetite and dehydration.

Patients with pancreatic adenocarcinoma ≥75 years of age should be carefully monitored for assessing the tolerability of combination therapy with the drug Abraxan and gemcitabine. At the same time, special attention should be paid to their general condition, concomitant diseases and an increased risk of infections (see sections "Dosing and Administration" and "Side effects").

Other

Taking into account the limited data available, there was no clear advantage of combination therapy with Apraxin and gemcitabine in the form of lengthening the overall survival in patients with pancreatic adenocarcinoma with normal CA 19-9 values prior to treatment (see Pharmacodynamics). Do not add erlotinib to the combination of the drug Apraksin and gemcitabine (see the section "Interaction with other medicinal products").

Excipients

After restoring 1 ml of the drug, Abraxane contains 183 mmol or 4.2 mg of sodium. This should be borne in mind by patients who restrict sodium intake.

The drug Abraxan is an albumin-stabilized nanodisperse paclitaxel, the pharmacological properties of which may be significantly different from those of other preparations of paclitaxel.

DO NOT USE TOGETHER OR REPLACE WITH OTHER MEDICINAL FORMS OF PACLITAXEL. CONCENTRATION OF THE READY SUSPENSION IS 5 MG / ML. DO NOT DILUTE BEFORE INTRODUCTION!

When working with the drug Abraxan should comply with the rules for handling cytotoxic substances and rules for their destruction. Preparation of the preparation for administration should be carried out by specially trained personnel in a room equipped for this purpose with observance of aseptic conditions. It is recommended to use protective gloves, goggles and protective clothing. Avoid contact with the skin and mucous membranes.If the product gets on the skin, the affected area should be rinsed immediately with soap and water. In this case, tingling / burning sensation and reddening of the skin may occur. If you get the drug Abraxane on the mucous membranes, you should thoroughly rinse the affected area with water. The inhalation of paclitaxel can cause shortness of breath, chest pain, burning sensation in the eyes, sore throat and nausea.

Pregnant employees should not work with the drug Abraksan.

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

Abraxan has little or moderate influence on the ability to drive vehicles and mechanisms. At the same time, Abraxan is capable of causing side reactions, in particular fatigue (very often) and dizziness (often), which can affect the ability of patients to drive vehicles and mechanisms. Patients should be advised to refrain from managing vehicles and mechanisms when developing fatigue or dizziness.

Form release / dosage:Lyophilizate for the preparation of a suspension for infusions, 100 mg.

Packaging:

In the bottles of transparent glass, sealed with rubber stoppers with aluminum clips and covered with detachable plastic caps.

Each bottle, together with instructions for use, is packed in a cardboard box.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-009047/10

Date of registration:31.08.2010 / 12.08.2016

Expiration Date:Unlimited

The owner of the registration certificate:Selden International SarlSelden International Sarl Switzerland

Manufacturer: & nbsp

Fresenius Kabi USA LLC USA

Abraxis BioScience LLC USA

Representation: & nbspSeldzhen International Holdings Corporation Seldzhen International Holdings Corporation USA

Information update date: & nbsp17.01.2017

Illustrated instructions

Instructions

Abraxan (Abraxane)