Abraxane (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Bristol-Myers Squibb Company (USA)

Manufactured By

Abraxis Bioscience, LLC (USA)

Or

Baxter Oncology, GmbH (Germany)

Packaging and Quality Control Release

ABRAXIS BIOSCIENCE, LLC (USA)

Or

BAXTER ONCOLOGY, GmbH (Germany)

ATC Code

L01CD01 (Paclitaxel)

Active Substances

Paclitaxel (Rec.INN registered by WHO)

Human albumin (BP British Pharmacopoeia)

Dosage Form

Abraxane

Lyophilisate for the preparation of suspension for infusions 100 mg+900 mg: fl. 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of suspension for infusions in the form of a lyophilized powder or porous mass of white or white with a yellowish tint color; after reconstitution: a semi-transparent homogeneous suspension of white or white with a yellowish tint color.

Components included in the human albumin solution: sodium caprylate and N-acetyl tryptophan.

100 mg – transparent glass vials (type I) with a capacity of 50 ml (1) – cardboard packs with first-opening control (2 special stickers).

Clinical-Pharmacological Group

Antitumor drug. Alkaloid

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

The mechanism of action of paclitaxel is based on its ability to stimulate the assembly of microtubules of the mitotic spindle from dimeric tubulin molecules and to stabilize microtubules by suppressing their depolymerization. This leads to the suppression of the normal dynamic reorganization of the microtubular network during the interphase of mitosis, and also causes the formation of abnormal microtubule clusters throughout the cell cycle and the appearance of multiple star-shaped clusters (asters) in the mitotic phase.

Abraxane 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, with an approximate size of 10 nm. It is known that albumin regulates the processes of transendothelial transport of plasma components, and in vitro studies have demonstrated that the presence of albumin in the Abraxane preparation stimulates the transport of paclitaxel across the endothelial cell layer. A hypothesis has been proposed that transendothelial transport is mediated by the gp-60 albumin transporter, and an increase in the accumulation of paclitaxel in the tumor is noted due to the presence of the albumin-binding protein – secreted protein acidic and rich in cysteine (SPARC).

Pharmacokinetics

The pharmacokinetics of paclitaxel were studied in clinical trials with 30-minute and 180-minute infusions of Abraxane at doses ranging from 80 to 375 mg/m². AUC values for paclitaxel increased linearly, from 2653 ng×h/ml to 16,736 ng×h/ml, in the dose range from 80 to 300 mg/m².

In a study involving patients with advanced solid tumors, the pharmacokinetic parameters of paclitaxel after intravenous administration of Abraxane at a dose of 260 mg/m² over 30 minutes were compared with the pharmacokinetic parameters after administration of solvent-based paclitaxel at a dose of 175 mg/m² over 3 hours. Based on the results of non-compartmental analysis, the clearance of paclitaxel (43%) and its V_d (53%) were higher with the administration of Abraxane than with solvent-based paclitaxel. No differences in terminal T_1/2 were recorded.

During a study of repeated intravenous administration of Abraxane at a dose of 260 mg/m² to 12 patients, the intra-individual variability of systemic exposure values (AUC) of paclitaxel was 19% (range = 3.21-27.7%). No signs of paclitaxel accumulation were recorded during several courses of therapy.

Distribution

After administration of Abraxane to patients with solid tumors, Paclitaxel was evenly distributed in blood cells and plasma. Plasma protein binding – 94%.

The binding of paclitaxel to proteins was assessed by ultrafiltration in a comparative study in the same patient. The fraction of free paclitaxel was significantly higher with the use of Abraxane (6.2%) than with the administration of solvent-based paclitaxel (2.3%). This provided significantly higher exposure values for the unbound fraction of paclitaxel with the administration of Abraxane compared to solvent-based paclitaxel, even with comparable total exposure values. This phenomenon is likely due to the absence of paclitaxel binding to Cremophor EL micelles, which is observed with the use of solvent-based paclitaxel. According to published studies that evaluated in vitro the binding of paclitaxel (at concentrations from 0.1 to 50 µg/ml) to human plasma proteins, the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect the binding of paclitaxel to plasma proteins.

Considering the results of population pharmacokinetic data analysis, the total V_d is approximately 1741 L, indicating extensive extravascular distribution and/or binding of paclitaxel to tissue proteins.

Metabolism and Excretion

In vitro studies using human liver microsomes and tissue slices have shown that Paclitaxel is metabolized primarily to form 6α-hydroxypaclitaxel, as well as two additional metabolites present in smaller amounts (3′-p-hydroxypaclitaxel and 6α,3′-p-dihydroxypaclitaxel). The formation of these hydroxylated metabolites is catalyzed by cytochrome isoenzymes CYP2C8, CYP3A4, and jointly by CYP2C8 and CYP3A4, respectively.

In patients with metastatic breast cancer after intravenous drip administration of Abraxane over 30 minutes at a dose of 260 mg/m², the mean cumulative urinary excretion of the unchanged active substance corresponded to 4% of the total administered dose of the drug; less than 1% of the administered dose was accounted for by the urinary metabolites 6α-hydroxypaclitaxel and 3′-p-hydroxypaclitaxel, indicating significant non-renal clearance of the drug. Paclitaxel is predominantly eliminated through hepatic metabolism and biliary excretion.

When the drug is administered at a therapeutic dose from 80 to 300 mg/m², the mean plasma clearance of paclitaxel varies from 13 to 30 L/h/m², and the mean terminal T_1/2 ranges from 13 to 27 hours.

Pharmacokinetics in Special Clinical Cases

Hepatic Impairment. Results from clinical studies have demonstrated that mild hepatic impairment (total bilirubin >1 to ≤1.5×ULN) did not have a clinically significant effect on the pharmacokinetic parameters of paclitaxel. In patients with moderate (total bilirubin >1.5 to ≤3×ULN) and severe (total bilirubin >3 to ≤5×ULN) hepatic impairment, a 22-26% decrease in the maximum elimination rate of paclitaxel and an approximately 20% increase in the mean AUC of paclitaxel were noted. Hepatic impairment did not affect the mean C_max of paclitaxel. Furthermore, the elimination of paclitaxel was inversely correlated with total bilirubin levels and directly correlated with plasma albumin concentrations.

Pharmacokinetic/pharmacodynamic modeling showed no correlation between liver function (based on baseline albumin concentration or total bilirubin) and neutropenia when considering exposure to Abraxane.

Pharmacokinetic analysis was not performed in patients with total bilirubin >5×ULN or patients with metastatic pancreatic adenocarcinoma.

Renal Impairment. Mild or moderate renal impairment (CrCl from ≥30 to <90 ml/min) did not have a clinically significant effect on the maximum elimination rate and systemic exposure (AUC and C_max) of paclitaxel. There is insufficient pharmacokinetic analysis data for patients with severe renal impairment, and no data for patients with end-stage renal disease.

Elderly Patients. The population pharmacokinetic analysis of Abraxane included data from patients aged 24 to 85 years. The 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 predisposed to developing neutropenia during the first cycle of therapy, although age did not affect plasma exposure to paclitaxel.

Other Intrinsic Factors. Population pharmacokinetic analysis of Abraxane demonstrated that gender, race (Mongoloid compared to Caucasian) and type of solid tumors do not have a clinically significant effect on the systemic exposure (AUC and C_max) of paclitaxel. The AUC of 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 these data is unknown.

Indications

• Second-line and subsequent lines of therapy in patients with metastatic breast cancer refractory to standard anthracycline-containing combination chemotherapy (or in the presence of contraindications), as well as in case of disease recurrence within 6 months after completion of adjuvant chemotherapy;
• In combination with gemcitabine – as first-line therapy in adult patients with metastatic pancreatic adenocarcinoma.

ICD codes

Dosage Regimen

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

Breast Cancer

Abraxane is administered intravenously by drip over 30 minutes at a dose of 260 mg/m² once every 3 weeks.

Dose adjustment for breast cancer treatment

If severe neutropenia develops (neutrophil count less than 500/mm³ for 1 week or longer) or severe sensory neuropathy, the dose of Abraxane should be reduced to 220 mg/m² for all subsequent courses of therapy.

If severe neutropenia or severe sensory neuropathy recurs, the dose should be reduced to 180 mg/m².

Abraxane should not be administered until the neutrophil count recovers to a level above 1500/mm³ and the platelet count recovers to a level above 100,000/mm³. In patients with grade 3 sensory neuropathy, treatment should be suspended until the neuropathy decreases to grade 1 or 2, followed by a dose reduction of Abraxane for all subsequent courses of therapy.

Pancreatic Adenocarcinoma

Abraxane in combination with gemcitabine is administered intravenously. Abraxane^® at a dose of 125 mg/m² is administered over 30 minutes on days 1, 8, and 15 of each 28-day cycle. Gemcitabine at the recommended dose of 1000 mg/m² is administered over 30 minutes immediately after the completion of Abraxane administration, on days 1, 8, and 15 of each 28-day cycle.

Dose adjustment for pancreatic adenocarcinoma treatment

Table 1. Dose reduction of drugs in patients with pancreatic adenocarcinoma

Table 3. Dose adjustment of drugs for the development of other adverse drug reactions (ADRs) in patients with pancreatic adenocarcinoma

^a see Table 1 for dose level reduction

Special Patient Groups

For patients with mild hepatic impairment (total bilirubin >1 to ≤1.5×ULN and AST ≤10×ULN), no dose adjustment is required, regardless of the indication. The same doses of the drug should be used as in patients with normal liver function.

In patients with metastatic breast cancer and moderate to severe hepatic impairment (total bilirubin >1.5 to ≤5×ULN and AST ≤10×ULN), a 20% dose reduction is recommended. This reduced dose can be increased to the normal therapeutic dose (as in patients with normal liver function) if the patient tolerated the first two cycles of therapy well.

For patients with metastatic pancreatic adenocarcinoma and moderate or severe hepatic impairment, there is insufficient data to develop recommendations regarding the dose adjustment of Abraxane.

For patients with total bilirubin >5×ULN and AST activity >10×ULN, regardless of the indication, there is insufficient data to develop dosing recommendations.

For patients with mild or moderate renal impairment (CrCl from ≥30 to <90 ml/min), no adjustment of the starting dose of Abraxane is required. There is insufficient data to develop dosing recommendations for patients with severe and end-stage (CrCl <30 ml/min) renal impairment.

The safety and efficacy of Abraxane in children and adolescents under 18 years of age have not been studied. There are no data on the use of Abraxane in pediatric patients for breast cancer or pancreatic adenocarcinoma.

For patients aged 65 years and older, no additional dose reduction beyond that recommended for all patients is provided.

The condition of a patient with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed before prescribing therapy.

Analysis of pharmacokinetic/pharmacodynamic modeling data for 125 patients with advanced solid tumors indicates 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 drug for administration

The reconstituted suspension of Abraxane is administered intravenously, using an infusion system with an in-line filter having a pore size of 15 µm.

Observing aseptic requirements, prepare the suspension for infusion as follows

1. Remove the protective cap from the vial, wipe the stopper with an alcohol solution.
2. Using a sterile syringe, slowly (over at least 1 minute) inject 20 ml of 0.9% sodium chloride injection solution into the vial. The syringe needle should be directed so that the solution flows down the wall of the vial.
3. Avoid directing the solution directly onto the lyophilisate to prevent foaming.
4. After all the sodium chloride solution has been injected into the vial, leave it for at least 5 minutes for the solution to be evenly absorbed by the lyophilisate.
5. Gently swirling and/or inverting the vial for at least 2 minutes, achieve complete and uniform dissolution of the lyophilisate in the volume of the injected sodium chloride solution to form a homogeneous suspension. Avoid foaming.
6. If foam or agglomerates form, leave the vial for at least 15 minutes until the foam completely settles. If necessary, repeat the above procedure until the agglomerates completely disappear.
7. The finished preparation is a homogeneous semi-transparent suspension of white or white with a yellowish tint color without visible mechanical inclusions. Some sedimentation of the reconstituted suspension is allowed. If sediment is present, before administering the drug, gently invert the vial again to achieve homogeneity of the suspension. Before administration, the suspension should be inspected for the presence of any visible mechanical particles. If such particles are found, administration of the reconstituted suspension is not permitted.
8. Each ml of the resulting suspension contains 5 mg of albumin-stabilized nanodispersed paclitaxel (no additional dilution is required before administration). The total volume of the infusion suspension is calculated as follows:

Infusion volume (ml) = total dose (mg)/5 (mg/ml).

1. Transfer the prepared suspension in the required volume, corresponding to the calculated dose of the drug, into an empty sterile PVC (or non-PVC) infusion bag. The use of medical devices (in particular, syringes and infusion bags) for the reconstitution and administration of Abraxane, in the production of which silicone oil is used as a lubricant, may lead to the formation of protein “threads”. Therefore, to eliminate the possibility of such protein “threads” entering the bloodstream, the infusion of Abraxane should be carried out using an in-line filter with a pore size of 15 µm. Such a filter removes these particles without altering the physical and chemical characteristics of the reconstituted drug suspension.

The use of a filter with a pore size of less than 15 µm may lead to its clogging and blockage.

Given the possibility of the drug entering perivascular tissues, it is necessary to carefully monitor the drug administration process, promptly identifying possible symptoms of infiltration at the site of intravenous injection.

Limiting the administration time of Abraxane to 30 minutes, in accordance with recommendations, reduces the likelihood of developing undesirable reactions at the infusion site.

Storage of the prepared suspension in vials

Use immediately after reconstitution; if necessary, the prepared suspension can be stored in the refrigerator at a temperature of 2-8°C (35.6-46.4°F) for no more than 8 hours. Store protected from bright light. Dispose of unused drug according to local requirements.

Storage of the prepared suspension in infusion bags

The drug ready for administration should be used immediately after reconstitution. If necessary, the prepared suspension in the infusion bag can be stored at room temperature (not exceeding 25°C (77°F)) under normal lighting conditions and used no later than 8 hours after reconstitution.

Adverse Reactions

The most frequent and clinically significant adverse drug reactions (ADRs) developing during the use of Abraxane were neutropenia, peripheral neuropathy, arthralgia/myalgia, and gastrointestinal disorders.

Below are the ADRs registered during treatment with Abraxane – both as monotherapy and in combination with gemcitabine – for all possible indications.

Definition of ADR frequency: very common (≥1/10), common (<1/10, ≥1/100), uncommon (<1/100, ≥1/1000), rare (<1/1000, ≥1/10,000), very rare (<1/10,000).

Breast cancer (Abraxane monotherapy)

Infections and infestations: common – infections, urinary tract infections, folliculitis, upper respiratory tract infections, candidiasis, sinusitis; uncommon – oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infections, pneumonia, catheter-related infections, fungal infections, herpes zoster, injection site infections, sepsis², neutropenic sepsis².

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon – metastatic pain, tumor necrosis.

Blood and lymphatic system disorders very common – neutropenia, anemia, leukopenia, thrombocytopenia, lymphopenia, bone marrow depression; common – febrile neutropenia; rare – pancytopenia.

Immune system disorders uncommon – hypersensitivity reactions; rare – severe hypersensitivity reactions.

Metabolism and nutrition disorders very common – anorexia; common – dehydration, decreased appetite, hypokalemia; uncommon – hypophosphatemia, fluid retention, hypoalbuminemia, polydipsia, hyperglycemia, hypokalemia, hypocalcemia, hypoglycemia, hyponatremia.

Psychiatric disorders common – insomnia, depression, anxiety; uncommon – restlessness.

Nervous system disorders very common – peripheral neuropathy, neuropathy, hypoesthesia, paresthesia; common – peripheral sensory neuropathy, headache, dysgeusia, dizziness, peripheral motor neuropathy, ataxia, sensory disturbances, somnolence; uncommon – polyneuropathy, decreased reflexes/areflexia, dyskinesia, neuralgia, loss of sensation, syncope, postural dizziness, neuropathic pain, tremor.

Eye disorders common – increased lacrimation, blurred vision, dry eye syndrome, dry keratoconjunctivitis, madarosis; uncommon – eye irritation, eye pain, visual impairment, reduced visual acuity, conjunctivitis, visual perception disturbances, eye pruritus, keratitis; rare – cystic macular edema².

Ear and labyrinth disorders: common – vertigo; uncommon – ear pain, tinnitus.

Cardiac disorders common – tachycardia, arrhythmia, supraventricular tachycardia, flushing, increased blood pressure, lymphedema; uncommon – decreased blood pressure; cold extremities, orthostatic hypotension; rare – bradycardia, cardiac arrest, left ventricular dysfunction, congestive heart failure, AV block², thromboses.

Respiratory, thoracic and mediastinal disorders: common – interstitial pneumonitis³, dyspnea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhea; uncommon – productive cough, exertional dyspnea, sinus mucosal edema, weakened breathing, pleural effusion, allergic rhinitis, hoarseness, nasal dryness/congestion, wheezing, pulmonary embolism/thromboembolism.

Gastrointestinal disorders very common – nausea, diarrhea, vomiting, constipation, stomatitis; common – abdominal pain, abdominal distension, epigastric pain, dyspepsia, gastroesophageal reflux, oral mucosal hypoesthesia; uncommon – dysphagia, flatulence, glossalgia, dry mouth, gingival pain, loose stools, esophagitis, lower abdominal pain, oral mucosal ulceration, mouth pain, rectal bleeding.

Hepatobiliary disorders: uncommon – hepatomegaly.

Skin and subcutaneous tissue disorders very common – alopecia, skin rash; common – nail disorders, pruritus, dry skin, erythema, nail plate disorders (pigmentation changes or discoloration of the nail bed), onycholysis (nail detachment), skin hyperpigmentation, nail changes; uncommon – nail bed tenderness, skin eruptions, skin pain, photosensitivity reactions, skin pigmentation disorders, pruritic rash, skin diseases, hyperhidrosis, onychomadesis (complete nail loss), erythematous rash, generalized rash, dermatitis, night sweats, maculopapular rash, vitiligo, hypotrichosis, nail discomfort, generalized pruritus, skin lesions, facial edema; very rare – Stevens-Johnson syndrome², toxic epidermal necrolysis².

Musculoskeletal and connective tissue disorders very common – arthralgia, myalgia; common – pain in extremity, bone pain, back pain, muscle spasms, pain in distal extremities; uncommon – chest pain, muscle weakness, neck pain, groin pain, muscle cramps, musculoskeletal pain, flank pain, discomfort in extremities.

Renal and urinary disorders uncommon – dysuria, pollakiuria, hematuria, nocturia, polyuria, urinary incontinence.

Reproductive system and breast disorders: uncommon – breast pain.

General disorders and administration site conditions very common – fatigue, asthenia, pyrexia; common – peripheral edema, mucosal inflammation, pain, chills, edema, weakness, decreased performance, chest pain, flu-like syndrome, malaise, somnolence, hyperthermia; uncommon – chest discomfort, gait disturbance, swelling, injection site reactions; rare – extravasation.

Investigations: common – weight decreased, increased ALT, increased AST, increased alkaline phosphatase, increased GGT, decreased red blood cell count, decreased hematocrit, increased body temperature; uncommon – weight increased, hyperbilirubinemia; increased serum creatinine, hyperphosphatemia, hyperglycemia, hyponatremia, increased LDH.

Injury, poisoning and procedural complications uncommon – contusion; rare – anamnestic radiation phenomenon, radiation pneumonitis³.

¹ The frequency of hypersensitivity reactions is determined based on one case definitely associated with Abraxane in a population of 789 patients.

²According to the post-marketing report for Abraxane.

³ The frequency of pneumonitis is calculated based on pooled data from 1310 patients who participated in clinical trials of Abraxane administered as monotherapy for breast cancer and for other indications.

Pancreatic adenocarcinoma (Abraxane in combination with gemcitabine)

Infections and infestations: common – sepsis, pneumonia, oral candidiasis.

Blood and lymphatic system disorders very common – neutropenia, anemia, thrombocytopenia; common – pancytopenia; uncommon – thrombotic thrombocytopenic purpura.

Metabolism and nutrition disorders very common – dehydration, decreased appetite, hypokalemia.

Psychiatric disorders very common – insomnia, depression; uncommon – anxiety.

Nervous system disorders very common – peripheral neuropathy, dysgeusia, headache, dizziness; uncommon – facial paralysis.

Eye disorders: common – increased lacrimation; uncommon – cystoid macular edema.

Cardiac disorders common – congestive heart failure, tachycardia, decreased and increased blood pressure.

Respiratory, thoracic and mediastinal disorders very common – dyspnea, epistaxis, cough; common – pneumonitis, nasal congestion; uncommon – pharyngeal/nasal dryness.

Gastrointestinal disorders very common – nausea, diarrhea, vomiting, constipation, abdominal pain, epigastric pain; common – stomatitis, intestinal obstruction, colitis, dry mouth.

Hepatobiliary disorders common – cholangitis.

Skin and subcutaneous tissue disorders very common – alopecia, skin rash; common – pruritus, dry skin, nail disorders, flushing.

Musculoskeletal and connective tissue disorders very common – pain in extremity, arthralgia, myalgia; common – muscle weakness, bone pain.

Renal and urinary disorders common – acute renal failure; uncommon – hemolytic-uremic syndrome.

General disorders and administration site conditions very common – fatigue, peripheral edema, pyrexia, asthenia, chills; common – injection site reactions.

Investigations very common – weight decreased, increased ALT; common – increased AST, hyperbilirubinemia, increased plasma creatinine.

Description of selected adverse reactions

Hematologic disorders

Table 4 provides information on the frequency and severity of changes in hematological test parameters in patients receiving Abraxane in combination with gemcitabine or gemcitabine alone.

Table 4. Pathological changes in hematological test parameters in patients with pancreatic adenocarcinoma

^a Data from 405 patients on Abraxane/gemcitabine combination therapy were evaluated.

^b Data from 388 patients on gemcitabine therapy were evaluated.

^c Data from 404 patients on Abraxane/gemcitabine combination therapy were evaluated.

Post-marketing experience

During post-marketing surveillance of Abraxane, cases of cranial nerve palsy, vocal cord paresis, and rare cases of severe hypersensitivity reactions have been described.

Rare cases of decreased visual acuity due to cystoid macular edema during therapy with Abraxane have also been reported. Abraxane should be discontinued if a diagnosis of cystoid macular edema is made.

Cases of palmar-plantar erythrodysesthesia have been observed in some patients who previously received capecitabine. Since reports of such complications were spontaneous during the clinical use of the drug, their true frequency and causal relationship cannot be determined.

Contraindications

• Neutropenia (less than 1500/mm³);
• Severe hepatic impairment;
• Pregnancy;
• Lactation (breastfeeding);
• Age under 18 years (lack of sufficient data on safety and efficacy);
• Hypersensitivity (to paclitaxel and human albumin).

With caution in bone marrow depression (including after chemotherapy or radiation therapy), mild to moderate hepatic impairment, heart and lung diseases, prior therapy with anthracyclines, neuropathy, acute infectious diseases.

Use in Pregnancy and Lactation

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. Experimental animal studies have shown reproductive toxicity of the drug.

The use of Abraxane during pregnancy is contraindicated.

It is not known whether Paclitaxel is excreted in breast milk. Given the potential for serious adverse reactions in breastfed infants, Abraxane is contraindicated in nursing women. Women who are indicated for treatment with Abraxane should discontinue breastfeeding.

Fertility

In vivo studies have established that Paclitaxel has genotoxic, teratogenic, embryo- and fetotoxic effects, and also reduces reproductive function in both males (testicular atrophy/degeneration) and females (decreased pregnancy rates and increased embryonic death).

Abraxane causes infertility in male rats. Therefore, men should be advised to consider the possibility of preserving samples of their own sperm before starting treatment, given the risk of developing irreversible infertility during treatment with Abraxane.

Contraception in men and women

Women of childbearing potential should use reliable methods of contraception during treatment and for 1 month after discontinuation of treatment with Abraxane.

Men taking Abraxane should not father a child throughout the course of therapy and for 6 months after its completion.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment, moderate and severe hepatic failure in patients with metastatic pancreatic adenocarcinoma, with bilirubin concentration >5×ULN or AST >10×ULN.

With caution in moderate and severe hepatic failure in patients with metastatic breast cancer.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment and end-stage renal disease.

For patients with mild or moderate renal impairment (CrCl from ≥30 to <90 ml/min), no adjustment of the starting dose of Abraxane is required.

Pediatric Use

The use of the drug is contraindicated in children under 18 years of age (lack of sufficient data on safety and efficacy).

Geriatric Use

For patients aged 65 years and older, no additional dose reduction is provided, beyond that recommended for all patients.

Special Precautions

Abraxane should be administered only under the supervision of a physician experienced in the use of anticancer drugs and in conditions necessary to manage possible complications.

Abraxane should not be mixed with other medicinal products except those listed in the “Preparation of the drug for intravenous administration” section.

Hypersensitivity

In rare cases, severe hypersensitivity reactions have been observed, including very rarely – fatal anaphylactic reactions. If the patient develops symptoms of hypersensitivity, treatment with the drug should be immediately discontinued without subsequent resumption. The patient should be prescribed symptomatic therapy.

Hematologic toxicity

Suppression of bone marrow function (primarily neutropenia) is common during treatment with Abraxane. Neutropenia is dose-dependent and is the main dose-limiting factor.

Regular monitoring of peripheral blood counts is necessary during treatment with Abraxane.

Repeated courses of treatment with Abraxane should be carried out only when the neutrophil count recovers to above 1500/mm³ and platelets to above 100,000/mm³.

Neuropathy

Sensory neuropathy often develops during treatment with Abraxane, although its severe forms are not common. In case of grade 1 or 2 sensory neuropathy, dose reduction is generally not required. If severe sensory neuropathy (grade 3) develops during monotherapy with Abraxane, treatment should be suspended until symptoms improve to grade 1-2 and the dose of Abraxane should be reduced for all subsequent courses. If sensory neuropathy ≥ grade 3 develops during combination therapy with Abraxane and gemcitabine, administration of Abraxane should be delayed, continuing therapy with gemcitabine at the unchanged dose. Therapy with Abraxane at a reduced dose is resumed after the severity of peripheral neuropathy decreases to grade 0 or 1.

Sepsis

Sepsis was reported in 5% of patients receiving Abraxane in combination with gemcitabine, regardless of the presence of neutropenia. Complications of pancreatic cancer, especially biliary obstruction and the presence of a biliary stent, were the main risk factors for sepsis. If a patient develops fever (regardless of neutrophil count), broad-spectrum antibiotic therapy should be initiated. If febrile neutropenia develops, administration of Abraxane and gemcitabine should be delayed until the fever resolves and the absolute neutrophil count recovers to ≥1500 cells/mm³, and then treatment with both drugs should be resumed at a reduced dose.

Pneumonitis

Pneumonitis was reported in 1% of patients receiving Abraxane monotherapy and in 4% of patients receiving Abraxane in combination with gemcitabine. Patients should be closely monitored for signs and symptoms of pneumonitis.

After excluding an infectious etiology and confirming the diagnosis of pneumonitis, treatment with Abraxane and gemcitabine must be discontinued (without the possibility of resumption), and appropriate therapeutic and supportive measures should be initiated immediately.

Hepatotoxicity

Since patients with hepatic impairment have an increased likelihood of paclitaxel toxicity, Abraxane should be used with caution in these patients. Due to a higher risk of toxic reactions, particularly myelosuppression, blood counts should be closely monitored in patients with hepatic impairment.

Abraxane should not be used in patients with bilirubin concentrations >5×ULN or AST >10×ULN. Furthermore, Abraxane is not recommended for use in patients with metastatic pancreatic adenocarcinoma who have moderate to severe hepatic impairment (total bilirubin >1.5×ULN and AST ≤10×ULN).

Cardiotoxicity

Isolated cases of congestive heart failure and left ventricular dysfunction have been reported in patients receiving Abraxane. Most of these patients had a history of heart disease or prior exposure to cardiotoxic agents, such as anthracyclines. Therefore, patients receiving Abraxane should be under constant medical supervision for cardiac monitoring.

CNS Metastases

The efficacy and safety of Abraxane in patients with CNS metastases have not been established. CNS metastases are generally poorly controlled by systemic chemotherapy.

Gastrointestinal Symptoms

If nausea, vomiting, and diarrhea occur during treatment with Abraxane, standard antiemetic and antidiarrheal agents can be used in patients.

Elderly Patients (over 75 years)

In patients aged 75 years and older, no advantage of combination therapy with Abraxane and gemcitabine over gemcitabine monotherapy was observed. In very elderly patients (≥75 years), therapy with the combination of Abraxane and gemcitabine was associated with an increased frequency of serious adverse reactions, as well as adverse reactions leading to premature discontinuation of therapy, including hematologic toxicity, peripheral neuropathy, decreased appetite, and dehydration. Patients with pancreatic adenocarcinoma aged ≥75 years should be closely monitored to assess their tolerance to the combination therapy with Abraxane and gemcitabine. Particular attention should be paid to their general condition, comorbidities, and increased risk of infections.

Other

Given the limited available data, no clear benefit of combination therapy with Abraxane and gemcitabine in terms of overall survival was found in patients with pancreatic adenocarcinoma who had normal CA 19-9 levels prior to treatment initiation.

Erlotinib should not be added to the combination of Abraxane and gemcitabine.

Excipients

After reconstitution, 1 ml of Abraxane contains 0.183 mmol or 4.2 mg of sodium. This should be taken into account by patients on a sodium-restricted diet.

Abraxane is an albumin-stabilized nanodispersed Paclitaxel, whose pharmacological properties may differ significantly from those of other paclitaxel formulations. Do not administer concomitantly or substitute with other dosage forms of paclitaxel.

The concentration of the prepared suspension is 5 mg/ml; do not dilute before administration.

Precautions

When handling Abraxane, the rules for handling cytotoxic substances and their disposal must be observed. Preparation of the drug for administration should be performed by specially trained personnel in a designated area under aseptic conditions. The use of protective gloves, goggles, and protective clothing is recommended. Contact of the drug with skin and mucous membranes should be avoided. If the drug comes into contact with the skin, the affected area should be washed immediately and thoroughly with soap and water. This may cause tingling/burning sensations and skin redness. If Abraxane comes into contact with mucous membranes, the affected area should be thoroughly rinsed with water. Inhalation of paclitaxel may cause dyspnea, chest pain, burning sensation in the eyes, sore throat, and nausea.

Pregnant employees should not handle Abraxane.

Effect on Ability to Drive and Operate Machinery

Abraxane has minor to moderate influence on the ability to drive and operate machinery. At the same time, Abraxane can cause adverse reactions, particularly fatigue (very common) and dizziness (common), which may affect patients’ ability to drive and operate machinery. Patients should be advised to refrain from driving and operating machinery if they experience fatigue or dizziness.

Overdose

Treatment no specific antidote for paclitaxel is known. In case of Abraxane overdose, symptomatic treatment and careful patient monitoring should be instituted. Treatment should be aimed at the main anticipated complications (myelosuppression, mucositis, and peripheral neuropathy).

Drug Interactions

No specific studies on the interaction of paclitaxel with other drugs have been conducted.

Since paclitaxel metabolism is partially mediated by cytochrome P450 isoenzymes CYP2C8 and CYP3A4, Abraxane should be used with caution when co-administered with inhibitors of these isoenzymes (including ketoconazole and other imidazole-derived antifungal agents, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir), as paclitaxel toxicity may increase with increased paclitaxel exposure. Co-administration of paclitaxel with inducers of CYP2C8 or CYP3A4 isoenzymes (including rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended due to a possible decrease in efficacy resulting from reduced paclitaxel exposure.

Paclitaxel and gemcitabine have different metabolic pathways. Paclitaxel clearance is primarily due to metabolism catalyzed by CYP2C8 and CYP3A4 isoenzymes, followed by biliary excretion; gemcitabine is inactivated by cytidine deaminase, followed by urinary excretion. No pharmacokinetic interaction studies of Abraxane and gemcitabine have been conducted in humans.

Abraxane is indicated as monotherapy for breast cancer or in combination with gemcitabine for the treatment of pancreatic adenocarcinoma. Abraxane should not be combined with other antineoplastic agents.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F) in the original packaging (carton).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.