Abraxane 5 mg/ml powder for suspension for infusion.
Each vial contains 100 mg of paclitaxel formulated as albumin bound nanoparticles. Each vial contains 250 mg of paclitaxel formulated as albumin bound nanoparticles. After reconstitution, each ml of suspension contains 5 mg of paclitaxel formulated as albumin bound nanoparticles.
Excipients with known effect
Each ml of concentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. For the full list of excipients, see section 6.1.
Powder for suspension for infusion. The reconstituted suspension has a pH of 6-7.5 and an osmolality of 300-360 mOsm/kg. The powder is white to yellow.
Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated (see section 4.4). Abraxane in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas.
Abraxane should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents. It should not be substituted for or with other paclitaxel formulations.
Posology
Breast cancer
The recommended dose of Abraxane is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.
Dose adjustments during treatment of breast cancer
Patients who experience severe neutropenia (neutrophil count < 500 cells/mm3 for a week or longer) or severe sensory neuropathy during Abraxane therapy should have the dose reduced to 220 mg/m2 for subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. Abraxane should not be administered until neutrophil counts recover to >1500 cells/mm3. For grade 3 sensory neuropathy withhold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses.
Pancreatic adenocarcinoma
The recommended dose of Abraxane in combination with gemcitabine is 125 mg/m2 administered intravenously over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommended dose of gemcitabine is 1000 mg/m2 administered intravenously over 30 minutes immediately after the completion of Abraxane administration on Days 1, 8 and 15 of each 28-day cycle.
Dose adjustments during treatment of pancreatic adenocarcinoma
| Dose Level | Abraxane Dose (mg/m 2 ) | Gemcitabine Dose (mg/m 2 ) |
| Full dose | 125 | 1000 |
| 1 s t dose level reduction | 100 | 800 |
| 2 n d dose level reduction | 75 | 600 |
| If additional dose reduction required | Discontinue treatment | Discontinue treatment |
| Cycle Day | ANC count (cells/mm 3 ) | Platelet count (cells/mm 3 ) | Abraxane Dose | Gemcitabine Dose | |
| Day 1 | < 1500 | OR | < 100,000 | Delay doses until recovery | |
| Day 8 | >= 500 but < 1000 | OR | >= 50,000 but < 75,000 | Reduce doses 1 dose level | |
| < 500 | OR | < 50,000 | Withhold doses | ||
| Day 15: IF Day 8 doses were given without modification: | |||||
| Day 15 | >= 500 but < 1000 | OR | >= 50,000 but < 75,000 | Treat with Day 8 dose level and follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 8 doses | |
| < 500 | OR | < 50,000 | Withhold doses | ||
| Day 15: IF Day 8 doses were reduced: | |||||
| Day 15 | >= 1000 | AND | >= 75,000 | Return to the Day 1 dose levels and follow with WBC Growth Factors OR Treat with same doses as Day 8 | |
| >= 500 but < 1000 | OR | >= 50,000 but < 75,000 | Treat with Day 8 dose levels and | ||
| follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 8 doses | ||||
| < 500 | OR | < 50,000 | Withhold doses | |
| Day 15: IF Day 8 doses were withheld: | ||||
| Day 15 | >= 1000 | AND | >= 75,000 | Return to Day 1 dose levels and follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 1 doses |
| >= 500 but < 1000 | OR | >= 50,000 but < 75,000 | Reduce 1 dose level and follow with WBC Growth Factors OR Reduce doses 2 dose levels from Day 1 doses | |
| < 500 | OR | < 50,000 | Withhold doses | |
Abbreviations: ANC=Absolute Neutrophil Count; WBC=white blood cell
| Adverse Drug Reaction (ADR) | Abraxane Dose | Gemcitabine Dose | |
| Febrile Neutropenia : Grade 3 or 4 | Withhold doses until fever resolves and ANC >= 1500; resume at next lower dose level a | ||
| Peripheral Neuropathy : Grade 3 or 4 | Withhold dose until improves to <= Grade 1; resume at next lower dose level a | Treat with same dose | |
| Cutaneous Toxicity: Grade 2 or 3 | Reduce to next lower dose level a ; discontinue treatment if ADR persists | ||
| Gastrointestinal Toxicity: Grade 3 mucositis or diarrhoea | Withhold doses until improves to <= Grade 1; resume at next lower dose level a | ||
a
See Table 1 for dose level reductions
Special populations
Patients with hepatic impairment
Insufficient data are currently available to recommend dose modifications in patients with mild to moderate hepatic impairment that ensure acceptable toxicity while maintaining efficacy of Abraxane. Patients with severe hepatic impairment should not be treated with paclitaxel (see sections 4.4.and 5.2).
Patients with renal impairment
Studies in patients with impaired renal function have not been performed and insufficient data are currently available to recommend dose modifications of Abraxane in patients with renal impairment (see section 5.2).
Older people
No additional dosage reductions, other than those for all patients, are recommended for patients 65 years and older. Of the 229 patients in the randomized study who received Abraxane monotherapy for breast cancer, 13% were at least 65 years of age and < 2% were 75 years and older. No toxicities occurred notably more frequently among patients at least 65 years of age who received Abraxane. Of the 421 patients with pancreatic adenocarcinoma in the randomized study who received Abraxane in combination with gemcitabine, 41% were 65 years and older and 10% were 75 years and older. In patients aged 75 years and older who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation (see section 4.4). Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed before treatment is considered (see section 4.4).
Paediatric population
The safety and efficacy of Abraxane in children and adolescents aged 0-17 years has not been established. There is no relevant use of Abraxane in the paediatric population in the indication of metastatic breast cancer or pancreatic adenocarcinoma.
Method of administration
Administer reconstituted Abraxane suspension intravenously using an infusion set incorporating a 15 um filter. For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Lactation (see section 4.6). Patients who have baseline neutrophil counts <1500 cells/mm3.
Abraxane is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantially different pharmacological properties compared to other formulations of paclitaxel (see sections 5.1 and 5.2). It should not be substituted for or with other paclitaxel formulations.
Hypersensitivity
Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactions with fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinal product should be discontinued immediately, symptomatic treatment should be initiated, and the patient should not be rechallenged with paclitaxel.
Haematology
Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Abraxane therapy. Patients should not be retreated with subsequent cycles of Abraxane until neutrophils recover to >1500 cells/mm3 and platelets recover to >100,000 cells/mm3 (see section 4.2).
Neuropathy
Sensory neuropathy occurs frequently with Abraxane, although development of severe symptoms is less common. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose reduction. When Abraxane is used as monotherapy, if grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of Abraxane is recommended (see section 4.2). For combination use of Abraxane and gemcitabine, if grade 3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine at the same dose. Resume Abraxane at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2).
Sepsis
Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC >= 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2).
Pneumonitis
Pneumonitis occurred in 1% of patients when Abraxane was used as monotherapy and in 4% of patients when Abraxane was used in combination with gemcitabine. Closely monitor all patients for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).
Hepatic impairment
Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Abraxane in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression, and such patients should be closely monitored for development of profound myelosuppression. Patients with severe hepatic impairment (bilirubin > 5 x ULN or AST/ALT > 10 x ULN) have not been studied and should not be treated with Abraxane. The appropriate dose regimen in patients with less severe hepatic impairment is unknown. A dose reduction in patients with bilirubin >2 ULN must be considered since paclitaxel clearance is decreased in patients with high bilirubin levels (see section 5.2).
Cardiotoxicity
Rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving Abraxane. Most of the individuals were previously exposed to cardiotoxic medicinal products such as anthracyclines, or had underlying cardiac history. Thus patients receiving Abraxane should be vigilantly monitored by physicians for the occurrence of cardiac events.
CNS metastases
The effectiveness and safety of Abraxane in patients with central nervous system (CNS) metastases has not been established. CNS metastases are generally not well controlled by systemic chemotherapy.
Gastrointestinal symptoms
If patients experience nausea, vomiting and diarrhoea following the administration of Abraxane, they may be treated with commonly used anti-emetics and constipating agents.
Patients 75 years and older
For patients of 75 years and older, no benefit for the combination treatment of Abraxane and gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (>=75 years) who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy, decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed for their ability to tolerate Abraxane in combination with gemcitabine with special consideration to performance status, co-morbidities and increased risk of infections (see section 4.2 and 4.8)
Other
Although limited data is available, no clear benefit in terms of prolonged overall survival has been demonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start of treatment with Abraxane and gemcitabine (see section 5.1). Erlotinib should not be coadministered to Abraxane plus gemcitabine (see section 4.5).
Excipients
When reconstituted, each ml of Abraxane concentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.
No interaction studies have been performed. The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4. Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance is primarily determined by CYP2C8 and CYP3A4 mediated metabolism followed by biliary excretion, while gemcitabine is inactivated by cytidine deaminase followed by urinary excretion. Pharmacokinetic interactions between Abraxane and gemcitabine have not been evaluated in humans. Abraxane is indicated as monotherapy for breast cancer, or in combination with gemcitabine for pancreatic adenocarcinoma (see section 4.1). Abraxane should not be used in combination with other anticancer agents.
Contraception in males and females
Women of childbearing potential should use effective contraception during treatment and up to 1 month after receiving treatment with Abraxane. Male patients treated with Abraxane are advised not to father a child during and up to six months after treatment.
Pregnancy
There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected to cause serious birth defects when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Abraxane should not be used in pregnancy, and in women of childbearing potential not using effective contraception, unless the clinical condition of the mother requires treatment with paclitaxel.
Breast-feeding
It is not known if paclitaxel is excreted in human milk. Because of potential serious adverse reactions in breast-feeding infants, Abraxane is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy.
Fertility
Abraxane induced infertility in male rats (see section 5.3). Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Abraxane.
Abraxane has minor or moderate influence on the ability to drive and use machines. Abraxane may cause adverse reactions such as tiredness (very common) and dizziness (common) that may affect the ability to drive and use machinery. Patients should be advised not to drive and use machines if they feel tired or dizzy.
Summary of the safety profile
The most common clinically significant adverse reactions associated with the use of Abraxane have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders. The frequencies of adverse reactions associated with the administration of Abraxane are listed in Table 4 (Abraxane as monotherapy) and Table 5 (Abraxane in combination with gemcitabine). Frequencies are defined as: very common (>=1/10), common (>=1/100 to <1/10), uncommon (>=1/1000 to <1/100), rare (>=1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Breast cancer (Abraxane administered as monotherapy)
Tabulated list of adverse reactions
Table 4 lists adverse reactions associated with the administration of Abraxane to patients from studies in which Abraxane has been administered as monotherapy at any dose in any indication (N = 789).
Table 4: Adverse reactions reported with Abraxane monotherapy at any dose in clinical studies
| Infections and infestations | Common : Infection, urinary tract infection, folliculitis, upper respiratory tract infection, candidiasis, sinusitis Uncommon : Oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, pneumonia, catheter-related infection, fungal infection, herpes zoster, injection site infection, sepsis 2 , neutropenic sepsis 2 |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Uncommon:Metastatic pain, tumour necrosis |
| Blood and lymphatic system disorders | Very common : Neutropenia, anaemia, leukopenia, thrombocytopenia, lymphopenia, bone marrow suppression Common : Febrile neutropenia Rare : Pancytopenia |
| Immune system disorders | Uncommon 1 : Hypersensitivity Rare:Severe hypersensitivity |
| Metabolism and nutrition disorders | Very common:Anorexia Common:Dehydration, decreased appetite, hypokalaemia Uncommon:Hypophosphataemia, fluid retention, hypoalbuminaemia, polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia, hyponatraemia |
| Psychiatric disorders | Common : Insomnia, depression, anxiety Uncommon : Restlessness |
| Nervous system disorders | Very common : Peripheral neuropathy, neuropathy, hypoaesthesia, paraesthesia Common : Peripheral sensory neuropathy, headache, dysgeusia, dizziness, peripheral motor neuropathy, ataxia, sensory disturbance, somnolence Uncommon : Polyneuropathy, areflexia, dyskinesia, hyporeflexia, neuralgia, sensory loss, syncope, postural dizziness, neuropathic pain, tremor |
| Eye disorders | Common:Increased lacrimation, blurred vision, dry eye, keratoconjunctivitis sicca, madarosis Uncommon : Eye irritation, eye pain, abnormal vision, reduced visual acuity, conjunctivitis, visual disturbance, eye pruritus, keratitis Rare : Cystoid macular oedema 2 |
| Ear and labyrinth disorders | Common : Vertigo Uncommon : Ear pain, tinnitus |
| Cardiac disorders | Common : Tachycardia, arrhythmia, supraventricular tachycardia Rare:bradycardia, cardiac arrest, left ventricular dysfunction, congestive heart failure, atrioventricular block 2 |
| Vascular disorders | Common : Flushing, hot flushes, hypertension, lymphoedema Uncommon : Hypotension, peripheral coldness, orthostatic hypotension Rare:Thrombosis |
| Respiratory, thoracic and mediastinal disorders | Common : Interstitial pneumonitis 3 , dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhoea Uncommon : Productive cough, exertional dyspnoea, sinus congestion, decreased breath sounds, pleural effusion, allergic rhinitis, hoarseness, nasal congestion, nasal dryness, wheezing, pulmonary emboli, pulmonary thromboembolism |
| Gastrointestinal disorders | Very common : Nausea, diarrhoea, vomiting, constipation, stomatitis Common : Abdominal pain, abdominal distension, upper abdominal pain, dyspepsia, gastrooesophageal reflux disease, oral hypoaesthesia Uncommon : Dysphagia, flatulence, glossodynia, dry mouth, gingival pain, loose stools, oesophagitis, lower abdominal pain, mouth ulceration, oral pain, rectal haemorrhage |
| Hepatobiliary disorders | Uncommon : Hepatomegaly |
| Skin and subcutaneous tissue disorders | Very common : Alopecia, rash Common : Nail disorder, pruritus, dry skin, erythema, nail pigmentation/discolouration, skin hyperpigmentation, onycholysis, nail changes Uncommon : Nail bed tenderness, urticaria, skin pain, photosensitivity reaction, pigmentation disorder, pruritic rash, skin disorder, hyperhidrosis, onychomadesis, erythematous rash, generalised rash, dermatitis, night sweats, maculo-papular rash, vitiligo, hypotrichosis, nail discomfort, generalized pruritus, macular rash, papular rash, skin lesion, swollen face Very rare:Stevens-Johnson syndrome 2 , toxic epidermal necrolysis 2 |
| Musculoskeletal and connective tissue disorders | Very common : Arthralgia, myalgia. Common : Pain in extremity, bone pain, back pain, muscle cramps, limb pain Uncommon : Chest wall pain, muscular weakness, neck pain, groin pain, muscle spasms, musculoskeletal pain, flank pain, limb discomfort, muscle weakness |
| Renal and urinary disorders | Uncommon : Dysuria, pollakiuria, haematuria, 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 oedema, mucosal inflammation, pain, rigors, oedema, weakness, decreased performance status, chest pain, influenza-like illness, malaise, lethargy, hyperpyrexia Uncommon : Chest discomfort, abnormal gait, swelling, injection site reaction Rare:Extravasation |
| Investigations | Common : Decreased weight, increased alanine aminotransferase, increased aspartate aminotransferase, decreased haematocrit, decreased red blood cell count, increased body temperature, increased gamma-glutamyltransferase, increased blood alkaline phosphatase Uncommon : Increased blood pressure, increased weight, increased blood lactate dehydrogenase, increased blood creatinine, increased blood glucose, increased blood phosphorus, decreased blood potassium, increased bilirubin |
| Injury, poisoning and procedural complications | Uncommon:Contusion Rare:Radiation recall phenomenon, radiation pneumonitis |
MedDRA = Medical Dictionary for Regulatory Activities. SMQ = Standardized MedDRA Query; SMQ is a grouping of several MedDRA preferred terms to capture a medical concept.
The frequency of hypersensitivity reactions is calculated based on one definitely related case in a
population of 789 patients. As reported in the post-marketing surveillance of Abraxane. The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Abraxane monotherapy for breast cancer and for other indications using MedDRA SMQ Interstitial lung disease. See section 4.4.
Description of selected adverse reactions
The following are the most common and clinically relevant adverse reactions related to 229 patients with metastatic breast cancer who were treated with 260 mg/m2 Abraxane once every three weeks in the pivotal phase III clinical study.
Blood and lymphatic system disorders
Neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (< 500 cells/mm3) occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on Abraxane, and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.
Nervous system disorders
In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving Abraxane. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on Abraxane with 10% being Grade 3, and no cases of Grade 4.
Gastrointestinal disorders
Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients.
Skin and subcutaneous tissue disorders
Alopecia was observed in >80% of the patients treated with Abraxane. The majority of alopecia events occurred less than one month after initiation of Abraxane. Pronounced hair loss >=50% is expected for the majority of patients who experience alopecia.
Musculoskeletal and connective tissue disorders
Arthralgia occurred in 32% of patients on Abraxane and was severe in 6% of cases. Myalgia occurred in 24% of patients on Abraxane and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after Abraxane administration and resolved within a week.
General disorders and administration site conditions
Asthenia/Fatigue was reported in 40% of the patients.
Pancreatic adenocarcinoma (Abraxane administered in combination with gemcitabine)
Tabulated list of adverse reactions
Adverse reactions were assessed in 421 patients treated with Abraxane in combination with gemcitabine and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas in a phase III randomized, controlled, open-label trial. Table 5 lists adverse reactions assessed in patients with pancreatic adenocarcinoma treated with Abraxane in combination with gemcitabine.
Table 5: Adverse reactions reported with Abraxane in combination with gemcitabine (N =421)
| Infections and infestations | Common : Sepsis, pneumonia, oral candidiasis |
| Blood and lymphatic system disorders | Very common : Neutropenia, anaemia, thrombocytopenia Common : Pancytopenia Uncommon : Thrombotic thrombocytopenic purpura |
| Metabolism and nutrition disorders | Very common : Dehydration, decreased appetite, hypokalaemia |
| Psychiatric disorders | Very common : Insomnia, depression Common : Anxiety |
| Nervous system disorders | Very common : Peripheral neuropathy a , dysgeusia, headache, dizziness Uncommon : VII t h nerve paralysis |
| Eye disorders | Common : Lacrimation increased Uncommon : Cystoid macular oedema |
| Cardiac disorders | Common : Cardiac failure congestive, tachycardia |
| Vascular disorders | Common : Hypotension, hypertension |
| Respiratory, thoracic and mediastinal disorders | Very Common : Dyspnoea, epistaxis, cough Common : Pneumonitis, nasal congestion Uncommon : Dry throat, nasal dryness |
| Gastrointestinal disorders | Very Common : Nausea, diarrhoea, vomiting, constipation, abdominal pain, abdominal pain upper Common : Stomatitis, intestinal obstruction, colitis, dry mouth |
| Hepatobiliary disorders | Common : Cholangitis |
| Skin and subcutaneous tissue disorders | Very Common : Alopecia, rash Common : Pruritus, dry skin, nail disorder, flushing |
| Musculoskeletal and connective tissue disorders | Very common : Pain in extremity, arthralgia, myalgia Common : Muscular weakness, bone pain |
| Renal and urinary disorders | Common : Acute renal failure Uncommon : Haemolytic uraemic syndrome |
| General disorders and administration site conditions | Very common : Fatigue, oedema peripheral, pyrexia, asthenia, chills Common : Infusion site reaction |
| Investigations | Very common : Weight decreased, alanine aminotransferase increased Common : Aspartate aminotransferase increased, blood bilirubin increased, blood creatinine increased |
MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept).
a
Peripheral neuropathy evaluated using the Standardized MedDRA Query (broad scope).
In this phase III randomized, controlled, open-label trial, adverse reactions resulting in death within 30 days of the last dose of study drug were reported for 4% of patients receiving Abraxane in combination with gemcitabine and for 4% of patients receiving gemcitabine monotherapy.
Description of selected adverse reactions
The following are the most common and important incidences of adverse reactions related to 421 patients with metastatic adenocarcinoma of the pancreas who were treated with 125 mg/m2 Abraxane in combination with gemcitabine at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle in the phase III clinical study.
Blood and lymphatic system disorders
Table 6 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with Abraxane in combination with gemcitabine or with gemcitabine.
Table 6: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial
| Abraxane(125 mg/m 2 )/ Gemcitabine | Gemcitabine | ||||
| Grades 1-4 (%) | Grade 3-4 (%) | Grades 1-4 (%) | Grade 3-4 (%) | ||
| Anaemia a ,b | 97 | 13 | 96 | 12 | |
| Neutropenia a ,b | 73 | 38 | 58 | 27 | |
| Thrombocytopenia b ,c | 74 | 13 | 70 | 9 | |
a
405 patients assessed in Abraxane/gemcitabine-treated group
b
388 patients assessed in gemcitabine-treated group
c
404 patients assessed in Abraxane/gemcitabine-treated group
Peripheral Neuropathy
For patients treated with Abraxane in combination with gemcitabine, the median time to first occurrence of grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was 21 days, and the median time to improvement from grade 3 peripheral neuropathy to Grade 0 or 1 was 29 days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were able to resume Abraxane at a reduced dose. No patients treated with Abraxane in combination with gemcitabine had grade 4 peripheral neuropathy.
Sepsis
Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC >= 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2).
Pneumonitis
Pneumonitis has been reported at a rate of 4% with the use of Abraxane in combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with Abraxane in combination with gemcitabine, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).
Post-marketing experience
Cranial nerve palsies, vocal cord paresis, and rare reports of severe hypersensitivity reactions have been reported during post-marketing surveillance of Abraxane. There have been rare reports of reduced visual acuity due to cystoid macular oedema during treatment with Abraxane. Upon diagnosis of cystoid macular oedema, treatment with Abraxane should be discontinued. In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae have been reported as part of the continuing surveillance of Abraxane. Because these events have been reported voluntarily during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be closely monitored. Treatment should be directed at the major anticipated toxicities, which are bone marrow suppression, mucositis and peripheral neuropathy.
Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, taxanes, ATC Code: L01CD01
Mechanism of action
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Abraxane contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, where the paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, the nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro studies demonstrated that the presence of albumin in Abraxane enhances transport of paclitaxel across endothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated by the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumour due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).
Clinical efficacy and safety
Breast cancer
Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated in a randomised Phase III comparative study are available to support the use of Abraxane in metastatic breast cancer. This information is presented below.
Single-arm open-label studies
In one study, Abraxane was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilised a dose of 300 mg/m2 as a 30 minute infusion in 63 patients with metastatic breast cancer. Patients were treated without steroid pre-treatment or planned G-CSF support. Cycles were administered at 3 week intervals. The response rates in all patients were 39.5% (95% CI: 24.9%-54.2%) and 47.6% (95% CI: 35.3%-60.0%), respectively. The median time to disease progression was 5.3 months (175 mg/m2; 95% CI: 4.6-6.2 months) and 6.1 months (300 mg/m2; 95% CI: 4.2-9.8 months).
Randomised comparative study
This multi-centre trial was conducted in patients with metastatic breast cancer, who were treated every 3 weeks with single-agent paclitaxel, either as solvent-based paclitaxel 175 mg/m2 given as a 3-hour infusion with premedication to prevent hypersensitivity (N = 225), or as Abraxane 260 mg/m2 given as a 30 minute infusion without premedication (N = 229). Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastatic setting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicinal product as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines. Results for overall response rate and time to disease progression, and progression-free survival and survival for patients receiving > 1st-line therapy, are shown below.
| Efficacy variable | Abraxane (260 mg/m 2 ) | Solvent-based paclitaxel (175 mg/m 2 ) | p-value |
| Response rate [95% CI] (%) | |||
| > 1 s t -line therapy | 26.5 [18.98, 34.05] (n = 132) | 13.2 [7.54, 18.93] (n = 136) | 0.006 a |
| *Median time to disease progression [95% CI] (weeks) | |||
| > 1 s t -line therapy | 20.9 [15.7, 25.9] (n = 131) | 16.1 [15.0, 19.3] (n = 135) | 0.011 b |
| *Median progression free survival [95% CI] (weeks) | |||
| > 1 s t -line therapy | 20.6 [15.6, 25.9] (n = 131) | 16.1 [15.0, 18.3] (n = 135) | 0.010 b |
| *Survival [95% CI] (weeks) | |||
| > 1 s t -line therapy | 56.4 [45.1, 76.9] (n = 131) | 46.7 [39.0, 55.3] (n = 136) | 0.020 b |
*
This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005)
a
Chi-squared test
b
Log-rank test
Two hundred and twenty nine patients treated with Abraxane in the randomized, controlled clinical trial were evaluated for safety. Neurotoxicity to paclitaxel was evaluated through improvement by one grade for patients experiencing grade 3 peripheral neuropathy at any time during therapy. The natural course of peripheral neuropathy to resolution to baseline due to cumulative toxicity of Abraxane after > 6 courses of treatment was not evaluated and remains unknown.
Pancreatic adenocarcinoma
A multicenter, multinational, randomized, open-label study was conducted in 861 patients to compare Abraxane/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Abraxane was administered to patients (N = 431) as an intravenous infusion over 30-40 minutes at a dose of 125 mg/m2 followed by gemcitabine as an intravenous infusion over 30-40 minutes at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle. In the comparator treatment arm, gemcitabine monotherapy was administered to patients (N = 430) in accordance with the recommended dose and regimen. Treatment was administered until disease progression or development of an unacceptable toxicity. Of the 431 patients with pancreatic adenocarcinoma who were randomized to receive Abraxane in combination with gemcitabine, the majority (93%) were white, 4% were black and 2% were Asian. 16% had a Karnofsky Performance Status of 100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70; and <1% of patients had a KPS of below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or of connective tissue disorders and/or interstitial lung disease were excluded from the study. Patients received a median treatment duration of 3.9 months in the Abraxane/gemcitabine arm and 2.8 months in the gemcitabine arm. 32% of patients in the Abraxane/gemcitabine arm compared with 15% of patients in the gemcitabine arm received 6 or more months of treatment. For the treated population, the median relative dose intensity for gemcitabine was 75% in the Abraxane/gemcitabine arm and 85% in the gemcitabine arm. The median relative dose intensity of Abraxane was 81%. A higher median cumulative dose of gemcitabine was delivered in the Abraxane/gemcitabine arm (11400 mg/m2) when compared with the gemcitabine arm (9000 mg/m2). The primary efficacy endpoint was overall survival (OS). The key secondary endpoints were progression- free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST guidelines (Version 1.0).
| Abraxane(125 mg/m 2 )/gemcitabine (N=431) | Gemcitabine (N=430) | |||
| Overall Survival | ||||
| Number of deaths (%) | 333 (77) | 359 (83) | ||
| Median Overall Survival, months (95% CI) | 8.5 (7.89, 9.53) | 6.7 (6.01, 7.23) | ||
| HR A (95% CI) a +G/G | 0.72 (0.617, 0.835) | |||
| P-value b | <0.0001 | |||
| Survival Rate % (95% CI) at | ||||
| 1 Year | 35% (29.7, 39.5) | 22% (18.1, 26.7) | ||
| 2 Year | 9% (6.2, 13.1) | 4% (2.3, 7.2) | ||
| 75 t h Percentile Overall Survival (months) | 14.8 | 11.4 | ||
| Progression-free Survival | ||||
| Death or progression, n (%) | 277 (64) | 265 (62) | ||
| Median Progression-free Survival, months (95% CI) | 5.5 (4.47, 5.95) | 3.7 (3.61, 4.04) | ||
| HR A (95% CI) a +G/G | 0.69 (0.581, 0.821) | |||
| P-value b | <0.0001 | |||
| Overall Response Rate | ||||
| Confirmed complete or partial overall response, n (%) | 99 (23) | 31 (7) | ||
| 95% CI | 19.1, 27.2 | 5.0, 10.1 | ||
| p A +G /p G (95% CI) | 3.19 (2.178, 4.662) | |||
| P-value ( chi-square test) | <0.0001 | |||
CI = confidence interval, HRA+G/G = hazard ratio of Abraxane+gemcitabine/gemcitabine, pA+G/pG=response rate ratio of Abraxane+gemcitabine/gemcitabine
a
stratified Cox proportional hazard model
b
stratified log-rank test, stratified by geographic region (North America versus others), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no).
There was a statistically significant improvement in OS for patients treated with Abraxane/gemcitabine versus gemcitabine alone, with 1.8 months increase in median OS, 28% overall reduction in risk of death, 59% improvement in 1-year survival, and 125% improvement in 2-year survival rates.
ABRAXANE+Gemcitabine Gemcitabine
Proportion of Survival
Survival
0.5
0.4
0.3
0.2
0.1
0.0
(PT at Risk)
ABX/GEM:
GEM:
Time (months)
Treatment effects on OS favoured the Abraxane/gemcitabine arm across the majority of pre-specified subgroups (including gender, KPS, geographic region, primary location of pancreatic cancer, stage at diagnosis, presence of liver metastases, presence of peritoneal carcinomatosis, prior Whipple procedure, presence of biliary stent at baseline, presence of pulmonary metastases, and number of metastatic sites). For patients >= 75 years of age in the Abraxane/gemcitabine and gemcitabine arms the survival Hazard Ratio (HR) was 1.08 (95% CI 0.653, 1. 797). For patients with normal baseline CA 19-9 levels the survival HR was 1.07 (95% CI 0.692, 1.661). There was a statistically significant improvement in PFS for patients treated with Abraxane/gemcitabine versus gemcitabine alone, with 1.8 months increase in median PFS.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Abraxane in all subsets of the paediatric population in the treatment of metastatic breast cancer and pancreatic adenocarcinoma (see section 4.2 for information on paediatric use).
The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of Abraxane at dose levels of 80 to 375 mg/m2 were determined in clinical studies. The paclitaxel exposure (AUC) increased linearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m2. Following intravenous administration of Abraxane to patients with metastatic breast cancer at the recommended clinical dose of 260 mg/m2, paclitaxel plasma concentrations declined in a multiphasic manner. The mean Cmax of paclitaxel, which occurred at the end of the infusion, was 18.7 ug/ml. The mean total clearance was 15 l/hr/m2. The terminal half-life was about 27 hours. The mean volume of distribution was 632 l/m2; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel. In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel following Abraxane administered intravenously at 260 mg/m2 over 30 minutes were compared with those following 175 mg/m2 of the solvent-based paclitaxel injection administered over 3 hours. The clearance of paclitaxel with Abraxane was larger (43%) than that following a solvent-based paclitaxel injection and its volume of distribution was also higher (53%). Differences in Cmax and Cmax corrected for dose reflected differences in total dose and rate of infusion. There were no differences in terminal half-lives. In a repeat dose study with 12 patients receiving Abraxane administered intravenously at the approved dose, intrapatient variability in systemic paclitaxel exposure (AUCinf) was 19% (range = 3.21%-27.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses. An analysis of patient exposure (AUCinf) against bodyweight indicated a trend toward reduced AUC at 260 mg/m2 Abraxane, with decreased body weight. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is uncertain. The protein binding of paclitaxel following Abraxane was evaluated by ultrafiltration. The fraction of free paclitaxel was significantly higher with Abraxane (6.2%) than with solvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with Abraxane compared with solvent- based paclitaxel, even though the total exposure is comparable. This is possibly due to paclitaxel not being trapped in Cremophor EL micelles as with solvent-based paclitaxel. Based on the published literature, in vitro studies of binding to human serum proteins, (using paclitaxel at 6uM) the presence of ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. Based on the published literature, in vitro studies with human liver microsomes and tissue slices show that paclitaxel is metabolised primarily to 6-hydroxypaclitaxel; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6-3'-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites is catalysed by CYP2C8, -3A4, and both -2C8 and -3A4 respectively. The pharmacokinetic profile of Abraxane administered as a 30 minute infusion was evaluated in 15 out of 30 patients with three levels of hepatic impairment based on serum bilirubin and liver enzyme levels. Figure 2 shows the correlation between paclitaxel clearance and total blood bilirubin as measured just prior to dosing.
Paclitaxel clearance (ml/h/m2)
Cl_obs (ml/
hr/m * *2)
10 20 30 40 50 60 70 80 90
Tot /l)
Cycle 1 bilirubin
al bilirubin (umol The effect of renal dysfunction on the disposition of paclitaxel has not been formally investigated. In patients with metastatic breast cancer, after a 30 minute infusion of Abraxane at 260 mg/m2, the mean value for cumulative urinary excretion of unchanged active substance accounted for 4% of the total administered dose with less than 1% as the metabolites 6-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel, indicating extensive non-renal clearance. Paclitaxel is principally eliminated by hepatic metabolism and biliary excretion. Pharmacokinetics of paclitaxel in patients aged over 65 years seems comparable to that in patients less than 65 years. However, little information in patients over 75 years is available as only 3 patients over 75 years of age where included in the pharmacokinetic analysis.
The carcinogenic potential of paclitaxel has not been studied. However, based on the published literature, paclitaxel is a potentially carcinogenic and genotoxic agent at clinical doses, based upon its pharmacodynamic mechanism of action. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel has been shown to be genotoxic in vivo (micronucleus test in mice), but it did not induce mutagenicity in the Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) gene mutation assay. Paclitaxel at doses below the human therapeutic dose was associated with low fertility and foetal toxicity in rats. Animal studies with Abraxane showed non-reversible, toxic effects on the male reproductive organs at clinically relevant exposure levels.
Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL tryptophanate).
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Unopened vials
3 years
Stability of reconstituted suspension in the vial
After first reconstitution, the suspension should be filled into an infusion bag immediately. However, chemical and physical in use stability has been demonstrated for 8 hours at 2degC-8degC in the original carton, and protected from bright light. Alternative light-protection may be used in the clean room.
Stability of the reconstituted suspension in the infusion bag
After reconstitution, the reconstituted suspension in the infusion bag should be used immediately. However chemical and physical in use stability has been demonstrated for 8 hours not above 25degC.
Unopened vials
Keep the vial in the outer carton in order to protect from light.
Reconstituted suspension
For storage conditions after reconstitution of the medicinal product, see section 6.3.
50 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 100 mg of paclitaxel formulated as albumin bound nanoparticles. 100 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 250 mg of paclitaxel formulated as albumin bound nanoparticles. Pack size of one vial.
Preparation and administration precautions
Paclitaxel is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, caution should be exercised in handling Abraxane. The use of gloves, goggles and protective clothing is recommended. If the suspension contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Abraxane should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant staff should not handle Abraxane. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during administration of the medicinal product. Limiting the infusion of Abraxane to 30 minutes, as directed, reduces the likelihood of infusion-related reactions.
Reconstitution and administration of the product
Abraxane is supplied as a sterile lyophilised powder for reconstitution before use. After reconstitution, each ml of suspension contains 5 mg of paclitaxel formulated as albumin bound nanoparticles.
100 mg vial:
Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be injected into a vial of Abraxane over a minimum of 1 minute.
250 mg vial:
Using a sterile syringe, 50 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be injected into a vial of Abraxane over a minimum of 1 minute.
The solution should be directed onto the inside wall of the vial. The solution should not be injected directly onto the powder as this will result in foaming. Once the addition is complete, the vial should be allowed to stand for a minimum of 5 minutes to ensure proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least 2 minutes until complete resuspension of any powder occurs. The generation of foam must be avoided. If foaming or clumping occurs, the solution must stand for at least 15 minutes until foam subsides. The reconstituted suspension should be milky and homogenous without visible precipitates. Some settling of the reconstituted suspension may occur. If precipitates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Inspect the suspension in the vial for particulate matter. Do not administer the reconstituted suspension if particulate matter is observed in the vial. The exact total dosing volume of 5 mg/ml suspension required for the patient should be calculated and the appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or non-PVC type intravenous bag. The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute and administer Abraxane may result in the formation of proteinaceous strands. Administer Abraxane using an infusion set incorporating a 15 um filter to avoid administration of these strands. Use of a 15 um filter removes strands and does not change the physical or chemical properties of the reconstituted product. Use of filters with a pore size less than 15 um may result in blockage of the filter. The use of specialized di(2-ethylhexyl)phthalate (DEHP)-free solution containers or administration sets is not necessary to prepare or administer Abraxane infusions. Any unused product or waste material should be disposed of in accordance with local requirements.
Celgene Europe Limited 1 Longwalk Road Stockley Park Uxbridge UB11 1DB United Kingdom
EU/1/07/428/001 EU/1/07/428/002
Date of first authorisation: 11 January 2008 Date of latest renewal: 11 January 2013
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu