post-title portfolio-title Paclitaxel (protein-bound particles) powder for suspension for infusion 100mg Taj Pharma 2020-01-25 10:26:20 no no

Paclitaxel (protein-bound particles) powder for suspension for infusion 100mg Taj Pharma

  1. NAME OF THE MEDICINAL PRODUCT

Paclitaxel (protein-bound particles) powder for suspension for infusion 100mg Taj Pharma
Paclitaxel (protein-bound particles) powder for suspension for infusion 250mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Each vial contains 100 mg of paclitaxel formulated as albumin-bound nanoparticles.
b) 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.

For the full list of excipients, see section 6.1.

  1. PHARMACEUTICAL FORM

Powder for suspension for infusion.

  1. CLINICAL PARTICULARS


4.1 Therapeutic indications
Paclitaxelmonotherapy 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).

Paclitaxel in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas.

Paclitaxel in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.

4.2 Posology and method of administration

Paclitaxelshould 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 Paclitaxelis 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 Paclitaxeltherapy 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. Paclitaxelshould 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 Paclitaxelin 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 Paclitaxeladministration on Days 1, 8 and 15 of each 28-day cycle.

Dose adjustments during treatment of pancreatic adenocarcinoma

Table 1: Dose level reductions for patients with pancreatic adenocarcinoma

Dose Level PaclitaxelDose (mg/m2) Gemcitabine Dose (mg/m2)
Full dose 125 1000
1st?dose level reduction 100 800
2nd?dose level reduction 75 600
If additional dose reduction required Discontinue treatment Discontinue treatment

Table 2: Dose modifications for neutropenia and/or thrombocytopenia at the start of a cycle or within a cycle for patients with pancreatic adenocarcinoma

Cycle Day ANC count (cells/mm3) Platelet count (cells/mm3) PaclitaxelDose 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

Table 3: Dose modifications for other adverse drug reactions in patients with pancreatic adenocarcinoma

Adverse Drug Reaction (ADR) PaclitaxelDose Gemcitabine Dose
Febrile Neutropenia:

Grade 3 or 4

Withhold doses until fever resolves and ANC ? 1500; resume at next lower dose levela
Peripheral Neuropathy:

Grade 3 or 4

Withhold dose until improves to ? Grade 1; resume at next lower dose levela Treat with same dose
Cutaneous Toxicity:

Grade 2 or 3

Reduce to next lower dose levela; discontinue treatment if ADR persists
Gastrointestinal Toxicity:

Grade 3 mucositis or diarrhoea

Withhold doses until improves to ? Grade 1; resume at next lower dose levela
  1. See Table 1 for dose level reductions

Non-small cell lung cancer:

The recommended dose of Paclitaxelis 100 mg/m2?administered as an intravenous infusion over 30 minutes on Days 1, 8 and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg?min/mL on Day 1 only of each 21-day cycle, beginning immediately after the end of Paclitaxeladministration.

Dose adjustments during treatment of non-small cell lung cancer:

Paclitaxel should not be administered on Day 1 of a cycle until absolute neutrophil count (ANC) is ?1500 cells/mm3?and platelet count is ?100,000 cells/mm3. For each subsequent weekly dose of Abraxane, patients must have an ANC ?500 cells/mm3?and platelets >50,000 cells/mm3?or the dose is to be withheld until counts recover. When counts recover, resume dosing the following week according to the criteria in Table 4. Reduce subsequent dose only if criteria in Table 4 are met.

Table 4: Dose reductions for haematologic toxicities in patients with non-small cell lung cancer

Haematologic Toxicity Occurrence Dose of Abraxane

(mg/m2)1

Dose of carboplatin

(AUC mg?min/mL)1

Nadir ANC <500/mm3?with neutropenic fever > 38?C

OR

Delay of next cycle due to persistent neutropenia2?(Nadir ANC <1500/mm3)

OR

Nadir ANC <500/mm3?for > 1 week

First 75 4.5
Second 50 3.0
Third Discontinue Treatment
Nadir platelets <50,000/mm3 First 75 4.5
Second Discontinue Treatment

1On Day 1 of the 21-day cycle reduce the dose of Paclitaxeland carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Abraxane; reduce the dose of carboplatin in the subsequent cycle.

2Maximum of 7 days post scheduled Day 1 dose of next cycle.

For Grade 2 or 3 cutaneous toxicity, Grade 3 diarrhoea, or Grade 3 mucositis, interrupt treatment until the toxicity improves to ? Grade 1, then restart treatment according to the guidelines in Table 5. For ? Grade 3 peripheral neuropathy, withhold treatment until resolution to ? Grade 1. Treatment may be resumed at the next lower dose level in subsequent cycles according to the guidelines in Table 5. For any other Grade 3 or 4 non-haematologic toxicity, interrupt treatment until the toxicity improves to ? Grade 2, then restart treatment according to the guidelines in Table 5.

Table 5: Dose reductions for non-haematologic toxicities in patients with non-small cell lung cancer

Non-haematologic Toxicity Occurrence Dose of Abraxane

(mg/m2)1

Dose of carboplatin

(AUC mg?min/mL)1

Grade 2 or 3 cutaneous toxicity

Grade 3 diarrhoea

Grade 3 mucositis

? Grade 3 peripheral neuropathy

Any other Grade 3 or 4 non-haematologic toxicity

First 75 4.5
Second 50 3.0
Third Discontinue Treatment
Grade 4 cutaneous toxicity, diarrhoea, or mucositis First Discontinue Treatment

1On Day 1 of the 21-day cycle reduce the dose of Paclitaxeland carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Abraxane; reduce the dose of carboplatin in the subsequent cycle.

Special populations

Patients with hepatic impairment

For patients with mild hepatic impairment (total bilirubin > 1 to ? 1.5 x ULN and aspartate aminotransferase [AST] ? 10 x ULN), no dose adjustments are required, regardless of indication. Treat with same doses as patients with normal hepatic function.

For metastatic breast cancer patients and non-small cell lung cancer patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to ? 5 x ULN and AST ? 10 x ULN), a 20% reduction in dose is recommended. The reduced dose may be escalated to the dose for patients with normal hepatic function if the patient is tolerating the treatment for at least two cycles (see sections 4.4 and 5.2).

For patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment, there are insufficient data to permit dosage recommendations (see sections 4.4 and 5.2).

For patients with total bilirubin > 5 x ULN or AST > 10 x ULN, there are insufficient data to permit dosage recommendations regardless of indication (see sections 4.4 and 5.2).

Patients with renal impairment

Adjustment of the starting Paclitaxeldose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ?30 to <90 ml/min). There are insufficient data available to recommend dose modifications of Paclitaxelin patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 ml/min) (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 Paclitaxelmonotherapy 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. However, a subsequent analysis in 981 patients receiving Paclitaxelmonotherapy for metastatic breast cancer, of which 15% were ? 65 years old and 2% were ? 75 years old, showed a higher incidence of epistaxis, diarrhoea, dehydration, fatigue and peripheral oedema in patients ? 65 years.

Of the 421 patients with pancreatic adenocarcinoma in the randomized study who received Paclitaxelin 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 Paclitaxeland 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).

Of the 514 patients with non-small cell lung cancer in the randomized study who received Paclitaxelin combination with carboplatin, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression events, peripheral neuropathy events, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years of age. There is limited experience of Abraxane/carboplatin use in patients 75 years or older.

Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumours indicates that patients ? 65 years of age may be more susceptible to development of neutropenia within the first treatment cycle.

Paediatric population

The safety and efficacy of Paclitaxelin children and adolescents aged 0-17 years has not been established. There is no relevant use of Paclitaxelin the paediatric population in the indication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lung cancer.

Method of administration

Administer reconstituted Paclitaxelsuspension intravenously using an infusion set incorporating a 15 ?m filter. Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete dose.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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.

4.4 Special warnings and precautions for use

Paclitaxelis 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 Paclitaxeltherapy. Patients should not be retreated with subsequent cycles of Paclitaxeluntil 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 Paclitaxelis 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 Paclitaxelis recommended (see section 4.2). For combination use of Paclitaxeland gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine at the same dose. Resume Paclitaxelat reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2). For combination use of Paclitaxeland carboplatin, if Grade 3 or higher peripheral neuropathy develops, treatment should be withheld until improvement to Grade 0 or 1 followed by a dose reduction for all subsequent courses of Paclitaxeland carboplatin (see section 4.2).

Sepsis

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Paclitaxelin 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 Paclitaxeland 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 Paclitaxelwas used as monotherapy and in 4% of patients when Paclitaxelwas 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 Paclitaxeland 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 Paclitaxelin patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.

Paclitaxelis not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, Paclitaxelis not recommended in patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ? 10 x ULN) (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 Paclitaxelshould be vigilantly monitored by physicians for the occurrence of cardiac events.

CNS metastases

The effectiveness and safety of Paclitaxelin 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 Paclitaxeland gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (?75 years) who received Paclitaxeland 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 Paclitaxelin 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 Paclitaxeland gemcitabine (see section 5.1).

Erlotinib should not be coadministered with Paclitaxelplus gemcitabine (see section 4.5).

Excipients

When reconstituted, each ml of Paclitaxelconcentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, in the absence of a PK drug-drug interaction study, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.

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 Paclitaxeland gemcitabine have not been evaluated in humans.

A pharmacokinetic study was conducted with Paclitaxeland carboplatin in non-small cell lung cancer patients. There were no clinically relevant pharmacokinetic interactions between Paclitaxeland carboplatin.

Paclitaxelis indicated as monotherapy for breast cancer, in combination with gemcitabine for pancreatic adenocarcinoma, or in combination with carboplatin for non-small cell lung cancer (see section 4.1). Paclitaxelshould not be used in combination with other anticancer agents.

4.6 Fertility, pregnancy and lactation

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 Paclitaxelare advised to use effective contraception and to avoid fathering 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). Women of childbearing potential should have a pregnancy test prior to starting treatment with Abraxane. Paclitaxelshould 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

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see section 5.3). It is not known if paclitaxel is excreted in human milk. Because of potential serious adverse reactions in breast-feeding infants, Paclitaxelis contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy.

Fertility

Paclitaxelinduced infertility in male rats (see section 5.3). Based on findings in animals, male and female fertility may be compromised. Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Abraxane.

4.7 Effects on ability to drive and use machines

Paclitaxelhas minor or moderate influence on the ability to drive and use machines. Paclitaxelmay 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.

4.8 Undesirable effects

Summary of the safety profile

The most common clinically significant adverse reactions associated with the use of Paclitaxelhave been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

The frequencies of adverse reactions associated with the administration of Paclitaxelare listed in Table 6 (Paclitaxelas monotherapy) and Table 7 (Paclitaxelin combination with gemcitabine), and Table 9 (Paclitaxelin combination with carboplatin).

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 (Paclitaxeladministered as monotherapy)

Tabulated list of adverse reactions

Table 6 lists adverse reactions associated with the administration of Paclitaxelto patients from studies in which Paclitaxelhas been administered as monotherapy at any dose in any indication (N = 789).

Table 6: Adverse reactions reported with Paclitaxelmonotherapy 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, sepsis2, neutropenic sepsis2

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 Uncommon1😕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 oedema2

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 block2

Vascular disorders Common: Flushing, hot flushes, hypertension, lymphoedema

Uncommon: Hypotension, peripheral coldness, orthostatic hypotension

Rare:?Thrombosis

Respiratory, thoracic and mediastinal disorders Common: Interstitial pneumonitis3, 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 syndrome2, toxic epidermal necrolysis2

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.

1?The frequency of hypersensitivity reactions is calculated based on one definitely related case in a population of 789 patients.

2?As reported in the post-marketing surveillance of Abraxane.

3?The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Paclitaxelmonotherapy 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?Paclitaxelonce 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 Paclitaxelwith 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 Paclitaxeland was severe in 6% of cases. Myalgia occurred in 24% of patients on Paclitaxeland was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after Paclitaxeladministration and resolved within a week.

General disorders and administration site conditions

Asthenia/Fatigue was reported in 40% of the patients.

Pancreatic adenocarcinoma (Paclitaxeladministered in combination with gemcitabine)

Tabulated list of adverse reactions

Adverse reactions were assessed in 421 patients treated with Paclitaxelin 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 7 lists adverse reactions assessed in patients with pancreatic adenocarcinoma treated with Paclitaxelin combination with gemcitabine.

Table 7: Adverse reactions reported with Paclitaxelin 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 neuropathy1, dysgeusia, headache, dizziness

Uncommon: VIIth?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: Pneumonitis2, 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).

1?Peripheral neuropathy evaluated using the SMQ (broad scope).

2?Pneumonitis is evaluated using the SMQ interstitial lung disease (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 Paclitaxelin 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?Paclitaxelin 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 8 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with Paclitaxelin combination with gemcitabine or with gemcitabine.

Table 8: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial

Abraxane(125 mg/m2)/ Gemcitabine Gemcitabine
Grades 1-4

(%)

Grade 3-4

(%)

Grades 1-4

(%)

Grade 3-4

(%)

Anaemiaa,b 97 13 96 12
Neutropenia?a,b 73 38 58 27
Thrombocytopeniab,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 Paclitaxelin 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 Paclitaxelat a reduced dose. No patients treated with Paclitaxelin 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 Paclitaxelin 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 Paclitaxeland 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 Paclitaxelin combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with Paclitaxelin 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 Paclitaxeland gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).

Non-small cell lung cancer (Paclitaxeladministered in combination with carboplatin)

Tabulated list of adverse reactions

Table 9 lists adverse reactions associated with the administration of Paclitaxelin combination with carboplatin.

Table 9: Adverse reactions reported with Paclitaxelin combination with carboplatin (N = 514)

Infections and infestations Common:?Pneumonia, bronchitis, upper respiratory tract infection, urinary tract infection

Uncommon:?Sepsis, oral candidiasis

Blood and lymphatic system disorders1 Very common:?Neutropenia1, thrombocytopenia1, anaemia1, leukopenia1

Common:?Febrile neutropenia, lymphopenia

Uncommon:?Pancytopenia

Immune system disorders Uncommon:?Drug hypersensitivity, hypersensitivity
Metabolism and nutrition disorders Very common:?Decreased appetite

Common:?Dehydration

Psychiatric disorders Common:?Insomnia
Nervous system disorders Very common:?Peripheral neuropathy2

Common:?Dysgeusia, headache, dizziness

Eye disorders Common:?Vision blurred
Vascular disorders Common:?Hypotension, hypertension

Uncommon:?Flushing

Respiratory thoracic and mediastinal disorders Very common:?Dyspnoea

Common:?Haemoptysis, epistaxis, cough

Uncommon:?Pneumonitis3

Gastrointestinal disorders Very common:?Diarrhoea, vomiting, nausea, constipation

Common:?Stomatitis, dyspepsia, abdominal pain, dysphagia

Hepatobiliary disordesrs Common:?Hyperbilirubinaemia
Skin and subcutaneous tissue disorders Very common:?Rash, alopecia

Common:?Pruritus, nail disorder

Uncommon:?Skin exfoliation, dermatitis allergic, urticaria

Musculoskeletal and connective tissue disorders Very common:?Arthralgia, myalgia

Common:?Back pain, pain in extremity, musculoskeletal pain

General disorders and administration site conditions Very common:?Fatigue, asthenia, oedema peripheral

Common: Pyrexia, chest pain

Uncommon:?Mucosal inflammation, infusion site extravasation, infusion site inflammation, infusion site rash

Investigations Common:?Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, weight decreased

MedDRA = Medical Dictionary for Regulatory Activities: SMQ = Standardized MedDRA Query

1?Based on laboratory assessments: maximal degree of myelosuppression (treated population)

2?Peripheral neuropathy is evaluated using the SMQ neuropathy (broad scope)

3?Pneumonitis is evaluated using the SMQ interstitial lung disease (broad scope)

For non-small cell lung cancer patients treated with Paclitaxeland carboplatin, the median time to first occurrence of Grade 3 treatment related peripheral neuropathy was 121 days, and the median time to improvement from Grade 3 treatment related peripheral neuropathy to Grade 1 was 38 days. No patients treated with Paclitaxeland carboplatin experienced Grade 4 peripheral neuropathy.

Anemia and thrombocytopenia were more commonly reported in the Paclitaxelarm than in the Taxol arm (54% versus 28% and 45% versus 27% respectively).

Patient-reported taxane toxicity was assessed using the 4 subscales of the Functional Assessment of Cancer Therapy (FACT)-Taxane questionnaire. Using repeated measure analysis, 3 of the 4 subscales (peripheral neuropathy, pain hands/feet, and hearing) favored Paclitaxeland carboplatin (p ? 0.002). For the other subscale (oedema), there was no difference in the treatment arms.

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 Paclitaxelshould be discontinued.

There have been reports of tumour lysis syndrome during treatment with Abraxane.

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.

4.9 Overdose

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.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, taxanes,

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.

Paclitaxelcontains 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 Paclitaxelenhances 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 Paclitaxelin metastatic breast cancer. This information is presented below.

Single-arm open-label studies

In one study, Paclitaxelwas 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 Paclitaxel260 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.

Table 10: Results for overall response rate, median time to disease progression, and progression-free survival as assessed by the investigator
Efficacy variable Abraxane

(260 mg/m2)

Solvent-based paclitaxel

(175 mg/m2)

p-value
Response rate [95% CI] (%)
> 1st-line therapy 26.5 [18.98, 34.05] (n = 132) 13.2 [7.54, 18.93] (n = 136) 0.006a
*Median time to disease progression [95% CI] (weeks)
> 1st-line therapy 20.9 [15.7, 25.9] (n = 131) 16.1 [15.0, 19.3] (n = 135) 0.011b
*Median progression free survival [95% CI] (weeks)
> 1st-line therapy 20.6 [15.6, 25.9] (n = 131) 16.1 [15.0, 18.3] (n = 135) 0.010b
*Survival [95% CI] (weeks)
> 1st-line therapy 56.4 [45.1, 76.9] (n = 131) 46.7 [39.0, 55.3] (n = 136) 0.020b

*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 Paclitaxelin 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 Paclitaxelafter > 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. Paclitaxelwas 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 Paclitaxelin 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 Paclitaxelwas 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).

Table 11: Efficacy results from randomized study in patients with pancreatic adenocarcinoma (Intent-to-treat population)

Abraxane(125 mg/m2)/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)
HRA+G/G?(95% CI)a 0.72 (0.617, 0.835)
P-valueb <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)
75th?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)
HRA+G/G?(95% CI)a 0.69 (0.581, 0.821)
P-valueb <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
pA+G/pG?(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.

Figure 1: Kaplan-Meier curve of overall survival (intent-to-treat population)

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.

Non-small cell lung cancer

A multicenter, randomized, open-label study was conducted in 1052 chemotherapy-naive patients with Stage IIIb/IV non-small cell lung cancer. The study compared Paclitaxelin combination with carboplatin versus solvent-based paclitaxel in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. Over 99% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patients with pre-existing neuropathy of Grade ? 2 or serious medical risk factors involving any of the major organ systems were excluded. Paclitaxelwas administered to patients (N=521) as an intravenous infusion over 30 minutes at a dose of 100 mg/m2?on Days 1, 8 and 15 of each 21-day cycle without any steroid premedication and without granulocyte colony stimulating factor prophylaxis. Beginning immediately after the end of Paclitaxeladministration, carboplatin at a dose of AUC = 6 mg?min/mL was administered intravenously on Day 1 only of each 21-day cycle. Solvent-based paclitaxel was administered to patients (N=531) at a dose of 200 mg/m2?as an intravenous infusion over 3 hours with standard premedication, immediately followed by carboplatin administered intravenously at AUC = 6 mg?min/mL. Each drug was administered on Day 1 of each 21-day cycle. In both study arms treatment was administered until disease progression or development of an unacceptable toxicity. Patients received a median of 6 cycles of treatment in both study arms.

The primary efficacy endpoint was overall response rate defined as the percentage of patients who achieved an objective confirmed complete response or partial response based on an independent, central, blinded radiological review using RECIST (Version 1.0). Patients in the Abraxane/carboplatin arm had a significantly higher overall response rate compared with patients in the control arm: 33% versus 25%, p = 0.005 (Table 12). There was a significant difference in overall response rate in the Abraxane/carboplatin arm compared to the control arm in patients with non-small cell lung cancer of squamous histology (N=450, 41% vs. 24%, p<0.001), however this difference did not translate into a difference in PFS or OS. There was no difference in ORR between the treatment arms in patients with non-squamous histology (N=602, 26% vs 25%, p=0.808).

Table 12: Overall response rate in randomized non-small cell lung cancer trial (intent-to-treat population)

Efficacy Parameter Paclitaxel(100 mg/m2/week) + carboplatin

(N=521)

Solvent-based paclitaxel (200 mg/m2?every 3 weeks) + carboplatin

(N=531)

Overall Response Rate (independent review)
Confirmed complete or partial overall response, n (%) 170 (33%) 132 (25%)
95% CI (%) 28.6, 36.7 21.2, 28.5
pA/pT?(95.1% CI) 1.313 (1.082, 1.593)
P-valuea 0.005

CI = confidence interval; HRA/T?= hazard ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin; pA/pT?= response rate ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin.

a?P-value is based on a chi-square test.

There was no statistically significant difference in progression-free survival (by blinded radiologist assessment) and overall survival between the two treatment arms. A non-inferiority analysis was conducted for PFS and OS, with a pre-specified non-inferiority margin of 15%. The non-inferiority criterion was met for both PFS and OS with the upper bound of the 95% confidence interval for the associated hazard ratios being less than 1.176 (Table 13).

Table 13: Non-inferiority analyses on progression-free survival and overall survival in randomized non-small cell lung cancer trial (intent-to-treat population)

Efficacy Parameter Paclitaxel(100 mg/m2/week) + carboplatin

(N=521)

Solvent-based paclitaxel (200 mg/m2?every 3 weeks) + carboplatin

(N=531)

Progression-free Survivala?(independent review)
Death or progression, n (%) 429 (82%) 442 (83%)
Median PFS (95% CI) (months) 6.8 (5.7, 7.7) 6.5 (5.7, 6.9)
HRA/T?(95% CI) 0.949 (0.830, 1.086)
Overall Survival
Number of deaths, n (%) 360 (69%) 384 (72%)
Median OS (95% CI) (months) 12.1 (10.8, 12.9) 11.2 (10.3, 12.6)
HRA/T?(95.1% CI) 0.922 (0.797, 1.066)

CI = confidence interval; HRA/T?= hazard ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin; pA/pT?= response rate ratio of Abraxane/carboplatin to solvent-based paclitaxel/carboplatin.

a?Per EMA methodological considerations for PFS endpoint, missing observations or initiation of subsequent new therapy were not used for censoring.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Paclitaxelin all subsets of the paediatric population in the treatment of metastatic breast cancer, pancreatic adenocarcinoma and non-small cell lung cancer (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of Paclitaxelat 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.

In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel following Paclitaxeladministered 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. Based on non-compartmental PK analysis, the plasma clearance of paclitaxel with Paclitaxelwas larger (43%) than that following a solvent-based paclitaxel injection and its volume of distribution was also higher (53%). There were no differences in terminal half-lives.

In a repeat dose study with 12 patients receiving Paclitaxeladministered intravenously at 260 mg/m2, intrapatient variability in AUC was 19% (range = 3.21%-37.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses.

Distribution

Following Paclitaxeladministration to patients with solid tumours, paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%).

The protein binding of paclitaxel following Paclitaxelwas evaluated by ultrafiltration in a within-patient comparison study. The fraction of free paclitaxel was significantly higher with Paclitaxel(6.2%) than with solvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with Paclitaxelcompared 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 concentrations ranging from 0.1 to 50 ?g/ml), indicate that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

Based on population pharmacokinetic analysis, the total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.

Biotransformation and elimination

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, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively.

In patients with metastatic breast cancer, after a 30-minute infusion of Paclitaxelat 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.

At the clinical dose range of 80 to 300 mg/m2, the mean plasma clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.

Hepatic impairment

The effect of hepatic impairment on population pharmacokinetics of Paclitaxelwas studied in patients with advanced solid tumours. This analysis included patients with normal hepatic function (n=130), and pre-existing mild (n=8), moderate (n=7), or severe (n=5) hepatic impairment (according to NCI Organ Dysfunction Working Group criteria). The results show that mild hepatic impairment (total bilirubin >1 to ?1.5 x ULN) has no clinically important effect on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin >1.5 to ?3 x ULN) or severe (total bilirubin >3 to ?5 x ULN) hepatic impairment have a 22% to 26% decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared with patients with normal hepatic function. Hepatic impairment has no effect on mean paclitaxel Cmax. In addition, elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive correlation with serum albumin.

Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepatic function (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting for Paclitaxelexposure.

Pharmacokinetic data are not available for patients with total bilirubin >5 x ULN or for patients with metastatic adenocarcinoma of the pancreas (see section 4.2).

Renal impairment

Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existing mild (n=61), moderate (n=23), or severe (n=l) renal impairment (according to draft FDA guidance criteria 2010). Mild to moderate renal impairment (creatinine clearance ?30 to <90 ml/min) has no clinically important effect on the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel. Pharmacokinetic data are insufficient for patients with severe renal impairment and not available for patients with end stage kidney disease.

Older people

Population pharmacokinetic analysis for Paclitaxelincluded patients with ages ranging from 24 to 85 years old and shows that age does not significantly influence the maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.

Pharmacokinetic/pharmacodynamic modelling using data from 125 patients with advanced solid tumours indicates that patients ? 65 years of age may be more susceptible to development of neutropenia within the first treatment cycle, although the plasma paclitaxel exposure is not affected by age.

Other intrinsic factors

Population pharmacokinetic analyses for Paclitaxelindicate that gender, race (Asian vs. White), and type of solid tumours do not have a clinically important effect on systemic exposure (AUC and Cmax) of paclitaxel. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is uncertain.

5.3 Preclinical safety data

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 when administered prior and during mating in male and female rats and foetal toxicity in rats. Animal studies with Paclitaxelshowed non-reversible, toxic effects on the male reproductive organs at clinically relevant exposure levels.

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Following intravenous administration of radiolabelled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.

  1. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL tryptophanate).

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials

2 years

Stability of reconstituted suspension in the vial

Chemical and physical in-use stability has been demonstrated for 24 hours at 2?C-8?C in the original carton, protected from light.

Stability of the reconstituted suspension in the infusion bag

Chemical and physical in-use stability has been demonstrated for 24 hours at 2?C-8?C followed by 4 hours at 25?C, protected from light.

However, from a microbiological point of view, unless the method of reconstituting and filling of the infusion bags precludes the risks of microbial contamination, the product should be used immediately after reconstitution and filling of the infusion bags.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

The total combined storage time of reconstituted medicinal product in the vial and in the infusion bag when refrigerated and protected from light is 24 hours. This may be followed by storage in the infusion bag for 4 hours below 25?C.

6.4 Special precautions for storage

Unopened vials

Keep the vial in the outer carton in order to protect from light. Neither freezing nor refrigeration adversely affects the stability of the product. This medicinal product does not require any special temperature storage conditions.

Reconstituted suspension

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

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. Paclitaxelshould 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 Paclitaxelto 30 minutes, as directed, reduces the likelihood of infusion-related reactions.

Reconstitution and administration of the product

Paclitaxelis 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 Paclitaxelover 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 Paclitaxelover 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 Paclitaxelshould 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 Paclitaxelmay result in the formation of proteinaceous strands. Administer Paclitaxelusing an infusion set incorporating a 15 ?m filter to avoid administration of these strands. Use of a 15 ?m 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 ?m 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 Paclitaxelinfusions.

Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete dose.

Any unused product or waste material should be disposed of in accordance with local requirements.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Paclitaxel (protein-bound particles) powder for suspension for infusion 100mg/250mg Taj Pharma

Package leaflet: Information for the user

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
Keep this leaflet. You may need to read it
If you have any further questions, ask your doctor or
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section

What is in this leaflet:

  1. What Paclitaxel is and what it is used for
    2. What you need to know before you are given Paclitaxel
    3. How to use Paclitaxel
    4. Possible side effects
    5. How to store Paclitaxel
    6. Contents of the pack and other information

 

  1. WHAT PACLITAXEL IS AND WHAT IT IS USED FOR

What Paclitaxel is

Paclitaxel contains, as its active substance, paclitaxel attached to the human protein albumin, in the form of tiny particles known as nanoparticles. Paclitaxel belongs to a group of medicines called ?taxanes? used in cancer.

  • Paclitaxel is the part of the medicine that affects the cancer, it works by stopping cancer cells from dividing ? this means that they die.
  • Albumin is the part of the medicine that helps paclitaxel dissolve in the blood and get across the walls of the blood vessels into the tumour. This means that other chemicals that can cause side effects that can be life threatening are not needed. Such side effects occur far less with Paclitaxel.

What Paclitaxel is used for

Paclitaxel is used to treat the following types of cancer:

Breast Cancer

  • Breast cancer which has spread to other parts of the body (this is called ?metastatic? breast cancer).
  • Paclitaxel is used in metastatic breast cancer when at least one other therapy has been tried but has not worked and you are unsuitable for treatments containing a group of medicines called

?anthracyclines?.

  • People with metastatic breast cancer who received Paclitaxel where another therapy had failed, were more likely to experience a reduction in tumour size, and lived longer than people who took an alternative therapy.

Pancreatic cancer

Paclitaxel is used together with a medicine called gemcitabine if you have metastatic cancer of the pancreas. People with metastatic pancreatic cancer (pancreatic cancer that has spread to other parts of the body) who received Paclitaxel with gemcitabine in a clinical trial lived longer than people who had only received gemcitabine.

Lung Cancer

  • Paclitaxel is also used together with a medicine called carboplatin if you have the most common type of lung cancer, called ?non-small cell lung cancer?.
  • Paclitaxel is used in non-small cell lung cancer where surgery or radiotherapy would not be suitable to treat the
  1. WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN PACLITAXEL

Do not use Paclitaxel

  • if you are allergic (hypersensitive) to paclitaxel or any of the other ingredients of Paclitaxel (listed in

section 6);

  • if you are breast-feeding;
  • if you have a low white blood cell count (baseline neutrophil counts <1500 cells/mm3 – your doctor will advise you on this).

Warnings and precautions

Talk to your doctor or nurse before using Paclitaxel

  • if you have poor kidney function;
  • if you have severe liver problems;
  • if you have heart problems.

Talk to your doctor or nurse if you experience any of these conditions whilst being treated with Paclitaxel, your doctor may wish to stop treatment or reduce the dose:

  • if you experience any abnormal bruising, bleeding, or signs of infections such as a sore throat or a fever;
  • if you experience numbness, tingling, pricking sensations, sensitivity to touch, or muscle weakness;
  • if you experience breathing problems, like shortness of breath or dry cough.

Children and adolescents

This medicine has not been studied in children and adolescents, as breast cancer, pancreatic cancer and lung cancer do not occur in these age groups.

Other medicines and Paclitaxel

Tell your doctor if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, including herbal medicines. This is because Paclitaxel can affect the way some other medicines work. Also, some other medicines can affect the way Paclitaxel works.

Take care and speak to your doctor when taking Paclitaxel at the same time as any of the following:

  • medicines for treating infections (i.e. antibiotics such erythromycin, rifampicin, etc.; ask your doctor, nurse or pharmacist if you are unsure whether the medicine you are taking is an antibiotic), and including medicines for treating fungal infections (e.g. ketoconazole)
  • medicines used to help you stabilize your mood also sometimes referred to as anti-depressants (e.g. fluoxetine)
  • medicines used to treat seizures (epilepsy) (e.g. carbamazepine, phenytoin)
  • medicines used to help you lower blood lipid levels (e.g. gemfibrozil)
  • medicine used for heartburn or stomach ulcers (e.g. cimetidine)
  • medicines used to treat HIV and AIDS (e.g. ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, nevirapine)
  • a medicine called clopidogrel used to prevent blood clots.

Pregnancy breast-feeding and fertility

Paclitaxel may cause serious birth defects and should therefore not be used if you are pregnant. Your doctor will arrange a pregnancy test before starting treatment with Paclitaxel.

Women of childbearing age should use effective contraception during and up to 1 month after receiving treatment with Paclitaxel.

Do not breast feed when taking Paclitaxel as it is not known if the active ingredient paclitaxel passes into the mother?s milk.

Male patients are advised to use effective contraception and to avoid fathering a child during and up to six months after treatment and should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Paclitaxel.

Ask your doctor for advice before taking this medicine.

Driving and using machines

Some people may feel tired or dizzy after being given Paclitaxel. If this happens to you, do not drive or use any tools or machines.

If you are given other medicines as part of your treatment, you should ask your doctor for advice on driving and using machines.

Paclitaxel contains sodium

Each ml of Paclitaxel contains approximately 4.2 mg of sodium. This should be taken into consideration if you are on a controlled sodium diet.

  1. HOW TO USE PACLITAXEL

Paclitaxel will be given to you by a doctor or nurse into a vein from an intravenous drip. The dose you receive is based on your body surface area and blood test results. The usual dose is for breast cancer is 260 mg/m2 of body surface area given over a 30 minute period. The usual dose for advanced pancreatic

cancer is 125 mg/m2 of body surface area given over a 30 minute period. The usual dose for non-small cell lung cancer is 100 mg/m2 of body surface area given over a 30 minute period.

How often will you receive Paclitaxel?

For treatment of metastatic breast cancer, Paclitaxel is usually given once every three weeks (on day 1 of a 21-day cycle).

For treatment of advanced pancreatic cancer, Paclitaxel is given on days 1, 8 and 15 of each 28-day treatment cycle with gemcitabine being given immediately after the Paclitaxel.

For treatment of non-small cell lung cancer Paclitaxel is given once every week (i.e. on days 1, 8 and 15 of a 21 day cycle), with carboplatin being given once every three weeks (i.e. only on day 1 of each 21-day cycle), immediately after the Paclitaxel dose has been given.

If you have any further questions on the use of this medicine, ask your doctor or nurse

  1. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everyone gets them. The very common side effects may affect more than 1 in 10 people:

  • Loss of hair (the majority of cases of hair loss happened less than one month after starting Paclitaxel. When it happens, hair loss is pronounced (over 50%) in the majority of patients)
  • Rash
  • Abnormal decrease in the number of types of white blood cells (neutrophils, lymphocytes or leukocytes) in the blood
  • Deficiency of red blood cells
  • Reduction in the number of platelets in the blood
  • Effect on peripheral nerves (pain, numbness, tingling or loss of feeling)
  • Pain in a joint or joints
  • Pain in the muscles
  • Nausea, diarrhoea, constipation, sore mouth, loss of appetite
  • Vomiting
  • Weakness and tiredness, fever
  • Dehydration, taste disturbance, weight loss
  • Low levels of potassium in the blood
  • Depression, sleep problems
  • Headache
  • Chills
  • Difficulty in breathing
  • Dizziness
  • Swelling of mucosal and soft tissues
  • Increased liver function tests
  • Pain in extremities
  • Cough
  • Abdominal pain
  • Nose bleeds

The common side effects may affect up to 1 in 10 people:

  • Itching, dry skin, nail disorder
  • Infection, fever with decrease in the number of a type of white blood cell (neutrophils) in the blood, flushing, thrush, severe infection in your blood which may be caused by reduced white blood cells
  • Reduction in all blood cell counts
  • Chest or throat pain
  • Indigestion, abdominal discomfort
  • Stuffy nose
  • Pain in back, bone pain
  • Diminished muscular coordination or difficulty in reading, increased or decreased tears, loss of eyelashes
  • Changes in heart rate or rhythm, heart failure
  • Decreased or increased blood pressure
  • Redness or swelling at the site where the needle entered the body
  • Anxiety
  • Infection in the lungs
  • Infection in the urinary tract
  • Obstruction in the gut, inflammation of the large bowel, inflammation of the bile duct
  • Acute kidney failure
  • Increased bilirubin in the blood
  • Coughing up blood
  • Dry mouth, difficulty in swallowing
  • Muscle weakness
  • Blurred vision

The uncommon side effects may affect up to 1 in 100 people:

  • Increased weight, increased lactate dehydrogenase in the blood, decreased kidney function, increased blood sugar, increased phosphorus in the blood
  • Decreased or lack of reflexes, involuntary movements, pain along a nerve, fainting, dizziness when standing up, shaking, facial nerve paralysis
  • Irritated eyes, painful eyes, red eyes, itchy eyes, double vision, reduced vision, or seeing flashing lights, blurred vision due to swelling of the retina (cystoid macular oedema)
  • Ear pain, ringing in your ears
  • Coughing with phlegm, shortness of breath when walking or climbing stairs, runny nose, or dry nose, decreased breath sounds, water on the lung, loss of voice, blood clot in the lung, dry throat
  • Gas, stomach cramps, painful or sore gums, rectal bleeding
  • Painful urination, frequent urination, blood in the urine, inability to hold your urine
  • Fingernail pain, fingernail discomfort, loss of fingernails, hives, skin pain, red skin from sunlight, skin discolouration, increased sweating, night sweats, white areas on the skin, sores, swollen face
  • Decreased phosphorus in the blood, fluid retention, low albumin in the blood, increased thirst, decreased calcium in the blood, decreased sugar in the blood, decreased sodium in the blood
  • Pain and swelling in the nose, skin infections, infection due to catheter line
  • Bruising
  • Pain at site of tumour, death of the tumour
  • Decreased blood pressure when standing up, coldness in your hands and feet
  • Difficulty walking, swelling
  • Allergic reaction
  • Decreased liver function, increased size of liver
  • Pain in the breast
  • Restlessness
  • Small bleedings in your skin due to blood clots
  • A condition involving destruction of red blood cells and acute kidney failure

The rare side effects may affect up to 1 in 1,000 people:

  • Skin reaction to another agent or lung inflammation following radiation
  • Blood clot
  • Very slow pulse, heart attack
  • Leaking of drug outside the vein
  • A disorder of the electrical conduction system of the heart (atrioventricular block)

The very rare side effects may affect up to 1 in 10,000 people:

  • Severe inflammation/eruption of the skin and mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis)

5.HOW TO STORE PACLITAXEL

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The expiry date refers to the last day of that month.

Unopened vials: Keep the vial in the outer carton in order to protect from light.

After first reconstitution the suspension should be used immediately. If not used immediately, the suspension may be stored in a refrigerator (2?C-8?C) for up to 24 hours in the vial when kept in the outer carton in order to protect it from light.

The reconstituted suspension in the intravenous drip may be stored in a refrigerator (2?C-8?C) for up to 24 hours protected from light.

The total combined storage time of reconstituted medicinal product in the vial and in the infusion bag when refrigerated and protected from light is 24 hours. This may be followed by storage in the infusion bag for 4 hours below 25?C.

Your doctor or pharmacist is responsible for disposing of any unused Paclitaxel correctly.

  1. CONTENTS OF THE PACK AND FURTHER INFORMATION WHAT PACLITAXEL CONTAINS

The active substance is paclitaxel.

a) Each vial contains 100 mg of paclitaxel formulated as albumin-bound nanoparticles.
b) 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.

The other ingredient is human albumin (containing sodium, sodium caprylate and N-acetyl DL tryptophanate).

What Paclitaxel looks like and contents of the pack

Paclitaxel is a white to yellow powder for suspension for infusion. Paclitaxel is available in glass vials containing 100 mg or 250 mg of paclitaxel formulated as albumin bound nanoparticles.

Each pack contains 1 vial.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Leave a Reply

What people say about our doctor?

Loading…

More from Portfolio

Loading…
  • Candesartan and Hydrochlorothiazide Tablets 32mg/12.5mg Taj Pharma

    Name of the medicinal product Candesartan and Hydrochlorothiazide Tablets 16mg/12.5mg Taj Pharma Candesartan and Hydrochlorothiazide Tablets 32mg/12.5mg Taj Pharma Qualitative and quantitative composition a) Each film-coated tablet contains: Candesartan Cilexetil USP?????16mg Hydrochlorothiazide USP??????12.5mg Excipients????????????????????q.s Colour: Lake Ponceau 4R & Titanium Dioxide USP. b) Each film-coated tablet contains: Candesartan Cilexetil USP?????32mg Hydrochlorothiazide USP????? 12.5mg Excipients?????????????????????q.s Colour: […]

  • Aripiprazole 10mg tablets Taj Pharma

    Name of the medicinal product Aripiprazole 10 mg tablets Taj Pharma Aripiprazole 15 mg tablets TajPharma Qualitative and quantitative composition a) Each film-coated tablet contains: Aripiprazole? ? ? ? ? ? ? ? ? ? ? 10mg Excipients? ? ? ? ? ? ? ? ? ? ? ? ? q.s Colour: Yellow Oxide of […]

  • Temozolomide capsules 180mg Taj Pharma

    NAME OF THE MEDICINAL PRODUCT Temozolomide capsules 5mg Taj Pharma Temozolomide capsules 20mg Taj Pharma Temozolomide capsules 100mg Taj Pharma Temozolomide capsules 140mg Taj Pharma Temozolomide capsules 180mg Taj Pharma Temozolomide capsules 250mg Taj Pharma QUALITATIVE AND QUANTITATIVE COMPOSITION a) Each hard capsule contains Temozolomide USP? ? ? ? ? ? ? ? ? ? […]

  • Candesartan Cilexetil Tablets 16mg Taj Pharma

    Name of the medicinal product Candesartan Cilexetil Tablets 16mg Taj Pharma Candesartan Cilexetil Tablets 32mg Taj Pharma Qualitative and quantitative composition a) Each Uncoated tablet contains: Candesartan Cilexetil Tablets USP? ?16mg Excipients:? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? q.s b) Each […]