4.1. Therapeutic indications

Tuxxalib 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).

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

Tuxxalib 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

Tuxxalib 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 Tuxxalib 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 Tuxxalib 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. Tuxxalib 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 Tuxxalib 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 Tuxxalib administration 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

Tuxxalib Dose (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)

Tuxxalib 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

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)

Tuxxalib Dose

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

a. See Table 1 for dose level reductions

Non-small cell lung cancer:

The recommended dose of Tuxxalib is 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 Tuxxalib administration.

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

Tuxxalib 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 Tuxxalib, 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 Tuxxalib (mg/m2)1

Dose of carboplatin (AUC mg•min/mL)1

Nadir ANC <500/mm3 with neutropenic fever > 38ºC

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 Tuxxalib and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Tuxxalib; 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 Tuxxalib (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 Tuxxalib and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Tuxxalib; reduce the dose of carboplatin in the subsequent cycle.

Special populations

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).

Renal impairment

Adjustment of the starting Tuxxalib dose 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 Tuxxalib in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 ml/min) (see section 5.2).

Elderly

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 Paclitaxel formulated as albumin bound nanoparicles 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 Paclitaxel formulated as albumin bound nanoparticles. However, a subsequent analysis in 981 patients receiving Paclitaxel formulated as albumin bound nanoparticles monotherapy 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 Paclitaxel formulated as albumin bound nanoparticles 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 Paclitaxel formulated as albumin bound nanoparticles 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).

Of the 514 patients with non-small cell lung cancer in the randomized study who received Paclitaxel formulated as albumin bound particles in 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 Paclitaxel formulated as albumin bound nanoparticles /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 Paclitaxel formulated as albumin bound nanoparticles in children and adolescents aged 0 to less than 18 years has not been established. Currently available data are described in section s 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. There is no relevant use of Tuxxalib in the paediatric population for the indication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lung cancer.

Method of administration

Administer reconstituted Tuxxalib dispersion intravenously using an infusion set incorporating a 15 µm 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

Tuxxalib 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 Paclitaxel formulated as albumin bound nanoparticles. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Tuxxalib therapy. Patients should not be retreated with subsequent cycles of Tuxxalib 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 Paclitaxel formulated as albumin bound nanoparticles, although development of severe symptoms is less common. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose reduction. When Tuxxalib 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 Tuxxalib is recommended (see section 4.2). For combination use of Tuxxalib and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Tuxxalib; continue treatment with gemcitabine at the same dose. Resume Tuxxalib at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2). For combination use of Tuxxalib and 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 Tuxxalib and carboplatin (see section 4.2).

Sepsis

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received paclitaxel formulated as albumin bound nanoparticles 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 Tuxxalib 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 paclitaxel formulated as albumin bound nanoparticles was used as monotherapy and in 4% of patients when paclitaxel formulated as albumin bound nanoparticles 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 Tuxxalib 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 Tuxxalib in 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.

Tuxxalib is not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, Tuxxalib is 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 paclitaxel formulated as albumin bound nanoparticles. Most of the individuals were previously exposed to cardiotoxic medicinal products such as anthracyclines or had underlying cardiac history.

Thus, patients receiving Tuxxalib should be vigilantly monitored by physicians for the occurrence of cardiac events.

CNS metastases

The effectiveness and safety of paclitaxel formulated as albumin bound nanoparticles 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 Tuxxalib, they may be treated with commonly used anti-emetics and constipating agents.

Eye disorders

Cystoid macular oedema (CMO) has been reported in patients treated with paclitaxel formulated as albumin bound nanparticles. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, Tuxxalib treatment should be discontinued and appropriate treatment initiated (see section 4.8).

Patients 75 years and older

For patients of 75 years and older, no benefit for the combination treatment of paclitaxel formulated as albumin bound nanoparticles and gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (≥ 75 years) who received paclitaxel formulated as albumin bound nanoparticles 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 Tuxxalib 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 paclitaxel formulated as albumin bound nanoparticles and gemcitabine (see section 5.1).

Erlotinib should not be co-administered with paclitaxel formulated as albumin bound nanoparticles plus gemcitabine (see section 4.5).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per ml reconstituted solution, that is to say essentially 'sodium free'.

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 paclitaxel formulated as albumin bound nanoparticles and gemcitabine have not been evaluated in humans.

A pharmacokinetic study was conducted with paclitaxel formulated as albumin bound nanoparticles and carboplatin in non-small cell lung cancer patients. There were no clinically relevant pharmacokinetic interactions between paclitaxel formulated as albumin bound nanoparticles and carboplatin.

Tuxxalib is 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). Tuxxalib should not be used in combination with other anticancer agents.

Paediatric population

Interaction studies have only been performed in adults.

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 paclitaxel formulated as albumin bound nanoparticles. Male patients treated with paclitaxel formulated as albumin bound nanoparticles are 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 paclitaxel formulated as albumin bound nanoparticles.

paclitaxel formulated as albumin bound nanoparticles 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

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, paclitaxel formulated as albumin bound nanoparticles is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy.

Fertility

Paclitaxel formulated as albumin bound nanoparticles induced 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 paclitaxel formulated as albumin bound nanoparticles.

4.7. Effects on ability to drive and use machines

Paclitaxel formulated as albumin bound nanoparticles has minor or moderate influence on the ability to drive and use machines. paclitaxel formulated as albumin bound nanoparticles 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.

4.8. Undesirable effects

Summary of the safety profile

The most common clinically significant adverse reactions associated with the use of paclitaxel formulated as albumin bound nanoparticles have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

Tabulated list of adverse reactions

Table 6 lists adverse reactions associated with paclitaxel formulated as albumin bound nanoparticles monotherapy at any dose in any indication during clinical trials (N = 789), paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine for pancreatic adenocarcinoma from the phase III clinical trial (N = 421), paclitaxel formulated as albumin bound nanoparticles in combination with carboplatin for non-small cell lung cancer from the phase III clinical trial (N = 514) and from post-marketing use.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 6: Adverse reactions reported with paclitaxel formulated as albumin bound nanoparticles

Monotherapy (N=789)

Combination therapy with gemcitabine

(N =421)

Combination therapy with carboplatin

(N = 514)

Infections and infestations

Common:

Infection, urinary tract infection, folliculitis, upper respiratory tract infection, candidiasis, sinusitis

Sepsis, pneumonia, oral candidiasis

Pneumonia, bronchitis, upper respiratory tract infection, urinary tract infection

Uncommon:

Sepsis1, neutropenic sepsis1, pneumonia, oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, herpes zoster, fungal infection, catheter-related infection, injection site infection

Sepsis, oral candidiasis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Uncommon:

Tumour necrosis, metastatic pain

Blood and lymphatic system disorders

Very common:

Bone marrow suppression, neutropenia, thrombocytopenia, anaemia, leukopenia, lymphopenia

Neutropenia, thrombocytopenia, anaemia

Neutropenia3, thrombocytopenia3, anaemia3, leukopenia3

Common:

Febrile neutropenia

Pancytopenia

Febrile neutropenia, lymphopenia

Uncommon:

Thrombotic thrombocytopenic purpura

Pancytopenia

Rare:

Pancytopenia

Immune system disorders

Uncommon:

Hypersensitivity

Drug hypersensitivity, hypersensitivity

Rare:

Severe hypersensitivity1

Metabolism and nutrition disorders

Very

common:

Anorexia

Dehydration, decreased appetite, hypokalaemia

Decreased appetite

Common:

Dehydration, decreased appetite, hypokalaemia

Dehydration

Uncommon:

Hypophosphataemia, fluid retention, hypoalbuminaemia, polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia, hyponatraemia

Psychiatric disorders

Very

common:

Depression, insomnia

Common:

Depression, insomnia, anxiety

Anxiety

Insomnia

Uncommon:

Restlessness

Nervous system disorders

Very common:

Peripheral neuropathy, neuropathy, hypoaesthesia, paraesthesia

Peripheral neuropathy, dizziness, headache, dysgeusia

Peripheral neuropathy

Common:

Peripheral sensory neuropathy, dizziness, peripheral motor neuropathy, ataxia, headache, sensory disturbance, somnolence, dysgeusia

Dizziness, headache, dysgeusia

Uncommon:

Polyneuropathy, areflexia, syncope, postural dizziness, dyskinesia, hyporeflexia, neuralgia, neuropathic pain, tremor, sensory loss

VIIth nerve paralysis

Not known:

Cranial nerve palsies multiple 1

Eye disorders

Common:

Vision blurred, lacrimation increased, dry eye, keratoconjunctivitis sicca, madarosis

Lacrimation increased

Vision blurred

Uncommon:

Reduced visual acuity, abnormal vision, eye irritation, eye pain, conjunctivitis, visual disturbance, eye pruritus, keratitis

Cystoid macular oedema

Rare:

Cystoid macular oedema1

Ear and labyrinth disorders

Common:

Vertigo

Uncommon:

Tinnitus, ear pain

Cardiac disorders

Common:

Arrhythmia, tachycardia, supraventricular tachycardia

Cardiac failure congestive, tachycardia

Rare:

Cardiac arrest, cardiac failure congestive, left ventricular dysfunction, atrioventricular block1, bradycardia

Vascular disorders

Common:

Hypertension, lymphoedema, flushing, hot flushes

Hypotension, hypertension

Hypotension, hypertension

Uncommon:

Hypotension, orthostatic hypotension, peripheral coldness

Flushing

Flushing

Rare:

Thrombosis

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea, epistaxis, cough

Dyspnoea

Common:

Interstitial pneumonitis2, dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhoea

Pneumonitis, nasal congestion

Haemoptysis, epistaxis, cough

Uncommon:

Pulmonary emboli, pulmonary thromboembolism, pleural effusion, exertional dyspnoea, sinus congestion, decreased breath sounds, productive cough, allergic rhinitis, hoarseness, nasal congestion, nasal dryness, wheezing

Dry throat, nasal dryness

Pneumonitis

Not known:

Vocal cord paresis1

Gastrointestinal disorders

Very common:

Diarrhoea, vomiting, nausea, constipation, stomatitis

Diarrhoea, vomiting, nausea, constipation, abdominal pain, abdominal pain upper

Diarrhoea, vomiting, nausea, constipation

Common:

Gastrooesophageal reflux disease, dyspepsia, abdominal pain, abdominal distension, abdominal pain upper, oral hypoaesthesia

Intestinal obstruction, colitis, stomatitis, dry mouth

Stomatitis, dyspepsia, dysphagia, abdominal pain

Uncommon:

Rectal haemorrhage, dysphagia, flatulence, glossodynia, dry mouth, gingival pain, loose stools, oesophagitis, abdominal pain lower, mouth ulceration, oral pain

Hepatobiliary disorders

Common:

Cholangitis

Hyperbilirubinaemia

Uncommon:

Hepatomegaly

Skin and subcutaneous tissue disorders

Very common:

Alopecia, rash

Alopecia, rash

Alopecia, rash

Common:

Pruritus, dry skin, nail disorder, erythema, nail pigmentation/discolouration, skin hyperpigmentation, onycholysis, nail changes

Pruritus, dry skin, nail disorder

Pruritus, nail disorder

Uncommon:

Photosensitivity reaction, urticaria, skin pain, generalised pruritus, pruritic rash, skin disorder, pigmentation disorder, hyperhidrosis, onychomadesis, erythematous rash, generalised rash, dermatitis, night sweats, maculo-papular rash, vitiligo, hypotrichosis, nail bed tenderness, nail discomfort, macular rash, papular rash, skin lesion, swollen face

Skin exfoliation, dermatitis allergic, urticaria

Very rare:

Stevens-Johnson syndrome1, toxic epidermal necrolysis1

Not known:

Palmar-plantar erythrodysaesthesiae syndrome1, 4, scleroderma1

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia

Arthralgia, myalgia, pain in extremity

Arthralgia, myalgia

Common:

Back pain, pain in extremity, bone pain, muscle cramps, limb pain

Muscular weakness, bone pain

Back pain, pain in extremity, musculoskeletal 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

Common:

Acute renal failure

Uncommon:

Haematuria, dysuria, pollakiuria, nocturia, polyuria, urinary incontinence

Haemolytic uraemic syndrome

Reproductive system and breast disorders

Uncommon:

Breast pain

General disorders and administration site conditions

Very common:

Fatigue, asthenia, pyrexia

Fatigue, asthenia, pyrexia, oedema peripheral, chills

Fatigue, asthenia, oedema peripheral

Common:

Malaise, lethargy, weakness, peripheral oedema, mucosal inflammation, pain, rigors, oedema, decreased performance status, chest pain, influenza-like illness, hyperpyrexia

Infusion site reaction

Pyrexia, chest pain

Uncommon:

Chest discomfort, abnormal gait, swelling, injection site reaction

Mucosal inflammation, infusion site extravasation, infusion site inflammation, infusion site rash

Rare:

Extravasation

Investigations

Very common:

Weight decreased, alanine aminotransferase increased

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

Aspartate aminotransferase increased, blood bilirubin increased, blood creatinine increased

Weight decreased, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased

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

1 As reported in the post-marketing surveillance of paclitaxel formulated as albumin bound nanoparticles.

2 The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving paclitaxel formulated albumin bound nanoparticles monotherapy for breast cancer and for other indications.

3 Based on laboratory assessments: maximal degree of myelosuppression (treated population).

4 In some patients previously exposed to capecitabine.

Description of selected adverse reactions

This section contains the most common and clinically relevant adverse reactions related to paclitaxel formulated as albumin bound nanoparticles.

Adverse reactions were assessed in 229 patients with metastatic breast cancer who were treated with 260 mg/m2 paclitaxel formulated as albumin bound nanoparticles once every three weeks in the pivotal phase III clinical study (paclitaxel formulated as albumin bound nanoparticles monotherapy).

Adverse reactions were assessed in 421 patients with metastatic pancreatic cancer who were treated with paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine (125 mg/m2 paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle) and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas (paclitaxel formulated as albumin bound nanoparticles /gemcitabine).

Adverse reactions were assessed in 514 patients with non-small cell lung cancer who were treated with paclitaxel formulated as albumin bound nanoparticles in combination with carboplatin (100mg/m2 paclitaxel formulated as albumin bound nanoparticles given on Days 1, 8 and 15 of each 21-day cycle in combination with carboplatin given on Day 1 of each cycle) in the phase III randomized, controlled clinical trial (paclitaxel formulated as albumin bound nanoparticles /carboplatin). 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 paclitaxel formulated as albumin bound nanoparticles and carboplatin (p ≤ 0.002). For the other subscale (oedema), there was no difference in the treatment arms.

Infections and infestations

Paclitaxel formulated as albumin bound nanoparticles /gemcitabine

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Of the 22 cases of sepsis reported in patients treated with paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine, 5 had a fatal outcome. 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 Tuxxalib and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2).

Blood and lymphatic system disorders

paclitaxel formulated as albumin bound nanoparticles monotherapy-metastatic breast cancer

In patients with metastatic breast cancer, 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 paclitaxel formulated as albumin bound nanoparticles. Febrile neutropenia occurred in four patients on paclitaxel formulated as albumin bound nanoparticles. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on paclitaxel formulated as albumin bound nanoparticles and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.

Paclitaxel formulated as albumin bound nanoparticles /gemcitabine

Table 7 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine or with gemcitabine.

Table 7: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial

Paclitaxel formulated as albumin bound nanoparticles (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 paclitaxel formulated as albumin bound nanoparticles /gemcitabine-treated group

b 388 patients assessed in gemcitabine-treated group

c 404 patients assessed in paclitaxel formulated as albumin bound nanoparticles /gemcitabine-treated group

Paclitaxel formulated as albumin bound nanoparticles /carboplatin

Anaemia and thrombocytopenia were more commonly reported in the paclitaxel formulated as albumin bound nanoparticles and carboplatin arm than in the Taxol and carboplatin arm (54% versus 28% and 45% versus 27% respectively).

Nervous system disorders

Paclitaxel formulated as albumin bound nanoparticles monotherapy-metastatic breast cancer

In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving paclitaxel formulated as albumin bound nanoparticles. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on paclitaxel formulated as albumin bound nanoparticles with 10% being Grade 3, and no cases of Grade 4.

Paclitaxel formulated as albumin bound nanoparticles /gemcitabine

For patients treated with paclitaxel formulated as albumin bound nanoparticles 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 paclitaxel formulated as albumin bound nanoparticles at a reduced dose. No patients treated with paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine had Grade 4 peripheral neuropathy.

Paclitaxel formulated as albumin bound nanoparticles/carboplatin

For non-small cell lung cancer patients treated with paclitaxel formulated as albumin bound nanoparticles and 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 paclitaxel formulated as albumin bound nanoparticles and carboplatin experienced Grade 4 peripheral neuropathy.

Eye disorders

There have been rare reports during post-marketing surveillance of reduced visual acuity due to cystoid macular oedema during treatment with paclitaxel formulated as albumin bound nanoparticles (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Paclitaxel formulated as albumin bound nanoparticles/gemcitabine

Pneumonitis has been reported at a rate of 4% with the use of paclitaxel formulated as albumin bound nanoparticles in combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with paclitaxel formulated as albumin bound nanoparticles 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 Tuxxalib and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).

Gastrointestinal disorders

paclitaxel formulated as albumin bound nanoparticles monotherapy-metastatic breast cancer

Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients.

Skin and subcutaneous tissue disorders

Paclitaxel formulated as albumin bound nanoparticles monotherapy-metastatic breast cancer

Alopecia was observed in >80% of the patients treated with paclitaxel formulated as albumin bound nanoparticles. The majority of alopecia events occurred less than one month after initiation of paclitaxel formulated as albumin bound nanoparticles. Pronounced hair loss ≥ 50% is expected for the majority of patients who experience alopecia.

Musculoskeletal and connective tissue disorders

Paclitaxel formulated as albumin bound nanoparticles monotherapy-metastatic breast cancer

Arthralgia occurred in 32% of patients on paclitaxel formulated as albumin bound nanoparticles and was severe in 6% of cases. Myalgia occurred in 24% of patients on paclitaxel formulated as albumin bound nanoparticles and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after paclitaxel formulated as albumin bound nanoparticles administration and resolved within a week.

General disorders and administration site conditions

Paclitaxel formulated as albumin bound nanoparticles monotherapy-metastatic breast cancer Asthenia/Fatigue was reported in 40% of the patients.

Paediatric population

The study consisted of 106 patients, 104 of whom were paediatric patients aged from 6 months to less than 18 years (see section 5.1). Every patient experienced at least 1 adverse reaction. The most frequently reported adverse reactions were neutropenia, anaemia, leukopenia and pyrexia. Serious adverse reactions reported in more than 2 patients were pyrexia, back pain, peripheral oedema and vomiting. No new safety signals were identified in the limited number of paediatric patients treated with paclitaxel formulated as albumin bound nanoparticles and the safety profile was similar to that of the adult population.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.