Pazenir - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Pazenir 5 mg/ml powder for dispersion for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg of paclitaxel formulated as albumin bound nanoparticles.

After reconstitution, each ml of dispersion contains 5 mg of paclitaxel formulated as albumin bound nanoparticles.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for dispersion for infusion.

The reconstituted dispersion has a pH of 6–7.5 and an osmolality of 300–360 mOsm/kg. The powder is white to yellow.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Pazenir 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).

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

Pazenir 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

Pazenir 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 Pazenir 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 Pazenir therapy should have the dose reduced to 220 mg/m2 for

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subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. Pazenir 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 Pazenir 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 Pazenir 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	Pazenir 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)	Pazenir Dose	Gemcitabine Dose
Day 1	< 1500	OR	< 100,000	Delay doses until recovery
Day 8	> 500 but < 1000	OR	> 50,000 but < 75,000	Reduce doses 1 dose level
	< 500	OR	< 50,000	Withhold doses
Day 15: If Day 8 doses were given without modification:
Day 15	> 500 but < 1000	OR	> 50,000 but < 75,000	Treat with Day 8 dose level and follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 8 doses
	< 500	OR	< 50,000	Withhold doses
Day 15: If Day 8 doses were reduced:
Day 15	> 1000	AND	> 75,000	Return to the Day 1 dose levels and follow with WBC Growth Factors ORTreat 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)	Pazenir 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

aSee Table 1 for dose level reductions

Non-small cell lung cancer

The recommended dose of Pazenir 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 Pazenir administration.

Dose adjustments during treatment of non-small cell lung cancer

Pazenir 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 Pazenir, 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	Occurrenc e	Dose of Pazenir (mg/m2)1	Dose of carboplatin (AUC mg^min/mL )'
Nadir ANC <500/mm3 with neutropenic fever > 38°C O R Delay of next cycle due to persistent neutropenia2 (Nadir ANC <1500/mm3) O R Nadir ANC <500/mm3 for > 1 week	Fir st	7 5	4. 5
	Second	5 0	3. 0
	Third	Discontinue Treatment
Nadir platelets <50,000/mm3	Fir st	7 5	4. 5
	Second	Discontinue Treatment

1On Day 1 of the 21-day cycle reduce the dose of Pazenir and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Pazenir; 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 Pazenir (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
Grade 4 cutaneous toxicity, diarrhoea, or mucositis	Third	Discontinue Treatment
	First	Discontinue Treatment

1On Day 1 of the 21-day cycle reduce the dose of Pazenir and carboplatin simultaneously. On Days 8 or 15 of the 21-day cycle reduce the dose of Pazenir; 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

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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 Pazenir 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 Pazenir 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 human serum albumin-paclitaxel nanoparticles 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 human serum albumin-paclitaxel nanoparticles. However, a subsequent analysis in 981 patients receiving human serum albumin-paclitaxel 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 human serum albumin-paclitaxel 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 human serum albumin-paclitaxel 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 human serum albumin-paclitaxel nanoparticles 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 human serum albumin-paclitaxel 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 human serum albumin-paclitaxel 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 human serum albumin-paclitaxel nanoparticles in the paediatric population for the indication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lung cancer.

Method of administration

Pazenir is for intravenous use. Reconstituted Pazenir dispersion should be administered intravenously using an infusion set incorporating a 15 pm 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

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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.

Breast-feeding (see section 4.6).

Patients who have baseline neutrophil counts <1500 cells/mm3.

4.4 Special warnings and precautions for use

Pazenir 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 human serum albuminpaclitaxel nanoparticles. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Pazenir therapy. Patients should not be retreated with subsequent cycles of Pazenir 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 human serum albumin-paclitaxel 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 Pazenir 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 Pazenir is recommended (see section 4.2). For combination use of Pazenir and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Pazenir; continue treatment with gemcitabine at the same dose. Resume Pazenir at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2). For combination use of Pazenir 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 Pazenir and carboplatin (see section 4.2).

Sepsis

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Pazenir 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 Pazenir 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 human serum albumin-paclitaxel nanoparticles was used as monotherapy and in 4% of patients when Pazenir was used in combination with gemcitabine. Closely monitor all patients for signs and symptoms of pneumonitis. After ruling out

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infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Pazenir 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 Pazenir 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.

Pazenir is not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN. In addition, Pazenir 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 human serum albumin-paclitaxel nanoparticles. Most of the individuals were previously exposed to cardiotoxic medicinal products such as anthracyclines, or had underlying cardiac history. Thus, patients receiving Pazenir should be vigilantly monitored by physicians for the occurrence of cardiac events.

Central nervous system metastases

The effectiveness and safety of human serum albumin-paclitaxel 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 Pazenir, 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 Pazenir and gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (>75 years) who received Pazenir 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 Pazenir 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 Pazenir and gemcitabine (see section 5.1).

Erlotinib should not be co-administered with Pazenir plus gemcitabine (see section 4.5).

Excipients

When reconstituted, Pazenir concentrate contains 4.2 mg of sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

• 4.5 Interactions 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 medicinal products 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 Pazenir and gemcitabine have not been evaluated in humans.

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

Pazenir 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). Pazenir 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 breast-feeding

Contraception in males and females

Women of childbearing potential should use effective contraception during treatment and up to 1 month after receiving treatment with Pazenir. Male patients treated with Pazenir 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 Pazenir. Pazenir 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, Pazenir is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy.

Fertility

Human serum albumin-paclitaxel 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 Pazenir.

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4.7 Effects on ability to drive and use machines

Paclitaxel has minor or moderate influence on the ability to drive and use machines. Paclitaxel 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 human serum albumin-paclitaxel nanoparticles have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders.

The frequencies of adverse reactions associated with the administration of human serum albuminpaclitaxel nanoparticles are listed in Table 6 (human serum albumin-paclitaxel nanoparticles as monotherapy) and Table 7 (human serum albumin-paclitaxel in combination with gemcitabine), and Table 9 (human serum albumin-paclitaxel nanoparticles in combination with carboplatin).

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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Breast cancer (human serum albumin-paclitaxel nanoparticles administered as monotherapy)

Tabulated list of adverse reactions

Table 6 lists adverse reactions associated with the administration of human serum albumin-paclitaxel nanoparticles to patients from studies in which human serum albumin-paclitaxel nanoparticles has been administered as monotherapy at any dose in any indication (N = 789).

Table 6: Adverse reactions reported with human serum albumin-paclitaxel nanoparticles­monotherapy 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 • 2 sepsis
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, influenzalike 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 gammaglutamyl­transferase, 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.

1The 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 human serum albumin-paclitaxel nanoparticles

3 The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving human serum albumin-paclitaxel nanoparticles­monotherapy for breast cancer and for other indications using MedDRA SMQ Interstitial lung disease. See section 4.4.

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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 human serum albumin-paclitaxel nanoparticlesonce 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 human serum albuminpaclitaxel nanoparticles. Febrile neutropenia occurred in four patients on human serum albuminpaclitaxel nanoparticles. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on human serum albumin-paclitaxel nanoparticles, 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 human serum albumin-paclitaxel nanoparticles. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on human serum albuminpaclitaxel nanoparticleswith 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 human serum albumin-paclitaxel nanoparticles. The majority of alopecia events occurred less than one month after initiation of human serum albumin-paclitaxel nanoparticles. 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 human serum albumin-paclitaxel nanoparticles and was severe in 6% of cases. Myalgia occurred in 24% of patients on human serum albumin-paclitaxel nanoparticles and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after human serum albumin-paclitaxel nanoparticles administration and resolved within a week.

General disorders and administration site conditions Asthenia/Fatigue was reported in 40% of the patients.

Pancreatic adenocarcinoma (Pazenir administered in combination with gemcitabine)

Tabulated list of adverse reactions

Adverse reactions were assessed in 421 patients treated with human serum albumin-paclitaxel nanoparticles in combination with gemcitabine and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas in a phase III randomized, controlled, open-label trial. Table 7 lists adverse reactions assessed in patients with pancreatic adenocarcinoma treated with human serum albumin-paclitaxel nanoparticles in combination with gemcitabine.

Table 7: Adverse reactions reported with human serum albumin-paclitaxel nanoparticles in combination with gemcitabine (N=421)

Infections and infestations	Common : Sepsis, pneumonia, oral candidiasis
Blood and lymphatic system disorders	Very common : Neutropenia, anaemia, thrombocytopenia Common : Pancytopenia Uncommon : Thrombotic thrombocytopenic purpura
Metabolism and nutrition disorders	Very common : Dehydration, decreased appetite, hypokalaemia
Psychiatric disorders	Very common : Insomnia, depression Common : Anxiety
Nervous system disorders	Very common : Peripheral 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 human serum albumin-paclitaxel nanoparticles in combination with gemcitabine and for 4% of patients receiving gemcitabine monotherapy.

Description of selected adverse reactions

The following are the most common and important incidences of adverse reactions related to 421 patients with metastatic adenocarcinoma of the pancreas who were treated with 125 mg/m2 human serum albumin-paclitaxel nanoparticlesin 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 human serum albumin-paclitaxel nanoparticlesin combination with gemcitabine or with gemcitabine.

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

	Human serum albuminpaclitaxel 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 human serum albumin-paclitaxel nanoparticles/gem­citabine-treated group

b 388 patients assessed in gemcitabine-treated group

c 404 patients assessed in human serum albumin-paclitaxel nanoparticles/gem­citabine-treated group

Peripheral neuropathy

For patients treated with human serum albumin-paclitaxel nanoparticlesin 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 human serum albumin-paclitaxel nanoparticlesat a reduced dose. No patients treated with human serum albumin-paclitaxel nanoparticlesin 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 human serum albumin-paclitaxel nanoparticlesin 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 Pazenir and gemcitabine until fever resolves and ANC > 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2).

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Pneumonitis

Pneumonitis has been reported at a rate of 4% with the use of human serum albumin-paclitaxel nanoparticlesin combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with human serum albumin-paclitaxel 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 Pazenir and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2).

Non-small cell lung cancer (human serum albumin-paclitaxel nanoparticles administered in combination with carboplatin)

Tabulated list of adverse reactions

Table 9 lists adverse reactions associated with the administration of human serum albuminpaclitaxel nanoparticles in combination with carboplatin.

Table 9: Adverse reactions reported with human serum albumin-paclitaxel nanoparticles in 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 paclitaxel 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 human serum albumin-paclitaxel nanoparticles and carboplatin experienced Grade 4 peripheral neuropathy.

Anemia and thrombocytopenia were more commonly reported in the human serum albumin-paclitaxel nanoparticles arm 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 human serum albuminpaclitaxel nanoparticles and 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 human serum albumin-paclitaxel nanoparticles.

There have been rare reports of reduced visual acuity due to cystoid macular oedema during treatment with human serum albumin-paclitaxel nanoparticles. Upon diagnosis of cystoid macular oedema, treatment with Pazenir should be discontinued.

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There have been reports of tumour lysis syndrome during treatment with human serum albuminpaclitaxel nanoparticles.

Scleroderma of the skin has been reported. In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaes­thesiae have been reported as part of the continuing surveillance of human serum albumin-paclitaxel nanoparticles. 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.

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 human serum albumin-paclitaxel 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 national reporting system listed i

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, taxanes, ATC Code: L01CD01

Mechanism of action

Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Pazenir contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, where the paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, the nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro studies demonstrated that the presence of albumin enhances transport of paclitaxel across endothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated by the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumour due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).

Clinical efficacy and safety

Breast cancer

Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated in a randomised Phase III comparative study are available to support the use of human serum albumin-paclitaxel nanoparticles in metastatic breast cancer. This information is presented below.

Single-arm open-label studies

In one study, human serum albumin-paclitaxel nanoparticles were 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 human serum albuminpaclitaxel nanoparticles 260 mg/m2 given as a 30 minute infusion without premedication (N = 229). Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastatic setting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicinal product as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.

Results for overall response rate and time to disease progression, and progression-free survival and survival for patients receiving > 1st-line therapy, are shown below.

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

Efficacy variable	human serum albuminpaclitaxel nanoparticles (260 mg/m2)	Solvent-based paclitaxel (175 mg/m2)	p-value
Response rate [95% CI] (%)
> Ist-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)
> Ist-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)

> Ist-line therapy	20.6 [15.6, 25.9] (n = 131)	16.1 [15.0, 18.3] (n = 135)	0.010b
*Survival [95% CI] (weeks)
> Ist-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 human serum albumin-paclitaxel nanoparticles in the randomized, controlled clinical trial were evaluated for safety. Neurotoxicity to paclitaxel was evaluated through improvement by one grade for patients experiencing Grade 3 peripheral neuropathy at any time during therapy. The natural course of peripheral neuropathy to resolution to baseline due to cumulative toxicity of human serum albumin-paclitaxel nanoparticles after > 6 courses of treatment was not evaluated and remains unknown.

Pancreatic adenocarcinoma

A multicenter, multinational, randomized, open-label study was conducted in 861 patients to compare human serum albumin-paclitaxel nanoparticles/gem­citabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. human serum albuminpaclitaxel nanoparticles were 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 human serum albumin-paclitaxel nanoparticles in combination with gemcitabine, the majority (93%) were white, 4% were black and 2% were Asian. 16% had a Karnofsky Performance Status of 100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70; and <1% of patients had a KPS of below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or of connective tissue disorders and/or interstitial lung disease were excluded from the study.

Patients received a median treatment duration of 3.9 months in the human serum albumin-paclitaxel nanoparticles/gem­citabine arm and 2.8 months in the gemcitabine arm. 32% of patients in the human serum albumin-paclitaxel nanoparticles/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 human serum albumin-paclitaxel nanoparticles/gem­citabine arm and 85% in the gemcitabine arm. The median relative dose intensity of human serum albumin-paclitaxel nanoparticles was 81%. A higher median cumulative dose of gemcitabine was delivered in the human serum albumin-paclitaxel nanoparticles/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)

	Human serum albumin-paclitaxel nanoparticles (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% Cl)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 Progressionfree Survival, months (95% CI)	5.5 (4.47, 5.95)	3.7 (3.61, 4.04)
HRA+G/G(95%Cl)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% Cl)	3.19 (2.178, 4.662)
P-value (chi-square test)	<0.0001

CI = confidence interval, HRA+G/G = hazard ratio of Paclitaxel human serum albumin-paclitaxel nanoparticles+gem­citabine/gemci­tabine, pA+G/pG=response rate ratio of human serum albumin-paclitaxel nanoparticles+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 human serum albumin-paclitaxel nanoparticles/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.

Treatment effects on OS favoured the human serum albumin-paclitaxel nanoparticles/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 human serum albumin-paclitaxel nanoparticles/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 human serum albumin-paclitaxel nanoparticles/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 human serum albumin-paclitaxel nanoparticles in 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. Human serum albumin-paclitaxel nanoparticles were 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 human serum albumin-paclitaxel nanoparticles administration, 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 medicinal product was administered on Day 1 of each 21-day cycle. In both study

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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 human serum albumin-paclitaxel nanoparticles/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 human serum albumin-paclitaxel nanoparticles/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	Human serum albumin-paclitaxel nanoparticles (100mg/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 reponse, n (%)	170 (33%)	132 (25%)
95% Cl (%)	28.6, 36.7	21.2, 28.5
Pa/Pt (95.1% Cl)	1.313 (1	1.082, 1.593)
P-valuea	0.005

CI = confidence interval; HRA/T = hazard ratio of Human serum albumin-paclitaxel nanoparticles/car­boplatin to solventbased paclitaxel/car­boplatin; pA/pT = response rate ratio of Human serum albumin-paclitaxel nanoparticles/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	Human serum albumin-paclitaxel nanoparticles (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 Human serum albumin-paclitaxel nanoparticles/car­boplatin to solventbased paclitaxel/car­boplatin; pA/pT = response rate ratio of Human serum albumin-paclitaxel nanoparticles/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

Safety and effectiveness in paediatric patients have not been established (see section 4.2).

Study ABI-007-PST-001, a Phase 1/2, multicenter, open-label, dose-finding study to assess the safety, tolerability and preliminary efficacy of weekly human serum albumin-paclitaxel nanoparticles in paediatric patients with recurrent or refractory solid tumours included a total of 106 patients aged > 6 months to < 24 years.

The Phase 1 portion of the study included a total of 64 patients aged from 6 months to less than 18 years old and determined the maximum tolerated dose (MTD) to be 240 mg/m2, administered as an intravenous infusion over 30 minutes, on Days 1, 8, and 15 of each 28-day cycle.

The Phase 2 portion enrolled a total of 42 patients using a Simon two-stage minimax design, aged from 6 months to 24 years with recurrent or refractory Ewing’s sarcoma, neuroblastoma or rhabdomyosarcoma for the evaluation of antitumour activity assessed by the overall response rate (ORR). Of the 42 patients, 1 patient was < 2, 27 were aged > 2 to < 12, 12 were aged >12 to < 18 and 2 adult patients were aged > 18 to 24 years old.

Patients were treated for a median of 2 cycles at the MTD. From the 41 patients eligible for efficacy evaluation in stage 1, 1 patient in the rhabdomyosarcoma group (N=14) had a confirmed partial response (PR) resulting in an ORR of 7.1% (95% CI: 0.2, 33.9). No confirmed complete response (CR) or PR was observed in either the Ewing’s sarcoma group (N=13) or the neuroblastoma group (N=14). None of the study arms continued into stage 2 because the protocol-defined requirement of > 2 patients to have a confirmed response was not met.

The median overall survival results, including the 1-year follow-up period were 32.1 weeks (95% CI: 21.4, 72.9), 32.0 weeks (95% CI: 12, not established) and 19.6 weeks (95% CI: 4, 25.7) for the Ewing’s sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively.

The overall safety profile of human serum albumin-paclitaxel nanoparticles in paediatric patients was consistent with the known safety profile of human serum albumin-paclitaxel nanoparticles in adults (see section 4.8). Based on these results, it was concluded that human serum albuminpaclitaxel nanoparticles as monotherapy does not have meaningful clinical activity or survival benefit that warrants further development in the paediatric population

5.2 Pharmacokinetic properties

The pharmacokinetics of total paclitaxel following 30– and 180-minute infusions of human serum albumin-paclitaxel nanoparticles at dose levels of 80 to 375 mg/m2 were determined in clinical studies. The paclitaxel exposure (AUC) increased linearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m2.

In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel following human serum albumin-paclitaxel nanoparticles administered intravenously at 260 mg/m2 over 30 minutes were compared with those following 175 mg/m2 of the solvent-based paclitaxel injection administered over 3 hours. Based on non-compartmental PK analysis, the plasma clearance of paclitaxel with human serum albumin-paclitaxel nanoparticles was 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 human serum albumin-paclitaxel nanoparticles administered intravenously at 260 mg/m2, intra-patient variability in AUC was 19% (range = 3.21%-37.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses.

Distribution

Following human serum albumin-paclitaxel nanoparticles administration 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 human serum albumin-paclitaxel nanoparticles was evaluated by ultrafiltration in a within-patient comparison study. The fraction of free paclitaxel was significantly higher with human serum albumin-paclitaxel nanoparticles (6.2%) than with solventbased paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with human serum albumin-paclitaxel nanoparticles compared with solvent-based paclitaxel, even though the total exposure is comparable. This is possibly due to paclitaxel not being trapped in Cremophor EL micelles as with solvent-based paclitaxel. Based on the published literature, in vitro studies of binding to human serum proteins, (using paclitaxel at 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 6a-hydroxypaclitaxel; and to two minor metabolites, 3’-p -hydroxypaclitaxel and 6a-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 human serum albuminpaclitaxel nanoparticles at 260 mg/m2, the mean value for cumulative urinary excretion of unchanged active substance accounted for 4% of the total administered dose with less than 1% as the metabolites 6a-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 human serum albumin-paclitaxel nanoparticles was 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 human serum albumin-paclitaxel nanoparticles exposure.

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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 preexisting 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.

Elderly

Population pharmacokinetic analysis for human serum albumin-paclitaxel nanoparticles included 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.

Paediatric population

The pharmacokinetics of paclitaxel following 30 minutes of intravenous administration at dose levels of 120 mg/m2 to 270 mg/m2 were determined in 64 patients (2 to < 18 years) in Phase 1 of a Phase 1/2 study in recurrent or refractory paediatric solid tumours. Following dosing increase from 120 to 270 mg/m2, the paclitaxel mean AUC(0-inf) and Cmax ranged from 8867 to 14361 ng*hr/ml and from 3488 to 8078 ng/ml, respectively.

Dose normalized peak drug exposure values were comparable across the dose range studied; however, dose-normalized total drug exposure values were only comparable across 120 mg/m2 to 240 mg/m2; with lower dose-normalized AUC, at the 270 mg/m2 dose level. At the MTD of 240 mg/m2, the mean CL was 19.1 L/h and the mean terminal half-life was 13.5 hours.

In children and adolescent patients, exposure to paclitaxel increased with higher dosing and weekly drug exposures were higher than in adult patients.

Other intrinsic factors

Population pharmacokinetic analyses for human serum albumin-paclitaxel nanoparticles indicate 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

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administered prior and during mating in male and female rats and foetal toxicity in rats. Animal studies with human serum albumin-paclitaxel nanoparticles showed 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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Albumin (human)

Sodium caprylate

N-acetyl-DL-tryptophan

Sodium chloride

Hydrochloric acid

Sodium hydroxide

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

3 years

Stability of reconstituted dispersion in the vial

Chemical and physical in-use stability has been demonstrated for 24 hours at 2–8 °C when the vial is in the original carton, and protected from bright light. Alternative light-protection may be used in the clean room. From a microbiological point of view, unless the method of opening/recon­stituting/dilu­tion precludes the risks of microbial contamination, the product should be filled into an infusion bag immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Stability of the reconstituted dispersion in the infusion bag

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C, protected from light followed by 4 hours at 15°C-25°C. From a microbiological point of view, unless the method of opening/recon­stituting/dilu­tion precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Unopened vials

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

Reconstituted dispersion

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.

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 Pazenir. The use of gloves, goggles and protective clothing is recommended. If the dispersion 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. Pazenir should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant staff should not handle Pazenir.

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 Pazenir to 30 minutes, as directed, reduces the likelihood of infusion-related reactions.

Reconstitution and administration of the product

Pazenir is supplied as a sterile lyophilised powder for reconstitution before use. After reconstitution, each ml of dispersion contains 5 mg of paclitaxel formulated as albumin bound nanoparticles.

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 Pazenir over a minimum of 1 minute.

The solution should be directed onto the inside wall of the vial. The solution should not be injected directly onto the powder as this will result in foaming.

Once the addition is complete, the vial should be allowed to stand for a minimum of 5 minutes to ensure proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least 2 minutes until complete redispersion 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 dispersion should be milky and homogenous without visible precipitates. Some settling of the reconstituted dispersion may occur. If precipitates or settling are visible, the vial should be gently inverted again to ensure complete redispersion prior to use. Inspect the dispersion in the vial for particulate matter. Do not administer the reconstituted dispersion if particulate matter is observed in the vial.

The exact total dosing volume of 5 mg/ml dispersion required for the patient should be calculated and the appropriate amount of reconstituted Pazenir should be injected into an empty, sterile, PVC or non-PVC type intravenous bag.

The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute and administer Pazenir may result in the formation of proteinaceous strands. Administer Pazenir using an infusion set incorporating a 15 pm filter to avoid administration of these strands. Use of a 15 pm 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 pm may result in blockage of the filter.

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The use of specialized di(2-ethylhexyl)phtha­late (DEHP)-free solution containers or administration sets is not necessary to prepare or administer Pazenir infusions.

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. MARKETING AUTHORISATION HOLDER

ratiopharm GmbH

Graf-Arco-Straße 3

89079 Ulm

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1317/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06 May 2019