NAVERUCLIF 5mg / ml powder for infusion dispersion medication leaflet

Naveruclif 5 mg/ml powder for dispersion for infusion

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 boundnanoparticles.

For the full list of excipients, see section 6.1.

Powder for dispersion for infusion (powder for infusion).

The reconstituted dispersion has a pH of 6-7.5 and an osmolality of 300-380 mOsm/kg.

White to yellow coloured powder or lyophilized cake.

Naveruclif monotherapy is indicated for the treatment of metastatic breast cancer in adult patients whohave failed first-line treatment for metastatic disease and for whom standard, anthracycline containingtherapy is not indicated (see section 4.4).

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

Naveruclif in combination with carboplatin is indicated for the first-line treatment of non-small celllung cancer in adult patients who are not candidates for potentially curative surgery and/or radiationtherapy.

Naveruclif should only be administered under the supervision of a qualified oncologist in unitsspecialised in the administration of cytotoxic agents. It should not be substituted for or with otherpaclitaxel formulations.

Breast cancer

The recommended dose of Naveruclif is 260 mg/m2 administered intravenously over 30 minutes every3 weeks.

Dose adjustments during treatment of breast cancer

Patients who experience severe neutropenia (neutrophil count < 500 cells/mm3 for a week or longer) orsevere sensory neuropathy during Naveruclif therapy should have the dose reduced to 220 mg/m2 forsubsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy,additional dose reduction should be made to 180 mg/m2. Naveruclif should not be administered untilneutrophil counts recover to >1500 cells/mm3. For Grade 3 sensory neuropathy, withhold treatment untilresolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses.

Pancreatic adenocarcinoma

The recommended dose of Naveruclif in combination with gemcitabine is 125 mg/m2 administeredintravenously over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommendeddose of gemcitabine is 1000 mg/m2 administered intravenously over 30 minutes immediately after thecompletion of Naveruclif 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 Naveruclif dose (mg/m2) Gemcitabine dose(mg/m2)

Full dose 125 10001st dose level reduction 100 8002nd 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 orwithin a cycle for patients with pancreatic adenocarcinoma

Cycle ANC count Platelet count Naveruclif Gemcitabine

Day (cells/mm3) (cells/mm3) dose dose

Day 1 < 1,500 OR < 100,000 Delay doses until recovery

Day 8 ≥ 500 but < 1,000 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 < 1,000 OR ≥ 50,000 but < 75,000 Treat with Day 8 dose level andfollow 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 ≥ 1,000 AND ≥ 75,000 Return to the Day 1 dose levels andfollow with WBC Growth Factors

OR

Treat with same doses as Day 8≥ 500 but < 1,000 OR ≥ 50,000 but < 75,000 Treat with Day 8 dose levels andfollow 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 ≥ 1,000 AND ≥ 75,000 Return to Day 1 dose levels andfollow with WBC Growth Factors

OR

Reduce doses 1 dose level from

Day 1 doses≥ 500 but < 1,000 OR ≥ 50,000 but < 75,000 Reduce 1 dose level and followwith 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 pancreaticadenocarcinoma

Adverse Drug Reaction (ADR) Naveruclif Dose Gemcitabine Dose

Febrile Neutropenia: Withhold doses until fever resolves and ANC ≥ 1500; resume at

Grade 3 or 4 next lower dose levela

Peripheral Neuropathy: Withhold dose until improves Treat with same dose

Grade 3 or 4 to ≤ Grade 1; resume at nextlower dose levela

Cutaneous Toxicity: Reduce to next lower dose levela; discontinue treatment if

Grade 2 or 3 ADR persists

Gastrointestinal Toxicity: Withhold doses until improves to ≤ Grade 1, resume at next

Grade 3 mucositis or diarrhoea lower dose levela

a. See Table 1 for dose level reductions

The recommended dose of Naveruclif is 100 mg/m2 administered as an intravenous infusion over30 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

Naveruclif administration.

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

Naveruclif 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

Naveruclif, patients must have an ANC ≥500 cells/mm3 and platelets >50,000 cells/mm3 or the dose isto be withheld until counts recover. When counts recover, resume dosing the following weekaccording 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 Occurrence Dose of Naveruclif Dose of carboplatin

Toxicity (mg/m2)1 (AUC mg*min/mL)1

Nadir ANC <500/mm3 First 75 4.5with neutropenic fever Second 50 3.0> 38°C Third Discontinue Treatment

OR

Delay of next cycledue to persistentneutropenia2 (Nadir

ANC <1500/mm3)

OR

Nadir ANC <500/mm3for > 1 week

Nadir platelets First 75 4.5<50,000/mm3 Second Discontinue Treatment1On Day 1 of the 21-day cycle reduce the dose of Naveruclif and carboplatin simultaneously. On

Days 8 or 15 of the 21-day cycle reduce the dose of Naveruclif; reduce the dose of carboplatin in thesubsequent 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 untilthe 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 beresumed at the next lower dose level in subsequent cycles according to the guidelines in Table 5. Forany 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 lungcancer

Non-haematologic Occurrence Dose of Naveruclif Dose of carboplatin

Toxicity (mg/m2)1 (AUC mg*min/mL)1

Grade 2 or 3 cutaneous First 75 4.5toxicity Second 50 3.0

Grade 3 diarrhoea Third Discontinue Treatment

Grade 3 mucositis≥ Grade 3 peripheralneuropathy Any other

Grade 3 or 4 non-haematologic toxicity

Grade 4 cutaneous First Discontinue Treatmenttoxicity, diarrhoea, ormucositis1On Day 1 of the 21-day cycle reduce the dose of Naveruclif and carboplatin simultaneously. On

Days 8 or 15 of the 21-day cycle reduce the dose of Naveruclif; reduce the dose of carboplatin in thesubsequent cycle.

For patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x ULN and aspartateaminotransferase [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 severehepatic impairment (total bilirubin > 1.5 to ≤ 5 x ULN and AST ≤ 10 x ULN), a 20% reduction indose is recommended. The reduced dose may be escalated to the dose for patients with normalhepatic function if the patient is tolerating the treatment for at least two cycles (see sections 4.4 and5.2).

For patients with metastatic adenocarcinoma of the pancreas that have moderate to severe hepaticimpairment, 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 permitdosage recommendations regardless of indication (see sections 4.4 and 5.2).

Adjustment of the starting Naveruclif dose is not required for patients with mild to moderate renalimpairment (estimated creatinine clearance ≥30 to <90 ml/min). There are insufficient data available torecommend dose modifications of Naveruclif in patients with severe renal impairment or end stage renaldisease (estimated creatinine clearance <30 ml/min) (see section 5.2).

No additional dosage reductions, other than those for all patients, are recommended for patients65 years and older.

Of the 229 patients in the randomized study who received human serum albumin-paclitaxelnanoparticles monotherapy for breast cancer, 13% were at least 65 years of age and < 2% were 75 yearsand older. No toxicities occurred notably more frequently among patients at least 65 years of age whoreceived human serum albumin-paclitaxel nanoparticles. However, a subsequent analysis in981 patients receiving human serum albumin-paclitaxel nanoparticles monotherapy for metastaticbreast cancer, of which 15% were ≥ 65 years old and 2% were ≥ 75 years old, showed a higherincidence 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 humanserum albumin-paclitaxel nanoparticles in combination with gemcitabine, 41% were 65 years andolder and 10% were 75 years and older. In patients aged 75 years and older who received humanserum albumin-paclitaxel nanoparticles and gemcitabine, there was a higher incidence of seriousadverse 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 beforetreatment is considered (see section 4.4).

Of the 514 patients with non-small cell lung cancer in the randomized study who received human serumalbumin-paclitaxel nanoparticles in combination with carboplatin, 31% were 65 years or older and3.5% were 75 years or older. Myelosuppression events, peripheral neuropathy events, and arthralgiawere 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 inpatients 75 years or older.

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

The safety and efficacy of human serum albumin-paclitaxel nanoparticles in children andadolescents aged 0 to less than 18 years has not been established. Currently available data aredescribed in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. There isno relevant use of human serum albumin-paclitaxel nanoparticles in the paediatric population forthe indication of metastatic breast cancer or pancreatic adenocarcinoma or non-small cell lungcancer.

Naveruclif is for intravenous use. Administer reconstituted Naveruclif dispersion intravenously usingan infusion set incorporating a 15 µm filter. Following administration, it is recommended that theintravenous line be flushed with sodium chloride 9 mg/ml (0.9%) solution for injection to ensureadministration of the complete dose.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Lactation (see section 4.6).

Patients who have baseline neutrophil counts < 1,500 cells/mm3.

Naveruclif is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantiallydifferent pharmacological properties compared to other formulations of paclitaxel (see sections 5.1and 5.2). It should not be substituted for or with other paclitaxel formulations.

Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylacticreactions with fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinalproduct should be discontinued immediately, symptomatic treatment should be initiated, and thepatient should not be rechallenged with paclitaxel.

Bone marrow suppression (primarily neutropenia) occurs frequently with human serumalbumin-paclitaxel nanoparticles. Neutropenia is dose-dependent and a dose-limiting toxicity.

Frequent monitoring of blood cell counts should be performed during Naveruclif therapy.

Patients should not be retreated with subsequent cycles of Naveruclif until neutrophils recoverto >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, althoughdevelopment of severe symptoms is less common. The occurrence of Grade 1 or 2 sensoryneuropathy does not generally require dose reduction. When Naveruclif is used as monotherapy, if

Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2followed by a dose reduction for all subsequent courses of Naveruclif is recommended (see section4.2). For combination use of Naveruclif and gemcitabine, if Grade 3 or higher peripheral neuropathydevelops, withhold Naveruclif; continue treatment with gemcitabine at the same dose. Resume

Naveruclif at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2).

For combination use of Naveruclif and carboplatin, if Grade 3 or higher peripheral neuropathydevelops, treatment should be withheld until improvement to Grade 0 or 1 followed by a dosereduction for all subsequent courses of Naveruclif and carboplatin (see section 4.2).

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received humanserum albumin-paclitaxel nanoparticles in combination with gemcitabine. Complications due to theunderlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, wereidentified as significant contributing factors. If a patient becomes febrile (regardless of neutrophilcount), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold

Naveruclif and gemcitabine until fever resolves and ANC ≥ 1,500 cells/mm3, then resume treatmentat reduced dose levels (see section 4.2).

Pneumonitis

Pneumonitis occurred in 1% of patients when human serum albumin-paclitaxel nanoparticles wasused as monotherapy and in 4% of patients when human serum albumin-paclitaxel nanoparticleswere used in combination with gemcitabine. Closely monitor all patients for signs and symptoms ofpneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis,permanently discontinue treatment with Naveruclif and gemcitabine and promptly initiate appropriatetreatment and supportive measures (see section 4.2).

Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of

Naveruclif in patients with hepatic impairment should be performed with caution. Patients withhepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; suchpatients should be closely monitored for development of profound myelosuppression.

Naveruclif is not recommended in patients that have total bilirubin > 5 x ULN or AST > 10 x ULN.

In addition, Naveruclif is not recommended in patients with metastatic adenocarcinoma of thepancreas that have moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and

AST ≤ 10 x ULN) (see section 5.2).

Rare reports of congestive heart failure and left ventricular dysfunction have been observed amongindividuals receiving human serum albumin-paclitaxel nanoparticles. Most of the individuals werepreviously exposed to cardiotoxic medicinal products such as anthracyclines or had underlyingcardiac history. Thus, patients receiving Naveruclif should be vigilantly monitored by physicians forthe occurrence of cardiac events.

CNS metastases

The effectiveness and safety of human serum albumin-paclitaxel nanoparticles in patients withcentral nervous system (CNS) metastases has not been established. CNS metastases are generally notwell controlled by systemic chemotherapy.

Gastrointestinal symptoms

If patients experience nausea, vomiting and diarrhoea following the administration of Naveruclif, theymay be treated with commonly used anti-emetics and constipating agents.

Cystoid macular oedema (CMO) has been reported in patients treated with human serumalbumin-paclitaxel nanoparticles. Patients with impaired vision should undergo a prompt andcomplete ophthalmologic examination. In case CMO is diagnosed, Naveruclif treatment shouldbe 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 human serumalbumin-paclitaxel nanoparticles and gemcitabine in comparison to gemcitabine monotherapy hasbeen demonstrated. In the very elderly (≥ 75 years) who received human serum albumin-paclitaxelnanoparticles and gemcitabine, there was a higher incidence of serious adverse reactions and adversereactions that led to treatment discontinuation including haematologic toxicities, peripheralneuropathy, decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged75 years and older should be carefully assessed for their ability to tolerate Naveruclif in combinationwith gemcitabine with special consideration to performance status, co-morbidities and increased riskof infections (see section 4.2 and 4.8).

Although limited data is available, no clear benefit in terms of prolonged overall survival has beendemonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start oftreatment with human serum albumin-paclitaxel nanoparticles and gemcitabine (see section 5.1).

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

This medicine contains less than 1 mmol sodium (23 mg) per 100 mg, that is to say essentially ‘sodiumfree’.

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, cautionshould be exercised when administering paclitaxel concomitantly with medicines known to inhibiteither 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. Administeringpaclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g.rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacymay be compromised because of lower paclitaxel exposures.

Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance isprimarily 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 Naveruclif and gemcitabine have not been evaluated in humans.

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

Naveruclif is indicated as monotherapy for breast cancer, in combination with gemcitabine forpancreatic adenocarcinoma, or in combination with carboplatin for non-small cell lung cancer (seesection 4.1).

Naveruclif should not be used in combination with other anticancer agents.

Interaction studies have only been performed in adults.

Women of childbearing potential should use effective contraception during treatment and up to1 month after receiving treatment with Naveruclif. Male patients treated with Naveruclif are advised touse effective contraception and to avoid fathering a child during and up to six months after treatment.

There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected tocause serious birth defects when administered during pregnancy. Studies in animals have shownreproductive toxicity (see section 5.3). Women of childbearing potential should have a pregnancy testprior to starting treatment with Naveruclif. Naveruclif should not be used in pregnancy, and in womenof childbearing potential not using effective contraception, unless the clinical condition of the motherrequires treatment with paclitaxel.

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats (see section 5.3). It is notknown if paclitaxel is excreted in human milk. Because of potential serious adverse reactions inbreast-feeding infants, Naveruclif is contraindicated during lactation. Breast-feeding must bediscontinued for the duration of therapy.

Human serum albumin-paclitaxel nanoparticles induced infertility in male rats (see section 5.3). Basedon findings in animals, male and female fertility may be compromised. Male patients should seek adviceon conservation of sperm prior to treatment because of the possibility of irreversible infertility due totherapy with Naveruclif.

Paclitaxel has minor or moderate influence on the ability to drive and use machines. Paclitaxel maycause adverse reactions such as tiredness (very common) and dizziness (common) that may affect theability to drive and use machinery. Patients should be advised not to drive and use machines if they feeltired or dizzy.

The most common clinically significant adverse reactions associated with the use of human serumalbumin-paclitaxel nanoparticles have been neutropenia, peripheral neuropathy, arthralgia/myalgiaand gastrointestinal disorders.

Table 6 lists adverse reactions associated with human serum albumin-paclitaxel nanoparticlesmonotherapy at any dose in any indication during clinical trials (N = 789), human serum albumin-paclitaxel nanoparticles in combination with gemcitabine for pancreatic adenocarcinoma from thephase III clinical trial (N = 421), human serum albumin-paclitaxel nanoparticles in combinationwith carboplatin for non-small cell lung cancer from the phase III clinical trial (N = 514) and frompost-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 theavailable data). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 6: Adverse reactions reported with human serum albumin-paclitaxel nanoparticles

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Common: Infection, urinary tract infection, Sepsis, pneumonia, oral Pneumonia, bronchitis,folliculitis, upper respiratory candidiasis upper respiratory tracttract infection, candidiasis, infection, urinary tractsinusitis infection

Uncommon: Sepsis1, neutropenic sepsis1, Sepsis, oral candidiasispneumonia, oral candidiasis,nasopharyngitis, cellulitis,herpes simplex, viral infection,herpes zoster, fungal infection,catheter-related infection,injection site infection

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

Uncommon: Tumour necrosis, metastaticpain

Very Bone marrow suppression, Neutropenia, Neutropenia3,common: neutropenia, thrombocytopenia, thrombocytopenia, thrombocytopenia3,anaemia, leukopenia, anaemia anaemia3, leukopenia3lymphopenia

Common: Febrile neutropenia Pancytopenia Febrile neutropenia,lymphopenia

Uncommon: Thrombotic Pancytopeniathrombocytopenicpurpura

Rare: Pancytopenia

Uncommon: Hypersensitivity Drug hypersensitivity,hypersensitivity

Rare: Severe hypersensitivity1

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Very Anorexia Dehydration, decreased Decreased appetitecommon: appetite, hypokalaemia

Common: Dehydration, decreased Dehydrationappetite, hypokalaemia

Uncommon: Hypophosphataemia, fluidretention, hypoalbuminaemia,polydipsia, hyperglycaemia,hypocalcaemia, hypoglycaemia,hyponatraemia

Not known: Tumour lysis syndrome1

Very Depression, insomniacommon:

Common: Depression, insomnia, anxiety Anxiety

Uncommon: Restlessness Insomnia

Very Peripheral neuropathy, Peripheral neuropathy, Peripheral neuropathycommon: neuropathy, hypoaesthesia, dizziness, headache,paraesthesia dysgeusia

Common: Peripheral sensory neuropathy, Dizziness, headache,dizziness, peripheral motor dysgeusianeuropathy, ataxia, headache,sensory disturbance,somnolence, dysgeusia

Uncommon: Polyneuropathy, areflexia, VIIth nerve paralysissyncope, postural dizziness,dyskinesia, hyporeflexia,neuralgia, neuropathic pain,tremor, sensory loss

Not known: Cranial nerve palsies multiple1

Common: Vision blurred, lacrimation Lacrimation increased Vision blurredincreased, dry eye,keratoconjunctivitis sicca,madarosis

Uncommon: Reduced visual acuity, Cystoid macularabnormal vision, eye irritation, oedemaeye pain, conjunctivitis, visualdisturbance, eye pruritus,keratitis

Rare: Cystoid macular oedema1

Ear and labyrinth disorders

Common: Vertigo

Uncommon: Tinnitus, ear pain

Common: Arrhythmia, tachycardia, Cardiac failuresupraventricular tachycardia congestive, tachycardia

Rare: Cardiac arrest, cardiac failurecongestive, left ventriculardysfunction, atrioventricularblock1, bradycardia

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Common: Hypertension, lymphoedema, Hypotension, Hypotension,flushing, hot flushes hypertension hypertension

Uncommon: Hypotension, orthostatic Flushing Flushinghypotension, peripheralcoldness

Rare: Thrombosis

Very Dyspnoea, epistaxis, Dyspnoeacommon: cough

Common: Interstitial pneumonitis2, Pneumonitis, nasal Haemoptysis,dyspnoea, epistaxis, congestion epistaxis, coughpharyngolaryngeal pain, cough,rhinitis, rhinorrhoea

Uncommon: Pulmonary emboli, pulmonary Dry throat, nasal Pneumonitisthromboembolism, pleural drynesseffusion, exertional dyspnoea,sinus congestion, decreasedbreath sounds, productivecough, allergic rhinitis,hoarseness, nasal congestion,nasal dryness, wheezing

Not known: Vocal cord paresis1

Very Diarrhoea, vomiting, nausea, Diarrhoea, vomiting, Diarrhoea, vomiting,common: constipation, stomatitis nausea, constipation, nausea, constipationabdominal pain,abdominal pain upper

Common: Gastrooesophageal reflux Intestinal obstruction, Stomatitis, dyspepsia,disease, dyspepsia, abdominal colitis, stomatitis, dry dysphagia, abdominalpain, abdominal distension, mouth painabdominal pain upper, oralhypoaesthesia

Uncommon: Rectal haemorrhage, dysphagia,flatulence, glossodynia, drymouth, gingival pain, loosestools, oesophagitis, abdominalpain lower, mouth ulceration,oral pain

Common: Cholangitis Hyperbilirubinaemia

Uncommon: Hepatomegaly

Very Alopecia, rash Alopecia, rash Alopecia, rashcommon:

Common: Pruritus, dry skin, nail disorder, Pruritus, dry skin, nail Pruritus, nail disordererythema, nail disorderpigmentation/discolouration,skin hyperpigmentation,onycholysis, nail changes

Uncommon: Photosensitivity reaction, Skin exfoliation,urticaria, skin pain, generalised dermatitis allergic,pruritus, pruritic rash, skin urticaria

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)disorder, pigmentation disorder,hyperhidrosis, onychomadesis,erythematous rash, generalisedrash, dermatitis, night sweats,maculo-papular rash, vitiligo,hypotrichosis, nail bedtenderness, nail discomfort,macular rash, papular rash, skinlesion, swollen face

Very rare: Stevens-Johnson syndrome1,toxic epidermal necrolysis1

Not known: Palmar-plantarerythrodysaesthesiaesyndrome1,4, scleroderma1

Very Arthralgia, myalgia Arthralgia, myalgia, Arthralgia, myalgiacommon: pain in extremity

Common: Back pain, pain in extremity, Muscular weakness, Back pain, pain inbone pain, muscle cramps, limb bone pain extremity,pain musculoskeletal pain

Uncommon: Chest wall pain, muscularweakness, neck pain, groin pain,muscle spasms, musculoskeletalpain, flank pain, limbdiscomfort, muscle weakness

Common: Acute renal failure

Uncommon: Haematuria, dysuria, Haemolytic uraemicpollakiuria, nocturia, polyuria, syndromeurinary incontinence

Uncommon: Breast pain

Very Fatigue, asthenia, pyrexia Fatigue, asthenia, Fatigue, asthenia,common: pyrexia, oedema oedema peripheralperipheral, chills

Common: Malaise, lethargy, weakness, Infusion site reaction Pyrexia, chest painperipheral oedema, mucosalinflammation, pain, rigors,oedema, decreased performancestatus, chest pain, influenza-likeillness, hyperpyrexia

Uncommon: Chest discomfort, abnormal Mucosal inflammation,gait, swelling, injection site infusion sitereaction extravasation, infusionsite inflammation,infusion site rash

Rare: Extravasation

Monotherapy (N=789) Combination therapy Combination therapywith gemcitabine with carboplatin(N =421) (N = 514)

Very Weight decreased,common: alanineaminotransferaseincreased

Common: Decreased weight, increased Aspartate Weight decreased,alanine aminotransferase, aminotransferase alanineincreased aspartate increased, blood aminotransferaseaminotransferase, decreased bilirubin increased, increased, aspartatehaematocrit, decreased red blood creatinine aminotransferaseblood cell count, increased body increased increased, bloodtemperature, increased gamma- alkaline phosphataseglutamyltransferase, increased increasedblood alkaline phosphatase

Uncommon: Increased blood pressure,increased weight, increasedblood lactate dehydrogenase,increased blood creatinine,increased blood glucose,increased blood phosphorus,decreased blood potassium,increased bilirubin

Uncommon: Contusion

Rare: Radiation recall phenomenon,radiation pneumonitis1As reported in the post-marketing surveillance of human serum albumin-paclitaxel nanoparticles.2The frequency of pneumonitis is calculated based on pooled data in 1,310 patients in clinicaltrials receiving human serum albumin-paclitaxel nanoparticles monotherapy for breast cancer andfor other indications.3Based on laboratory assessments: maximal degree of myelosuppression (treated population).4In some patients previously exposed to capecitabine.

This section contains the most common and clinically relevant adverse reactions related to human serumalbumin-paclitaxel nanoparticles injection.

Adverse reactions were assessed in 229 patients with metastatic breast cancer who were treated with260 mg/m2 human serum albumin-paclitaxel nanoparticles once every three weeks in the pivotal phase

III clinical study (human serum albumin-paclitaxel nanoparticles monotherapy).

Adverse reactions were assessed in 421 patients with metastatic pancreatic cancer who were treated withserum albumin-paclitaxel nanoparticles in combination with gemcitabine (125 mg/m2 human serumalbumin-paclitaxel 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 receivingfirst-line systemic treatment for metastatic adenocarcinoma of the pancreas (human serumalbumin-paclitaxel nanoparticles /gemcitabine).

Adverse reactions were assessed in 514 patients with non-small cell lung cancer who were treated withhuman serum albumin-paclitaxel nanoparticles in combination with carboplatin (100 mg/m2 humanserum albumin-paclitaxel nanoparticles given on Days 1, 8 and 15 of each 21-day cycle in combinationwith carboplatin given on Day 1 of each cycle) in the phase III randomized, controlled clinical trial(human serum albumin-paclitaxel nanoparticles/carboplatin). Patient-reported taxane toxicity wasassessed using the 4 subscales of the Functional Assessment of Cancer Therapy (FACT)- Taxanequestionnaire. Using repeated measure analysis, 3 of the 4 subscales (peripheral neuropathy, painhands/feet and hearing) favoured human serum albumin-paclitaxel nanoparticles and carboplatin(p ≤ 0.002). For the other subscale (oedema), there was no difference in the treatment arms.

Human serum albumin-paclitaxel nanoparticles/gemcitabine

Sepsis was reported at a rate of 5% in patients with or without neutropenia who received human serumalbumin-paclitaxel nanoparticles in combination with gemcitabine during the conduct of a trial inpancreatic adenocarcinoma. Of the 22 cases of sepsis reported in patients treated with human serumalbumin-paclitaxel nanoparticles in combination with gemcitabine, 5 had a fatal outcome.

Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence ofbiliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardlessof neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold

Naveruclif and gemcitabine until fever resolves and ANC ≥ 1,500 cells/mm3, then resume treatment atreduced dose levels (see section 4.2).

Human serum albumin-paclitaxel nanoparticles monotherapy-metastatic breast cancer

In patients with metastatic breast cancer, neutropenia was the most notable important haematologicaltoxicity (reported in 79% of patients) and was rapidly reversible and dose-dependent; leukopenia wasreported in 71% of patients. Grade 4 neutropenia (< 500 cells/mm3) occurred in 9% of patients treatedwith human serum albumin-paclitaxel nanoparticles. Febrile neutropenia occurred in four patients onhuman serum albumin-paclitaxel nanoparticles. Anaemia (Hb < 10 g/dl) was observed in 46% ofpatients on human serum albumin-paclitaxel nanoparticles and was severe (Hb < 8 g/dl) in three cases.

Lymphopenia was observed in 45% of the patients.

Human serum albumin-paclitaxel nanoparticles/gemcitabine

Table 7 provides the frequency and severity of haematologic laboratory-detected abnormalities forpatients treated with human serum albumin-paclitaxel nanoparticles in combination with gemcitabine orwith gemcitabine.

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

Human serum albumin-paclitaxel Gemcitabinenanoparticles(125 mg/ m2)/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 9a405 patients assessed in human serum albumin-paclitaxel nanoparticles/gemcitabine-treated groupb388 patients assessed in gemcitabine-treated groupc404 patients assessed in human serum albumin-paclitaxel nanoparticles/gemcitabine-treated group

Human serum albumin-paclitaxel nanoparticles/carboplatin

Anaemia and thrombocytopenia were more commonly reported in the human serum albumin-paclitaxelnanoparticles and carboplatin arm than in the Taxol and carboplatin arm (54% versus 28% and 45%versus 27% respectively).

Human serum albumin-paclitaxel nanoparticles monotherapy-metastatic breast cancer

In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving humanserum albumin-paclitaxel nanoparticles. Peripheral neuropathy (mostly Grade 1 or 2 sensoryneuropathy) was observed in 68% of patients on human serum albumin-paclitaxel nanoparticles with10% being Grade 3, and no cases of Grade 4.

Human serum albumin-paclitaxel nanoparticles/gemcitabine

For patients treated with human serum albumin-paclitaxel nanoparticles in combination withgemcitabine, the median time to first occurrence of Grade 3 peripheral neuropathy was 140 days. Themedian 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 interrupteddue to peripheral neuropathy, 44% (31/70 patients) were able to resume human serum albumin-paclitaxel nanoparticles at a reduced dose. No patients treated with human serum albumin-paclitaxelnanoparticles in combination with gemcitabine had Grade 4 peripheral neuropathy.

Human serum albumin-paclitaxel nanoparticles/carboplatin

For non-small cell lung cancer patients treated with human serum albumin-paclitaxel nanoparticles andcarboplatin, the median time to first occurrence of Grade 3 treatment-related peripheral neuropathy was121 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 andcarboplatin experienced Grade 4 peripheral neuropathy.

There have been rare reports during post-marketing surveillance of reduced visual acuity due to cystoidmacular oedema during treatment with human serum albumin-paclitaxel nanoparticles (see section 4.4).

Human serum albumin-paclitaxel nanoparticles/gemcitabine

Pneumonitis has been reported at a rate of 4% with the use of human serum albumin-paclitaxelnanoparticles in combination with gemcitabine. Of the 17 cases of pneumonitis reported in patientstreated with human serum albumin-paclitaxel nanoparticles in combination with gemcitabine, 2 had afatal outcome. Monitor patients closely for signs and symptoms of pneumonitis.

After ruling out infectious aetiology and upon making a diagnosis of pneumonitis, permanentlydiscontinue treatment with Naveruclif and gemcitabine and promptly initiate appropriate treatment andsupportive measures (see section 4.2).

Human serum albumin-paclitaxel nanoparticles monotherapy-metastatic breast cancer

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

Human serum albumin-paclitaxel nanoparticles monotherapy-metastatic breast cancer

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

Human serum albumin-paclitaxel nanoparticles monotherapy-metastatic breast cancer

Arthralgia occurred in 32% of patients on human serum albumin-paclitaxel nanoparticles and wassevere in 6% of cases. Myalgia occurred in 24% of patients on human serum albumin-paclitaxelnanoparticles and was severe in 7% of cases. The symptoms were usually transient, typically occurredthree days after human serum albumin-paclitaxel nanoparticles administration and resolved within aweek.

Human serum albumin-paclitaxel nanoparticles monotherapy-metastatic breast cancer

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

The study consisted of 106 patients, 104 of whom were paediatric patients aged from 6 months to lessthan 18 years (see section 5.1). Every patient experienced at least 1 adverse reaction. The mostfrequently reported adverse reactions were neutropenia, anaemia, leukopenia and pyrexia. Seriousadverse reactions reported in more than 2 patients were pyrexia, back pain, peripheral oedema andvomiting. No new safety signals were identified in the limited number of paediatric patients treatedwith human serum albumin-paclitaxel nanoparticles and the safety profile was similar to that of theadult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should beclosely monitored. Treatment should be directed at the major anticipated toxicities, which are bonemarrow suppression, mucositis and peripheral neuropathy.

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

ATC code: L01CD01

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

Naveruclif contains human serum albumin-paclitaxel nanoparticles of approximately 180 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 approximately10 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 acrossendothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediatedby the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area oftumour due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC).

Breast cancer

Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated ina 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-minuteinfusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utiliseda dose of 300 mg/m2 as a 30- minute infusion in 63 patients with metastatic breast cancer. Patientswere 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 treatedevery 3 weeks with single-agent paclitaxel, either as solvent-based paclitaxel 175 mg/m2 given as a3-hour infusion with premedication to prevent hypersensitivity (N = 225), or as human serumalbumin-paclitaxel 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 patientshad 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-ninepercent 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 andsurvival for patients receiving > 1st-line therapy, are shown below.

Table 8: Results for overall response rate, median time to disease progression, and progression-free survival as assessed by the investigator

Efficacy variable Human serum Solvent-based p-valuealbumin-paclitaxel paclitaxel (175 mg/m2)nanoparticles(260 mg/m2)

Response rate [95% CI] (%)> 1st-line therapy 26.5 [18.98, 34.05] 13.2 [7.54, 18.93] 0.006a(n = 132) (n = 136)

*Median time to disease progression [95% CI] (weeks)> 1st-line therapy 20.9 [15.7, 25.9] 16.1 [15.0, 19.3] 0.011b(n = 131) (n = 135)

*Median progression free survival [95% CI] (weeks)> 1st-line therapy 20.6 [15.6, 25.9] 16.1 [15.0, 18.3] 0.010b(n = 131) (n = 135)

*Survival [95% CI] (weeks)> 1st-line therapy 56.4 [45.1, 76.9] 46.7 [39.0, 55.3] 0.020b(n = 131) (n = 136)

*This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005)aChi-squared testbLog-rank test

Two hundred and twenty nine patients treated with human serum albumin-paclitaxel nanoparticles in therandomized, controlled clinical trial were evaluated for safety. Neurotoxicity to paclitaxel was evaluatedthrough improvement by one grade for patients experiencing Grade 3 peripheral neuropathy at any timeduring therapy. The natural course of peripheral neuropathy to resolution to baseline due to cumulativetoxicity of human serum albumin-paclitaxel nanoparticles after > 6 courses of treatment was notevaluated and remains unknown.

Pancreatic adenocarcinoma

A multicenter, multinational, randomized, open-label study was conducted in 861 patients to comparehuman serum albumin-paclitaxel nanoparticles/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Human serumalbumin-paclitaxel nanoparticles were administered to patients (N = 431) as an intravenous infusionover 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 comparatortreatment arm, gemcitabine monotherapy was administered to patients (N = 430) in accordance with therecommended dose and regimen. Treatment was administered until disease progression or developmentof an unacceptable toxicity. Of the 431 patients with pancreatic adenocarcinoma who were randomizedto 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 of100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70; and <1% of patients had a KPSof below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or ofconnective 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-paclitaxelnanoparticles/gemcitabine arm and 2.8 months in the gemcitabine arm. 32% of patients in the humanserum albumin-paclitaxel nanoparticles/gemcitabine arm compared with 15% of patients in thegemcitabine arm received 6 or more months of treatment. For the treated population, the medianrelative dose intensity for gemcitabine was 75% in the human serum albumin-paclitaxelnanoparticles/gemcitabine arm and 85% in the gemcitabine arm. The median relative dose intensity ofhuman serum albumin-paclitaxel nanoparticles was 81%. A higher median cumulative dose ofgemcitabine 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 wereprogression- free survival (PFS) and overall response rate (ORR), both assessed by independent, central,blinded radiological review using RECIST guidelines (Version 1.0).

Table 9: Efficacy results from randomized study in patients with pancreatic adenocarcinoma(Intent-to-treat population)

Human serum albumin-paclitaxel Gemcitabine (N=430)nanoparticles(125 mg/m2)/gemcitabine (N=431)

Overall Survival

Number of deaths (%) 333 (77) 359 (83)

Median Overall Survival, months 8.5 (7.89, 9.53) 6.7 (6.01, 7.23)(95% CI)

HRA+G/G (95% CI) a 0.72 (0.617, 0.835)

P-valueb <0.0001

Survival Rate % (95% CI) at1 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 Survival14.8 11.4(months)

Progression-free Survival

Death or progression, n (%) 277 (64) 265 (62)

Median Progression-free 5.5 (4.47, 5.95) 3.7 (3.61, 4.04)

Survival, months (95% CI)

HRA+G/G (95% CI) a 0.69 (0.581, 0.821)

P-valueb <0.0001

Overall Response Rate

Confirmed complete or partial 99 (23) 31 (7)

Human serum albumin-paclitaxel Gemcitabine (N=430)nanoparticles(125 mg/m2)/gemcitabine (N=431)overall response, n (%)95% CI 19.1, 27.2 5.0, 10.1pA+G /pG (95% CI) 3.19 (2.178, pct. 4.662)

P-value (chi-square test) <0.0001

CI = confidence interval, HRA+G/G = hazard ratio of human serum albumin-paclitaxelnanoparticles+gemcitabine/gemcitabine, pA+G/pG=response rate ratio of human serum albumin-paclitaxel nanoparticles+gemcitabine/gemcitabinea stratified Cox proportional hazard modelb stratified log-rank test, stratified by geographic region (North America versus others), KPS (70 to 80versus 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 in2-year survival rates.

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

Treatment effects on OS favoured the human serum albumin-paclitaxel nanoparticles/gemcitabine armacross the majority of pre-specified subgroups (including gender, KPS, geographic region, primarylocation of pancreatic cancer, stage at diagnosis, presence of liver metastases, presence of peritonealcarcinomatosis, prior Whipple procedure, presence of biliary stent at baseline, presence of pulmonarymetastases, 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 serumalbumin-paclitaxel nanoparticles /gemcitabine versus gemcitabine alone, with 1.8 months increase inmedian PFS.

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-paclitaxelnanoparticles in combination with carboplatin versus solvent-based paclitaxel in combination withcarboplatin as first-line treatment in patients with advanced non-small cell lung cancer. Over 99% ofpatients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Patientswith pre-existing neuropathy of Grade ≥ 2 or serious medical risk factors involving any of the majororgan systems were excluded. Human serum albumin-paclitaxel nanoparticles were administered topatients (N=521) as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8 and15 of each 21-day cycle without any steroid premedication and without granulocyte colony stimulatingfactor prophylaxis. Beginning immediately after the end of human serum albumin-paclitaxelnanoparticles administration, carboplatin at a dose of AUC = 6 mg*min/mL was administeredintravenously on Day 1 only of each 21-day cycle. Solvent- based paclitaxel was administered topatients (N=531) at a dose of 200 mg/m2 as an intravenous infusion over 3 hours with standardpremedication, immediately followed by carboplatin administered intravenously at AUC =6 mg*min/mL. Each drug was administered on Day 1 of each 21-day cycle. In both study armstreatment 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 whoachieved 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 withpatients in the control arm: 33% versus 25%, p = 0.005 (Table 10). There was a significant difference inoverall response rate in the human serum albumin-paclitaxel nanoparticles/carboplatin arm comparedto 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 nodifference in ORR between the treatment arms in patients with non-squamous histology (N=602, 26%vs 25%, p=0.808).

Table 10: Overall response rate in randomized non-small cell lung cancer trial (intent-to-treatpopulation)

Efficacy Parameter Human serum Solvent-basedalbumin-paclitaxel paclitaxel (200 mg/m2nanoparticles every 3 weeks) +(100 mg/m2/week) carboplatin (N=531)+ carboplatin(N=521)

Overall Response Rate (independent review)

Confirmed complete or partial overall response, n (%) 170 (33%) 132 (25%)95% CI (%) 28.6, 36.7 21.2, 28.5pA/pT (95.1% CI) 1.313 (1.082, 1.593)

P-valuea 0.005

CI = confidence interval; HRA/T = hazard ratio of human serum albumin-paclitaxelnanoparticles/carboplatin to solvent-based paclitaxel/carboplatin;pA/pT = response rate ratio of human serum albumin-paclitaxel nanoparticles/carboplatin to solvent-based paclitaxel/carboplatin.aP-value is based on a chi-square test.

There was no statistically significant difference in progression-free survival (by blinded radiologistassessment) and overall survival between the two treatment arms. A non-inferiority analysis wasconducted for PFS and OS, with a pre-specified non-inferiority margin of 15%. The non-inferioritycriterion was met for both PFS and OS with the upper bound of the 95% confidence interval for theassociated hazard ratios being less than 1.176 (Table 11).

Table 11: Non-inferiority analyses on progression-free survival and overall survival inrandomized non-small cell lung cancer trial (intent-to-treat population)

Efficacy Parameter Human serum albumin- Solvent-based paclitaxelpaclitaxel nanoparticles (200 mg/m2 every 3 weeks) +(100 mg/m2/week) + carboplatin (N=531)carboplatin (N=521)

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-paclitaxelnanoparticles/carboplatin to solvent-based paclitaxel/carboplatin;pA/pT = response rate ratio of human serum albumin-paclitaxel nanoparticles/carboplatin to solvent-based paclitaxel/carboplatin.aPer EMA methodological considerations for PFS endpoint, missing observations or initiation ofsubsequent new therapy were not used for censoring.

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 inpaediatric patients with recurrent or refractory solid tumours included a total of 106 patients aged ≥ 6months to ≤ 24 years.

The Phase 1 portion of the study included a total of 64 patients aged from 6 months to less than 18 yearsold and determined the maximum tolerated dose (MTD) to be 240 mg/m2, administered as anintravenous 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 from6 months to 24 years with recurrent or refractory Ewing’s sarcoma, neuroblastoma orrhabdomyosarcoma 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 and2 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 efficacyevaluation in stage 1, 1 patient in the rhabdomyosarcoma group (N=14) had a confirmed partialresponse (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 patientsto 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) forthe Ewing’s sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively.

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

The pharmacokinetics of total paclitaxel following 30- and 180 minute infusions of human serumalbumin-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 from80 to 300 mg/m2.

In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxelfollowing human serum albumin-paclitaxel nanoparticles administered intravenously at 260 mg/m2 over30 minutes were compared with those following 175 mg/m2 of the solvent-based paclitaxel injectionadministered over 3 hours. Based on non-compartmental PK analysis, the plasma clearance of paclitaxelwith 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 nodifferences in terminal half-lives.

In a repeat dose study with 12 patients receiving human serum albumin-paclitaxel nanoparticlesadministered 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.

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 wasevaluated by ultrafiltration in a within-patient comparison study. The fraction of free paclitaxel wassignificantly higher with human serum albumin-paclitaxel nanoparticles (6.2%) than with solvent-basedpaclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with humanserum albumin-paclitaxel nanoparticles compared with solvent-based paclitaxel, even though the totalexposure is comparable. This is possibly due to paclitaxel not being trapped in Cremophor EL micellesas with solvent-based paclitaxel. Based on the published literature, in vitro studies of binding to humanserum proteins, (using paclitaxel at concentrations ranging from 0.1 to 50 µg/ml), indicate that thepresence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein bindingof 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 ofpaclitaxel.

Based on the published literature, in vitro studies with human liver microsomes and tissue slices showthat paclitaxel is metabolised primarily to 6α-hydroxypaclitaxel; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α-3’-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites iscatalysed by CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4 isoenzymes, respectively.

In patients with metastatic breast cancer, after a 30-minute infusion of human serum albumin-paclitaxelnanoparticles at 260 mg/m2, the mean value for cumulative urinary excretion of unchanged activesubstance accounted for 4% of the total administered dose with less than 1% as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel, indicating extensive non-renal clearance. Paclitaxel isprincipally 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 from13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.

The effect of hepatic impairment on population pharmacokinetics of human serum albumin-paclitaxelnanoparticles was studied in patients with advanced solid tumours. This analysis included patients withnormal hepatic function (n=130), and pre-existing mild (n=8), moderate (n=7), or severe (n=5) hepaticimpairment (according to NCI Organ Dysfunction Working Group criteria). The results show that mildhepatic impairment (total bilirubin >1 to ≤1.5 x ULN) has no clinically important effect onpharmacokinetics 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 maximumelimination rate of paclitaxel and approximately 20% increase in mean paclitaxel AUC compared withpatients with normal hepatic function. Hepatic impairment has no effect on mean paclitaxel Cmax. Inaddition, elimination of paclitaxel shows an inverse correlation with total bilirubin and a positivecorrelation with serum albumin.

Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation between hepaticfunction (as indicated by the baseline albumin or total bilirubin level) and neutropenia after adjusting forhuman serum albumin-paclitaxel nanoparticles exposure.

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

Population pharmacokinetic analysis included patients with normal renal function (n=65), and pre-existing mild (n=61), moderate (n=23), or severe (n=l) renal impairment (according to draft FDAguidance 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 andnot available for patients with end stage kidney disease.

Population pharmacokinetic analysis for human serum albumin-paclitaxel nanoparticles includedpatients with ages ranging from 24 to 85 years old and shows that age does not significantly influencethe maximum elimination rate and systemic exposure (AUC and Cmax) of paclitaxel.

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

The pharmacokinetics of paclitaxel following 30 minutes of intravenous administration at dose levels of120 mg/m2 to 270 mg/m2 were determined in 64 patients (2 to ≤ 18 years) in Phase 1 of a Phase 1/2study in recurrent or refractory paediatric solid tumours. Following dosing increase from 120 to270 mg/m2, the paclitaxel mean AUC(0-inf) and Cmax ranged from 8867 to 14361 ng*hr/ml and from3488 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 drugexposures were higher than in adult patients.

Other intrinsic factors

Population pharmacokinetic analyses for human serum albumin-paclitaxel nanoparticles indicate thatgender, race (Asian vs. White), and type of solid tumours do not have a clinically important effect onsystemic exposure (AUC and Cmax) of paclitaxel. Patients weighing 50 kg had paclitaxel AUCapproximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is uncertain.

The carcinogenic potential of paclitaxel has not been studied. However, based on the publishedliterature, paclitaxel is a potentially carcinogenic and genotoxic agent at clinical doses, based upon itspharmacodynamic 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 hasbeen 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 whenadministered prior and during mating in male and female rats and foetal toxicity in rats. Animal studieswith human serum albumin-paclitaxel nanoparticles showed non-reversible, toxic effects on the malereproductive organs at clinically relevant exposure levels.

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

Albumin (human) (containing sodium caprylate and N-acetyl-L-tryptophan).

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

Unopened vials2 years

Stability of reconstituted dispersion in the vial

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C in the originalcarton when protected from light.

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 whenprotected from light followed by 4 hours at 25°C, when not protected from light.

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

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

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

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

Reconstituted dispersion

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

50 ml vial (type 1 glass) with a stopper (bromobutyl rubber), with an overseal (aluminium),containing 100 mg of paclitaxel formulated as albumin bound nanoparticles.

Pack size of one vial.

Preparation and administration precautions

Paclitaxel is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds,caution should be exercised in handling Naveruclif. The use of gloves, goggles and protectiveclothing is recommended. If the dispersion contacts the skin, the skin should be washed immediatelyand thoroughly with soap and water. If it contacts mucous membranes, the membranes should beflushed thoroughly with water. Naveruclif should only be prepared and administered by personnelappropriately trained in the handling of cytotoxic agents. Pregnant staff should not handle Naveruclif.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possibleinfiltration during administration of the medicinal product. Limiting the infusion of Naveruclif to30 minutes, as directed, reduces the likelihood of infusion-related reactions.

Reconstitution and administration of the product

Naveruclif is supplied as a sterile lyophilised powder for reconstitution before use. Afterreconstitution, each ml of dispersion contains 5 mg of paclitaxel formulated as albumin boundnanoparticles.

100 mg vial: Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusionshould slowly be injected into a vial of Naveruclif over a minimum of 1 minute.

The solution should be directed onto the inside wall of the vial. The solution should not be injecteddirectly 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 toensure proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or invertedfor at least 2 minutes until complete redispersion of any powder occurs. The generation of foam mustbe avoided. If foaming or clumping occurs, the dispersion must stand for at least 15 minutes untilfoam subsides.

The reconstituted dispersion should be milky and homogenous without visible precipitates. Somesettling of the reconstituted dispersion may occur. If precipitates or settling are visible, the vial shouldbe gently inverted again to ensure complete redispersion prior to use.

Inspect the dispersion in the vial for particulate matter. Do not administer the reconstituted dispersionif particulate matter is observed in the vial.

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

The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) toreconstitute and administer Naveruclif may result in the formation of proteinaceous strands.

Administer Naveruclif using an infusion set incorporating a 15 µm filter to avoid administration ofthese strands. Use of a 15 µm filter removes strands and does not change the physical or chemicalproperties of the reconstituted product.

Use of filters with a pore size less than 15 µm may result in blockage of the filter.

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

Following administration, it is recommended that the intravenous line be flushed with sodiumchloride 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.

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est 6ª planta08039 Barcelona

Spain

EU/1/23/1778/001

Date of first authorisation: 05 January 2024.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu