NAVERUCLIF

Naveruclif® 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 Naveruclif® 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 Naveruclif® therapy should have the dose reduced to 220 mg/m2 for subsequent courses.

Following recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. Naveruclif® 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 Naveruclif® 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 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 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) Naveruclif® Dose Gemcitabine 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 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 ≥ 1,000 AND ≥ 75,000 Return to the Day 1 dose levels and follow with WBC Growth Factors OR Treat with same doses as Day 8 ≥ 500 but < 1,000 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 ≥ 1,000 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 < 1,000 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) Naveruclif® Dose Gemcitabine Dose Febrile Neutropenia: Grade 3 or 4 Withhold doses until fever resolves and ANC ≥ 1500; resume at next lower dose levela Peripheral Neuropathy: Grade 3 or 4 Withhold dose until improves to ≤ Grade 1; resume at next lower dose levela Treat with same dose Cutaneous Toxicity: Grade 2 or 3 Reduce to next lower dose levela; discontinue treatment if ADR persists Gastrointestinal Toxicity: Grade 3 mucositis or diarrhoea Withhold doses until improves to ≤ Grade 1, resume at next lower dose levela a.

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.

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

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

Table 6:

Adverse reactions reported with human serum albumin-paclitaxel nanoparticles Monotherapy (N=789) Combination therapy with gemcitabine (N =421) Combination therapy with carboplatin (N = 514) Infections and infestations Common: Infection, urinary tract infection, folliculitis, upper respiratory tract infection, candidiasis, sinusitis Sepsis, pneumonia, oral candidiasis Pneumonia, bronchitis, upper respiratory tract infection, urinary tract infection Uncommon: Sepsis1, neutropenic sepsis1, pneumonia, oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, herpes zoster, fungal infection, catheter- related infection, injection site infection Sepsis, oral candidiasis Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: Tumour necrosis, metastatic pain Blood and lymphatic system disorders Very common: Bone marrow suppression, neutropenia, thrombocytopenia, anaemia, leukopenia, lymphopenia Neutropenia, thrombocytopenia, anaemia Neutropenia3, thrombocytopenia3, anaemia3, leukopenia3 Common: Febrile neutropenia Pancytopenia Febrile neutropenia, lymphopenia Uncommon: Thrombotic Pancytopenia Monotherapy (N=789) Combination therapy with gemcitabine (N =421) Combination therapy with carboplatin (N = 514) thrombocytopenic purpura Rare: Pancytopenia Immune system disorders Uncommon: Hypersensitivity Drug hypersensitivity, hypersensitivity Rare: Severe hypersensitivity1 Metabolism and nutrition disorders Very common: Anorexia Dehydration, decreased appetite, hypokalaemia Decreased appetite Common: Dehydration, decreased appetite, hypokalaemia Dehydration Uncommon: Hypophosphataemia, fluid retention, hypoalbuminaemia, polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia, hyponatraemia Not known: Tumour lysis syndrome1 Psychiatric disorders Very common: Depression, insomnia Common: Depression, insomnia, anxiety Anxiety Insomnia Uncommon: Restlessness Nervous system disorders Very common: Peripheral neuropathy, neuropathy, hypoaesthesia, paraesthesia Peripheral neuropathy, dizziness, headache, dysgeusia Peripheral neuropathy Common: Peripheral sensory neuropathy, dizziness, peripheral motor neuropathy, ataxia, headache, sensory disturbance, somnolence, dysgeusia Dizziness, headache, dysgeusia Uncommon: Polyneuropathy, areflexia, syncope, postural dizziness, dyskinesia, hyporeflexia, neuralgia, neuropathic pain, tremor, sensory loss VIIth nerve paralysis Not known: Cranial nerve palsies multiple1 Eye disorders Common: Vision blurred, lacrimation increased, dry eye, keratoconjunctivitis sicca, madarosis Lacrimation increased Vision blurred Uncommon: Reduced visual acuity, abnormal vision, eye irritation, eye pain, conjunctivitis, visual disturbance, eye pruritus, keratitis Cystoid macular oedema Rare: Cystoid macular oedema1 Ear and labyrinth disorders Common: Vertigo Uncommon: Tinnitus, ear pain Cardiac disorders Common: Arrhythmia, tachycardia, supraventricular tachycardia Cardiac failure congestive, tachycardia Rare: Cardiac arrest, cardiac failure congestive, left ventricular Monotherapy (N=789) Combination therapy with gemcitabine (N =421) Combination therapy with carboplatin (N = 514) dysfunction, atrioventricular block1, bradycardia Vascular disorders Common: Hypertension, lymphoedema, flushing, hot flushes Hypotension, hypertension Hypotension, hypertension Uncommon: Hypotension, orthostatic hypotension, peripheral coldness Flushing Flushing Rare: Thrombosis Respiratory, thoracic and mediastinal disorders Very common: Dyspnoea, epistaxis, cough Dyspnoea Common: Interstitial pneumonitis2, dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhoea Pneumonitis, nasal congestion Haemoptysis, epistaxis, cough Uncommon: Pulmonary emboli, pulmonary thromboembolism, pleural effusion, exertional dyspnoea, sinus congestion, decreased breath sounds, productive cough, allergic rhinitis, hoarseness, nasal congestion, nasal dryness, wheezing Dry throat, nasal dryness Pneumonitis Not known: Vocal cord paresis1 Gastrointestinal disorders Very common: Diarrhoea, vomiting, nausea, constipation, stomatitis Diarrhoea, vomiting, nausea, constipation, abdominal pain, abdominal pain upper Diarrhoea, vomiting, nausea, constipation Common: Gastrooesophageal reflux disease, dyspepsia, abdominal pain, abdominal distension, abdominal pain upper, oral hypoaesthesia Intestinal obstruction, colitis, stomatitis, dry mouth Stomatitis, dyspepsia, dysphagia, abdominal pain Uncommon: Rectal haemorrhage, dysphagia, flatulence, glossodynia, dry mouth, gingival pain, loose stools, oesophagitis, abdominal pain lower, mouth ulceration, oral pain Hepatobiliary disorders Common: Cholangitis Hyperbilirubinaemia Uncommon: Hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, rash Alopecia, rash Alopecia, rash Common: Pruritus, dry skin, nail disorder, […]

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 albumin-paclitaxel nanoparticles.

Neutropenia is dose-dependent and a dose- limiting toxicity. Frequent monitoring of blood cell counts should be performed during Naveruclif® therapy. 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. 2). For combination use of Naveruclif® and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Naveruclif®; continue treatment with gemcitabine at the same dose.

2). 2). Sepsis Sepsis was reported at a rate of 5% in patients with or without neutropenia who received human serum albumin-paclitaxel nanoparticles in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors.

If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. 2). Pneumonitis Pneumonitis occurred in 1% of patients when human serum albumin-paclitaxel nanoparticles was used as monotherapy and in 4% of patients when human serum albumin-paclitaxel nanoparticles were used in combination with gemcitabine.

Closely monitor all patients for signs and symptoms of pneumonitis. 2). Hepatic impairment Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Naveruclif® in patients with hepatic impairment should be performed with caution.

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