Apexelsin · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-288906 · has-adverse-reaction-information · PDF-Seite 10

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 Combination therapy with therapy with gemcitabine carboplatin (N = 421) (N = 514) Infections and infestations Infection, urinary tract Sepsis, pneumonia, Pneumonia, infection, folliculitis, upper oral candidiasis bronchitis, upper Common: respiratory tract infection, respiratory tract candidiasis, sinusitis infection, urinary tract infection Sepsis1, neutropenic sepsis1, Sepsis, oral pneumonia, oral candidiasis, candidiasis nasopharyngitis, cellulitis, herpes simplex, viral Uncommon: infection, herpes zoster, fungal infection, catheter

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HOS-288902 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Lactation (see section 4.6). 6 Patients who have baseline neutrophil counts < 1500 cells/mm3.

HOS-288901 · has-indication-information · PDF-Seite 2

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

HOS-288904 · has-interaction-information · PDF-Seite 8

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, 8 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 Apexelsin 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 nanoparticles and carboplatin. Apexelsin 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). Apexelsin should not be used in combination with other anticancer agents. Paediatric population Interaction studies have only been performed in adults.

HOS-288905 · has-pregnancy-information · PDF-Seite 9

Contraception in males and females Women of childbearing potential should use effective contraception during treatment and for at least six months after the last dose of Apexelsin. Male patients with female partners of reproductive potential are advised to use effective contraception and to avoid fathering a child during treatment with Apexelsin and for at least three months after the last dose of Apexelsin. 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 Apexelsin. Apexelsin 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, Apexelsin 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 Apexelsin.

HOS-288903 · has-warning-information · PDF-Seite 7

Apexelsin 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 albumin-paclitaxel nanoparticles. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Apexelsin therapy. Patients should not be retreated with subsequent cycles of Apexelsin 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 Apexelsin 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 Apexelsin is recommended (see section 4.2). For combination use of Apexelsin and gemcitabine, if Grade 3 or higher peripheral neuropathy develops, withhold Apexelsin; continue treatment with gemcitabine at the same dose. Resume Apexelsin at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2). For combination use Apexelsin 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 Apexelsin and carboplatin (see section 4.2). Sepsis Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Apexelsin 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 neu

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