Abraxane

Original submission contained the wrong date of revision hence a new version has been uploaded.

• In section 2, update with regards to sodium content.
• In section 4.4, update with regards to cystoid macular oedema and to sodium content.
• In section 4.8, update with regards to cystoid macular oedema
• In section 6.1, updated to now read: ‘Human albumin solution (containing sodium caprylate and N-acetyl-L-tryptophan)’.
• Throughout the SPC, replaced "powder for suspension for infusion" to now read "powder for dispersion for infusion".
• Minor changes throughout the document

MAH transfer to BMS.

MAH Transfer to BMS

·          In section 4.3 (Contraindications), format changes.

·          In section 4.4 (Special warnings and precautions for use), format changes in subsection "Patients 75 years and older"

·          In section 4.8 (Undesirable effects ), combine the 3 ADR tables and post-approval ADR’s into a single table.

·          In section 5.1 (Pharmacodynamic properties), updated the table numbers and format changes in subsections Breast cancer, Pancreatic adenocarcinoma and Non-small cell lung cancer.

·          In Section 5.2 (Pharmacokinetic properties), format changes in subsection "Other intrinsic factors".

·          In section 6.6 (Special precautions for disposal and other handling), format changes in subsection "Reconstitution and administration of the product".

In sections 4.2, 4.5, 4.8, 5.1 and 5.2, was updated with information on the paediatric population.

In section 4.4, typograhical corrections

Sections 2 and 4, was updated with information on the paediatric population.

In section 4.8 (undesirable effects), scleroderma has been added.

In section 4.8 (undesirable effects), scleroderma has been added.

• Update of Annex I Section 4.6 and 5.3 to add new information on pregnancy, fertility and lactation.

Update to section 4.6 under Pregnancy to introduce additional recommendation to perform a pregnancy test prior treatment with paclitaxel.

Update of Annex I, Annex IIIA and IIIB to extend the in-use shelf-life of the finished product - after dilution reconstitution:

Stability of the reconstituted product in vials and bags is extended from 8 to 24 hours when stored in either the vial or infusion bag at 2-8°C and protected from light.

·         Annual PSUR in Europe covering 07 Jan 2015 to 06 Jan 2016 to add “clopidogrel” to Section 4.5 of the SmPC and section 2 of the PIL as an example of drugs known to interact with Cytochrome P450 isoenzymes inhibitors and inducers. In addition, minor editorial changes were made to section 4.5

·         Correction in section 5.2 of the smPC (range = 3.21%-37.70%).-37.70% replaced 27.70%

·          sections 4.1, 4.2, 4.4, 4.5, 4.8, 5.1 and 6.6 to add the new indication below and an instruction to flush the infusion line following ABX administration.

Abraxane 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.

The following sections of the SPC have been changed:

·         Section 4.2 (dose adjustment in special populations)

·         Section 4.4 (warning for hepatic impairment)

·         Section 5.2 (added pharmacokinetic data)

·         Section 6.4 (additional information on special precautions for storage)

Section 2 -  update to the amount of sodium on the excipients section

Section 4.1 -  update to the therapeutic indications, now including metastatic adencarcinoma of the pancreas

Section 4.2

-         units change in breast cancer posology

-          Section added for pancreatic cancer posology

-          Pancreatic info added for pancreatic cancer indication in special populations, specifically older people and the paediatric  population

Section 4.3

-          Units change in neutrophil counts

Section 4.4

-          Units change in haematology section

-          Pancreatic combination dosing with gemcitabine added for neuropathy section

-          Sepsis section added and and pnemonitis section mover higher up

-          Patients ≥ 75 years section added

-          ‘Other’ section has been added comprising of pancreatic cancer info

-          Excipients section has been updated regarding the amount of sodium

Section 4.5

-          Section added regarding paclitaxel and gemcitabine, as these are used in combination in our pancreatic licence.

Section 4.8

-          The summary info has been updated to partition abraxane monotherapy (table 4) and abraxane with gemcitabine (table 5) for the breast cancer and pancreatic cancer indications respectively.

-          The skin and subcutaneous tissue disorder section has been updated with respect to info on alopecia

Section 5.1

-          Clinical data has been added for pancreatic cancer

Section  7

-          Manufacturing has been removed

Section 10

-          Date of revision of the text has been updated to 16/01/2014

section 2

Each vial contains 100 mg of paclitaxel formulated as albumin bound nanoparticles. [as opposed to "paclitaxel albumin"
Excipients "with known effect" added. "the full list" amended to "a full list"
section 4.2

"Abraxane 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." removed from the end of paragraph and added to the start

"impaired renal function" replaced with "renal impairment"
modified section on elderly population.
Paediatric population
"and adolescent aged 0-17 years" added
section 4.3
excipients - "listed in section 6.1" added
Lactation - "see section 4.6" added
 Cardiotoxicity section:"drugs" replaced with "medicinal products"
section 4.6 "treatment" added.
section 4.8
title added "summary of the safety profile"
this text was added:

Tabulated summary of adverse reactions

this text was deleted: from "blood and lymphatic system disorders" up to 6 paragraphs down "general disorders...40% of the patients"
this section was added after the table:

Description of selected adverse reactions

Blood and lymphatic system disorders

Neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (< 0.5 x 109/l) occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on Abraxane, and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients.

Nervous system disorders

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

Gastrointestinal disorders

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

Skin and subcutaneous tissue disorders

Alopecia was observed in 90% of the patients treated with Abraxane.

Musculoskeletal and connective tissue disorders

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

General disorders and administration site conditions

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

start of section 5.1 was modified as follows:

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

Mechanism of action

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

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

Clinical efficacy and safety

Breast cancer ("carcinoma" deleted)

"229" patients replaced with number in letters: "Two hundred and twenty nine"
section 6.3
"3 years" formatting change only
section 6.4
"this medicinal does not require... conditions" replaced with "keep the vial in the outer carton in order to protect from light"
section 6.5
"(as paclitaxel albumin)" modified to "formulated as albumin bound nanoparticles"
section 6.6
"drug" to "medicinal product"
"(as paclitaxel albumin)" modified to "formulated as albumin bound nanoparticles"
last paragraph modified to:
"

The exact total dosing volume of 5 mg/ml suspension required for the patient should be calculated and the appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or non‑PVC type intravenous bag. The use of specialized di(2-ethylhexyl)phthalate (DEHP)‑free solution containers or administration sets is not necessary to prepare or administer Abraxane infusions. In‑line filters should not be used.

"

Section 4.8 - Addition of Stevens-Johnson syndrome, toxic epidermal necrolysis as very rare side effects. Addition of Extravasation as a rare side effect.
Footnote under Table 1 added to state: "As reported in the postmarketing surveillance of Abraxane"

section 6.5 - Addition of generic drug name.

Section 6.6 - Addition of paragraph regarding extravasation and addition of generic drug name in third paragraph.

Section7.0 - Change of address

Section 10.0 - update to 07/2011