Review of the Available Evidence on Taxanes (Paclitaxel and Docetaxel) for Breast Cancer

Review of the available evidence on Taxanes (Paclitaxel and Docetaxel) for Breast Cancer

FOR THE INCLUSION IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES

NHS CeVEAS NHS Centre for the Evaluation of Effectiveness of Health Care Emilia Romagna Regional Health System, Modena – Italy

WHO Collaborating Centre for Evidence-Based Research Synthesis and Guideline Development in Reproductive Health

Person to contact:

Maria Chiara Banzi T. +39 059 435220

CeVEAS NHS Centre for the Evaluation of Effectiveness of Health Care Emilia Romagna Regional Health System, Modena – Italy

November 2010 DRAFT October 12, 2010

CONTENTS

WHO Model List Application, November 2010

1. Summary statement of the proposal for inclusion, change or deletion 5 2. Name of the focal point in WHO submitting or supporting the application 5 3. Name of the organization(s) consulted and/or supporting the application 5 4. International Nonproprietary Name (INN, generic name) of the medicine 5 5. Formulation proposed for inclusion; including adult and pediatric (if appropriate) 5 6. International availability - sources, if possible manufacturers (Appendix A) 5 7. Whether listing is requested as an individual medicine or as an example 6 of a therapeutic group 8. Information supporting the public health relevance (epidemiological information 6 on disease burden, assessment on current use, target population) 9. Treatment details 8 Table of evidence systematic review: taxanes for metastatic cancer 11 Table of evidence systematic review: taxanes in adjuvant setting 15 9.1 Indications for use 16 9.2 Dosage regimens 17 9.3 Duration of therapy 20 9.4 Reference to existing WHO and other clinical guidelines 20 9.5 Need for special diagnostic or treatment facilities and skills 21 10. Summary of comparative effectiveness in a variety of clinical settings 21 10.1 Identification of clinical evidence (search strategy, systematic reviews 21 identified, reasons for selection/exclusion of particular data) 10.2 Summary of available estimates of comparative effectiveness (appraisal 21 of quality, outcome measures, summary of results) 11. Summary of comparative evidence on safety 21 11.1 Estimate of total patient exposure to date 21 11.2 Description of adverse effects/reactions 22 11.3 Identification of variation in safety due to health systems and patient factors 23 11.4 Summary of comparative safety against comparators 23 12. Summary of available data on comparative costs and cost-effectiveness 29 12.1 Range of cost of the proposed medicine 29 12.2 Comparative cost-effectiveness presented as range of cost per routine outcome 29 13. Summary of regulatory status of the medicine (in country of origin, and preferably in 29 other countries as well)

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14. Availability of pharmacopoeial standards (British Pharmacopoeia, International 29 Pharmacopoeia, United States Pharmacopeia) 15. Proposed (new/adapted) text for the WHO Model Formulary 29 16. References 31

ANNEX A. List of FDA-approved products i ANNEX B. Global manufacturers of taxanes iii ANNEX C. Table of evidence (GRADE profiles) v

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Contributors:

CeVEAS, Modena, Italy NHS Centre for the Evaluation of the Effectiveness of Health Care WHO Collaborating Centre for Evidence-Based Research Synthesis and Guideline Development in Reproductive Health

Maria Chiara Banzi Oncologist

Simona Di Mario Pediatrician, Epidemiologist

Lucia Magnano Pharmacist

Nicola Magrini Director, Clinical Pharmacologist

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1. Summary statement of the proposal

Based on currently available evidence the inclusion of a taxane is requested for breast cancer treatment both in adjuvant and metastatic settings. The request is based on a favourable benefit-risk profile showing an absolute reduction in mortality of about 2 – 3% corresponding to a NNT between 35 to 50 for women treated in adjuvant setting.

2. Name of the focal point in WHO submitting or supporting the application

Dr Suzanne Hill, scientist Medicines, Access and Rational Use Essential Medicines and Pharmaceutical Policies WHO HQ, Geneva.

3. Name of the organization(s) consulted and/or supporting the application

The application has been developed by CEVEAS, NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence Based Research Synthesis and Guideline Development in Reproductive Health; Modena, Italy.

4. International Nonproprietary Name (INN, generic name) of the medicine:

1. Paclitaxel (formerly named taxol, the use of this name now is limited because it is a tradename) 2. Docetaxel

INNs were taken from US Pharmacopeia (USP) and EMA/FDA website. Paclitaxel and some formulation of docetaxel have lost their patent both in USA and in Europe; generic formulations of paclitaxel are available in many countries (USA and Europe), generic formulations of docetaxel are already available in Europe (see Annex A).

5. Formulation proposed for inclusion; including adult and pediatric (if appropriate)

- 6 mg/ml paclitaxel solution for injection vials; available in different package size: 30 mg/5 ml; 100 mg/16.7ml; 150 mg/25ml; 300 mg/50ml. - 20 mg/ml, 40 mg/ml docetaxel solution for injection vials; available in different package size: 80 mg/2 ml; 20 mg/ml; 20 mg/0.5 ml; 80mg/4 ml; 160 mg/8 ml.

Package size will be selected according to recommended dose for m2 body surface.

6. International availability - sources, if possible manufacturers (Annex B)

A list of manufacturers that have active status in the Drug Master File of the Food and Drug Administration is available in Annex B.

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Paclitaxel is registered in many countries in the developed and developing world, in addition to the U.S. The choice of the manufacturer for taxanes will depend on the price and availability at the local or national level.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

Listing is requested on the Model List of Essential Medicines either as a therapeutic group (taxanes) or as individual medicines (either the two available or both: paclitaxel and docetaxel) to be listed within the major group 8.2. “Cytotoxic medicines”.

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment on current use, target population)

Breast cancer is the first cancer in term of incidence and prevalence in women both in the developed and the developing world. It comprises 16% of all female cancers. Incidence rates vary greatly worldwide, with age standardized rates as high as 99.4 per 100 000 in North America. Eastern Europe, South America, Southern Africa, and western Asia have moderate incidence rates, but these are increasing. The lowest incidence rates are found in most African countries but also here incidence is increasing due to increased life expectancy, urbanization and adoption of western lifestyles. Although some risk reduction might be achieved with prevention, these strategies cannot eliminate the majority of breast cancers that develop in low- and middle-income countries where breast cancer is diagnosed in very late stages.

Latest data from GLOBOCAN 2008 [1] reports an estimated incidence of breast cancer in developed countries of 692 thousand new cases per year: the incidence is almost identical in developing countries (691 thousand new cases per year). Age adjusted incidence rate (ASRs) is 66.4 in developed countries and 27.3 in less developed countries [1].

The differences in breast cancer incidence between developed and developing countries can partly be explained by dietary effects combined with later first childbirth, lower parity, and shorter breastfeeding [2]. The increasing adoption of western life-style in low- and middle-income countries is an important determinant in the increase of breast cancer incidence in these countries.

It is estimated that 519 000 women died in 2004 due to breast cancer; a majority of all breast cancer deaths (69%) occurs in developing countries [3]: 268 thousand women dye each year in developing countries and 189 thousand in developed countries (Figure 1) [1]. Breast cancer survival rates, in fact, varies greatly worldwide, ranging from 80% or over in North America, Sweden and Japan to around 60% in middle-income countries and below 40% in low-income countries [4]. The low survival rates in less developed countries can be explained mainly by the lack of early detection programmes, resulting in a high proportion of women presenting with late-stage disease, as well as by the lack of adequate diagnosis and treatment facilities. Breast cancer survival increases with GDP (Figure 2).

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Figure 1 Estimated numbers (thousands) of new cancer cases (incidence) and deaths (mortality) in women in developed and developing regions of the world [1].

Figure 2. Relationship between GDP per capita and 5-year relative survival: breast and cervical cancers [1].

Several risk factors for breast cancer have been well documented. However, for the majority of women presenting with breast cancer it is not possible to identify specific risk factors [5,6].

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A familial history of breast cancer increases the risk by a factor of two or three. Some mutations, particularly in BRCA1, BRCA2 and p53 result in a very high risk for breast cancer. However, these mutations are rare and account for a small portion of the total breast cancer burden.

Reproductive factors associated with prolonged exposure to endogenous estrogens, such as early menarche, late menopause, late age at first childbirth are among the most important risk factors for breast cancer. Exogenous hormones also exert a higher risk for breast cancer. Oral contraceptive and hormone replacement therapy users are at higher risk than non-users. Breastfeeding has a protective effect [5,6].

The contribution of various modifiable risk factors, excluding reproductive factors, to the overall breast cancer burden has been calculated [7]. The study concludes that 21% of all breast cancer deaths worldwide are attributable to alcohol use, overweight and obesity, and physical inactivity. This proportion is higher in high-income countries (27%), and the most important contributor is overweight and obesity. In low- and middle-income countries, the proportion of breast cancers attributable to these risk factors is 18%.

9. Treatment details

Taxanes, as many other chemotherapies, have been used first in the treatment of metastatic cancer. Based on effectiveness data in this group of patients taxanes have also been tested in adjuvant and neoadjuvant setting; therefore we report data on effectiveness of taxanes first for metastatic breast cancer and then for adjuvant treatment. i. Taxanes in metastatic breast cancer.

The activity of taxanes has been demostrated in monotherapy studies in women with metastatic breast cancer. Paclitaxel showed activity in both doxorubicin-naive (response rate 35-55%) and doxorubicin-refractory MBC (RR consistently >20%) [8,9]. The infusion of 175 mg/m2 over 3 h every 3 weeks is considered a reasonable standard approach [10,11]. Like paclitaxel, docetaxel was highly effective in pre-treated patients, with response rates of 35-60% [12,13]. Its recommended single-agent dose is 100 mg/ m2 over 1 h infusion every 221 days, although the lower dose of 75 mg/ m2 may be appropriate for some patients [14]. Like paclitaxel, a low initial dose and hematologic monitoring are needed in heavily pre-treated patients and in those with hepatic dysfunction [15]. In attempt to improve therapeutic efficacy and toxicity profile of taxanes many randomized trials were developed to compare the weekly vs. three-weekly schedule. Weekly paclitaxel (80 mg/ m2) was compared to every three week regimen (175 mg/ m2) in 735 women with MBC in the CALGB 9840 trial [16]. The weekly chemotherapy was associated with a significantly higher response rate - RR (42 vs 29%, p=0.004), longer time to progression - TTP (9 vs5 months, p<0.0001), and median survival (24 vs 12 months, p=0.0092), with higher neuropathy grade 3 with weekly dosing (24 vs 12%, p=0.0003). In the Anglo-Celtic IV trial [17], the overall response rate - ORR favoured the weekly dose, but TTP, overall survival - OS and the toxicity were not significantly different. The results from these trials support the hipothesis that not only the treatment schedule but also the total dose of paclitaxel is important for efficacy. Weekly docetaxel (30-40 mg/ m2 over 1 h) has a RR of 40-50% [18,19], and as with paclitaxel, is less mielosuppressive [19,20]. A phase III trial [21] was conducted in patients with MBC who were treated with docetaxel either 3 weeks or once weekly to determine and compare RR and duration, TTP, progression free survival - PFS, OS and toxicity. Despite lower RR, weekly docetaxel was associated with similar PFS and OS and a more acceptable toxicity profile.

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Many of the above described studies have been included in a Cochrane systemic review published in 2008 [22]. Twenty one eligible trials compared taxanes containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer. When all trials are considered, taxanes containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer [see table of evidence at page 11, Table 1]

i.i. Single-agent studies

-Antracycline-naive patients Docetaxel was compared with doxorubicin in the TAX 303 trial [23]. Docetaxel produced a superior RR (48 vs 33%, p=0.008), but there was no difference in terms of time to treatment failure or OS; docetaxal was however less myelotoxic, with lower incidence of thrombocytopenia, neutropenic fever and need to transfusions of blood and platelet. Paclitaxel was compared to doxorubicin in a trial of the EORTC [24]. In this trial doxorubicin was associated with greater toxicity, but it achieved better disease and symptom control than 3-weekly paclitaxel. In another first line trial [25], 739 women with MBC were randomized to receive front- line treatment with doxorubicin, 24-h infusion of paclitaxel or the combination of doxorubicin and paclitaxel. The results clearly demonstrated that doxorubicin and 24-h paclitaxel have a comparable efficacy profile, which is inferior to that of their combination. Front-line paclitaxel has also been compared with CMFP combination (cyclophosphamide, methotrexate, 5-fluorouracil, prednisone) [26]. Results showed that patients who received paclitaxel survived significantly longer than those who received CMFP.

-Antracycline-pretreated patients In antracycline-pretreated patients, docetaxel was superior to mitomycin/vinblastine (MV) [27] and methotrexate/5-FU [28] but equivalent to continuous infusion of 5-FU with vinorelbine. In another trial, docetaxel and paclitaxel were directly compared [29]. RR, the primary end-point was similar between the two arms, but docetaxel produced a significantly better median TTP and OS, with worse hematologic and non-hematologic toxicities.

-Taxanes-pretreated patients The cross-resistance between the two taxanes, at least in the preclinical setting, is incomplete [30]. In the clinical setting, up to 25% of patients to progress while on paclitaxel have disease stabilization or response to docetaxel, as proven in a phase II trial [31].

i.ii. Combination regimens

-Anthracycline-taxane combinations The docetaxel-anthracycline combination in comparison to older anthracycline-based regimens produced a superior RR [32-34] and OS [35]. In a randomized phase II-III study, the overall RR, median TTP and OS were significantly longer for patients on AT (doxorubicin plus docetaxel) compared with FAC (fluorouracil, doxorubicin and cyclophosphamide). Data for paclitaxel- anthracycline combination were less consistent and an advantage was observed only in one trial [36]. The combination of doxorubicin with either taxane was evaluated in the ERASME 3 study [37]. The efficacy results demonstrated that paclitaxel or docetaxel combination with doxorubicin were not significantly different in term of QoL score and efficacy, but had different toxicity profile: hematologic toxicity and asthenia were significantly more frequent with docetaxel, while neuropathy occurred more frequently with paclitaxel.

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-Non-anthracycline-taxane combination The capecitabine-taxane regimens were shown to be active, even in women previously treated with taxane [38-42]. In a phase III study, the combination of capecitabine plus docetaxel was compared with docetaxel alone in 511 women with anthracycline-refractory MBC [43]. The combination was associated with a significantly higher overall response rate, TTP and OS, with more gastrointestinal toxicity and hand-foot syndrome. Similarly, comparison of the gemcitabine-paclitaxel combination with paclitaxel alone, revealed a significantly higher response rate, TTP and OS, in favour of the combination [44]. The combination of docetaxel-gemcitabine was compared with docetaxel plus capecitabine in a phase III study [45]: the PFS was similar in the two arms but docetaxel plus capecitabine was more toxic. -Targeted therapy/taxane combinations In clinical setting a favourable interaction between paclitaxel and the anti-HER2 antibody (trastuzumab) was shown in the pivotal trial by Slamon et colleagues [46]. In other studies the weekly paclitaxel-trastuzumab combination was a particularly well tolerated regimen [47-48]. A large multicenter cooperative group trial is now underway comparing weekly vs 3-weekly paclitaxel plus trastuzumab combination. Similar response rates (50-76%) and a favourable toxicity profile have been reported in a randomized phase II trial [49] where the docetaxel-trastuzumab combination compared to docetaxel alone was significantly superior in term of RR, TTP and OS (31 vs 23 months, p=0.0325). 57% of patients crossed over from docetaxel monotherapy to the combination with trastuzumab. Paclitaxel was the first taxane to be evaluated in combination with the anti-VEGF monoclonal antibody, bevacizumab, in a randomized phase III trial (ECOG 2100) [50]. The addiction of bevacizumab was associated to a significantly higher RR and PFS, but OS was similar in the two arms. Recently docetaxel has also been combined to bevacizumab in the AVADO trial [51]. PFS was significantly superior in both combination arms compared with docetaxel alone, but OS is similar.

There below we present effectiveness data in a summery of finding table using GRADE methodology.

10 Table 1. Question: Should taxane containing chemotherapy vs regimens not containing a taxane be used in women with metastatic breast cancer? Bibliography: Ghersi D, Wilcken N, Simes J, Donoghue E. Taxane containing regimens for metastatic breast cancer. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003366. DOI: 10.1002/14651858

Summary of findings Quality assessment No of patients Effect taxane regimens not Importance No of Other Relative Quality Design Limitations Inconsistency Indirectness Imprecision containing containing a Absolute studies considerations (95% CI) chemotherapy taxane overall survival (follow-up 1.5-58 months; number of deaths considering time (measured as HR)) 13 randomised serious1 no serious no serious no serious none 26 fewer per trials inconsistency indirectness imprecision 1230/1695 1000 (from (72.6%) 54 fewer to 0 more) HR 0.93 23 fewer per 1391/1948 1000 (from ⊕⊕⊕Ο 44.4% (0.86 to CRITICAL (71.4%) MODERATE 1.00) 48 fewer to 0 more) 23 fewer per 1000 (from 81.9% 49 fewer to 0 more) time to progression (follow-up 1.5-58 months; number of deaths taking in consideration time (measured as HR)) 12 randomised serious2 serious3 no serious no serious none 23 fewer per trials indirectness imprecision 1401/1605 1000 (from 3 (87.3%) fewer to 46 fewer) 30 fewer per 1000 (from 4 74.1% HR 0.92 1564/1862 fewer to 58 ⊕⊕ΟΟ (0.85 to CRITICAL (84%) fewer) LOW 0.99) 97.2% 9 fewer per 1000 (from 1 fewer to 20 fewer)

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Notes

1 Seven out of thirteen studies have unclear allocation concealment (ECOG E1 193 A/ECOG E1 193 B-Sledge 2003; 303 study group-Chan 1997; Dieras 1995; Sjostrom -Luoma 2003;TOG - Icli 2002; TXT - Bonneterre 2002) 2 Six out of twelve studies have unclear allocation concealment (ECOG E1 193 A/ECOG E1 193 B-Sledge 2003; 303 study group-Chan 1997; Dieras 1995; Sjostrom -Luoma 2003;TOG - Icli 2002) 3 There is strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials 4 Ten out of sixteen studies have unclear allocation concealment (ECOG E1 193 A/ECOG E1 193 B-Sledge 2003; 303 study group-Chan 1997; Dieras 1995; Sjostrom -Luoma 2003;TOG - Icli 2002; TXT - Bonneterre 2002, Bontenbal 2003; Nabholt 2001; Talbot 2002)

ii. Taxanes in early breast cancer The significant activity of taxanes in metastatic breast cancer, the partial non-cross resistance with anthracycline, and unique mechanism of action of these agents comported its evaluation as neoadjuvant and adjuvant therapy for women with early disease.

ii.i. Studies in the adjuvant setting

A recent review has described 21 clinical trials that randomly allocated over 35,000 women with early-stage breast cancer to taxane-based, either concomitantly o sequentially, versus taxane-free adjuvant therapies [52]. Studies differ for the dosage of anthracycline (strength) used in the control harm (see Figure 3 for a detailed description of the studies). Of the 12 trials which randomly allocated more than 17,000 women with early breast cancer to taxane-containing regimens versus low-strength anthracycline reference regimens (FEC75, FEC60, FEC50, FAC, AC, EC), eight studies suggested a benefit for taxane regimens with regard to DFS. Only three of the 10 trials that reported survival data showed a statistically significant overall survival benefit for the taxane-containing regimen [53-64]. Results are available from nine of the trials of standard-stregth anthracycline (FEC100, FEC90, CEF, CAF, A75 or E100 followed by CMF), which randomly allocated 17,000 women with early-stage breast cancer to these therapies. Some studies reported benefit in terms of DFS and overall survival, other in terms of DFS with a non significant improvement in overall survival [65-73]. The ECOG 1199 [74] compared the two taxanes, weekly or every three weeks, after four cycles of AC (standard dose). The authors concluded that weekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improved DFS and OS in women with breast cancer, though there were no differences in term of PFS when comparing paclitaxel vs docetaxel or 3-weekly vs weekly schedules.

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Figure 3. Efficacy results for reported adjuvant taxanes trials according to the strength of anthracycline arm [52].

Three pooled analysis or meta-analysis indicate that taxane-based adjuvant chemotherapy provides improvement in disease-free survival and overall survival (~5% and ~3% absolute benefit, respectively, corresponding approximately to a NNT=20 for DFS and NNT=30 for OS ) when compared with standard anthracycline polichemotherapy, irrespective of the type of taxanes, schedule of administration, extent of nodal involvement, and hormone-receptor expression status [75-77]. Below a summary table of effectiveness is reported for De Laurentiis metanalysis [76]. In Annex C is reported a GRADE profile of evidence for the Cochrane systematic review [77], while

14 DRAFT October 12, 2010 no table of evidence are provided for Bria study [75], since all the studies included in this review are also present in the more recent Cochrane review.

It has not been feasible to develop a GRADE profile for this systematic review since no raw data and no information on study quality have been reported. However, many of the studies included are present also in the Cochrane systematic review [77], for which a GRADE profile is provided in Annex C.

Outcome No of studies Design HR Importance (95% CI) Comparison I: taxanes versus any chemotherapy not containing taxanes Overall survival 12 RCT 0.83 (0.76, 0.91) CRITICAL Disease free 13 RCT 0.83 (0.79, 0.88) CRITICAL survival Comparison II: paclitaxel versus any chemotherapy not containing taxanes Overall survival 5 RCT 0.81 (0.70, 0.94) CRITICAL Disease free 6 RCT 0.80 (0.74, 0.86) CRITICAL survival Comparison III: docetaxel versus any chemotherapy not containing taxanes Overall survival 7 RCT 0.84 (0.73, 0.96) CRITICAL Disease free 7 RCT 0.86 (0.80, 0.92) CRITICAL survival Table 2. Summary of studies effectiveness [76].

In Figure 4 pooled DFS and OS curves for studies included in the meta-analysis are reported [76]

15 ii.ii. Studies in neoadjuvant setting

In patients with locally advanced and operable breast cancer, neoadjuvant chemotherapy has been demonstrated to increase the chance of breast-conserving surgery -BCS when compared with adjuvant treatment; moreover, patients who achieve a pathologic complete response -pCR have a better outcome. A meta-analysis of 7 randomized clinical trials (2455 patients) exploring the role of taxanes in neoadjuvant setting was conducted [78]. The rate of BCS was significantly higher for patients receiving taxanes, with an absolute differences of 3.4% (p=0.012), which translates into a NNT of 29 patients. The rate of pCR was higher for patients receiving taxanes, although not statistically significant. In the sensitivity analysis, patients receiving taxanes as a sequential schedule had a significant higher probability to achieved pCR, with an absolute difference of 2.4% (p=0.013).

9.1 Indications for use

The tables below report the FDA and EMA currently approved indications for taxanes (November 2010). FDA approved indications Paclitaxel Docetaxel AIDS-related Kaposi's sarcoma, second line Breast cancer, adjuvant treatment in combination with doxorubicin treatment and cyclophosphamide for patients with operable node-positive disease Breast cancer, adjuvant therapy for node- Breast cancer, locally advanced/metastatic disease, after failure of positive disease, administered sequentially to prior chemotherapy standard doxorubicin-containing regimen Breast cancer, after failure of combination Gastric cancer chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. Non-small cell lung cancer, first-line therapy, Head and neck cancer, locally advanced squamous cell disease, in combination with cisplatin in patients who are induction treatment in combination with cisplatin and fluorouracil not candidates for surgery and/or radiation Ovarian cancer, advanced , first-line therapy in Hormone refractory prostate cancer, metastatic, in combination with combination with cisplatin prednisone Ovarian cancer, advanced, in patients Non-small cell lung cancer, locally advanced/metastatic disease, as previously treated with chemotherapy monotherapy after failure of prior platinum-based chemotherapy Non-small cell lung cancer, unresectable, locally advanced/metastatic disease, first-line therapy in combination with cisplatin

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EMA approved indications Paclitaxel Docetaxel Advanced AIDS-related Kaposi's sarcoma Breast cancer in combination with doxorubicin and cyclophosphamide is (AIDS-KS) who have failed prior liposomal indicated for the adjuvant treatment of patients with: operable node-positive anthracycline therapy breast cancer or Operable node-negative breast cancer Metastatic carcinoma of the breast (MBC) Breast cancer in combination with doxorubicin is indicated for the who have failed, or are not candidates for treatment of patients with locally advanced or metastatic breast cancer who standard anthracycline containing therapy have not previously received cytotoxic therapy for this condition. In monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent Advanced carcinoma of the ovary (AOC) Breast cancer in combination with trastuzumab is indicated for the or with residual disease (> 1 cm) after initial treatment of patients with metastatic breast cancer whose tumours over laparotomy, in combination with cisplatin as express HER2 and who previously have not received chemotherapy for first-line treatment metastatic disease Metastatic carcinoma of the ovary (MOC) Breast cancer in combination with capecitabine is indicated for the after failure of platinum containing treatment of patients with locally advanced or metastatic breast cancer after combination therapy without taxanes as failure of cytotoxic chemotherapy. Previous therapy should have included an second-line treatment anthracycline Non-small cell lung carcinoma (NSCLC) Non-small cell lung cancer is indicated for the treatment of patients with who are not candidates for potentially locally advanced or metastatic non-small cell lung cancer after failure of curative surgery and/or radiation therapy, in prior chemotherapy combination with cisplatin. Limited efficacy data supports this indication Docetaxel (Teva ® e docefrez®) in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition Prostate cancer in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer Gastric adenocarcinoma, in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for metastatic disease Head and neck cancer, in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck

Breast cancer is certainly the most important indication for use, but also ovarian cancer should be included in the EML list.

9.2 Dosage regimens

Premedication. All patients should be premedicated prior to paclitaxel administration to prevent a severe hypersensitivity reaction. A suggested premedication regimen is dexamethasone 20 mg orally at 12 and 6 hours prior to paclitaxel plus diphenhydramine (or equivalent) 50 mg IV and either cimetidine 300 mg IV or ranitidine 50 mg IV at 30 to 60 minutes prior to paclitaxel (Prod Info TAXOL® IV injection, 2010).

Paclitaxel

Breast cancer, adjuvant therapy for node-positive disease, administered sequentially to standard doxorubicin-containing regimen

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Every 3 Weeks Dosing For the adjuvant treatment of node-positive breast cancer when administered sequentially to standard doxorubicin-containing combination chemotherapy, the recommended dose of paclitaxel is 175 mg/m2 IV infused over 3 hours every 3 weeks for 4 courses (Prod Info TAXOL® IV injection, 2010).

Weekly Dosing Paclitaxel 80 mg/m2 IV over 1 hour once weekly for 12 doses was used for the adjuvant treatment of node-positive or high-risk, node-negative breast cancer following 4 cycles of doxorubicin 60 mg/ m2 and cyclophosphamide 600 mg/ m2 IV given every 3 weeks in a trial [75] and following 4 cycles of doxorubicin 50 mg/ m2 IV and paclitaxel 200 mg/m2 IV given every 3 week in another trial (Micromedex ®).

Breast cancer, after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated

For the treatment of metastatic breast cancer in patients who have failed combination chemotherapy or who have relapsed within 6 months of adjuvant chemotherapy, the recommended dose of paclitaxel is 175 mg/m2 infused IV over 3 hours every 3 weeks (Prod Info TAXOL® IV injection, 2010).

Docetaxel

In the adjuvant treatment of operable node-positive and node-negative breast cancer

Every 3 Weeks Dosing The recommended dose of docetaxel is 75 mg/ m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (TAC regimen) The patient's neutrophil count should be 1500 cells/mm3 or greater prior to treatment (Prod Info TAXOTERE® injection concentrate IV infusion, 2010).

For the treatment of advanced or metastatic breast cancer in patients who have failed prior chemotherapy

Every 3 Weeks Dosing The recommended dose of docetaxel is 60 to 100 mg/m2 administered over 1 hour every 3 weeks (Prod Info TAXOTERE ® injection concentrate IV infusion, 2010).

Weekly Dosing A weekly dose of 35 mg/m2 for 6 weeks followed by 2 weeks rest produced an overall response of 34% and reduced toxicity in heavily pre-treated patients with metastatic breast cancer (n=35). A modified schedule for additional cycles was used with docetaxel (35 mg/m2) administered on days 1, 8, and 15 every 29 days. Docetaxel was administered as an intravenous infusion over 30 minutes with dexamethasone (8 mg) given 1 hour before docetaxel infusion. Dosing was postponed for 1 week or until marrow recovery for leukocyte counts of 3000/microliter (mcL) or less and/or platelet counts of 100,000/mcL or less (Micromedex ®). In first-line treatment, docetaxel 75 mg/ m2 is given in combination therapy with doxorubicin (50 mg/ m2).

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Dosage in Renal Failure

Docetaxel

Only small amounts of unchanged docetaxel are eliminated unchanged in the urine, suggesting a lack of need for dose adjustments in renal insufficiency (Micromedex ®). However, pharmacokinetics of the drug in these patients or those with hepatorenal syndrome have not been studied.

Dosage in Hepatic Insufficiency

Paclitaxel Patients with hepatic impairment, receiving their first course of paclitaxel 135 mg/m2 IV over 24 hours or 175 mg/m2 IV over 3 hour, should be dosed according to the following table (Prod Info TAXOL® IV injection, 2010)

Transaminase Levels Bilirubin Levels Recommended Paclitaxel Dose 24 HOUR INFUSION Less than 2 x ULN AND Less than or equal to 1.5 mg/dL 135 mg/ m2 2 to less than 10 x ULN AND Less than or equal to 1.5 mg/dL 100 mg/ m2 Less than 10 x ULN AND 1.6 to 7.5 mg/dL 50 mg/ m2 Greater than or equal to OR Greater than 7.5 mg/dL Not recommended 10 x ULN 3 HOUR INFUSION Less than 10 x ULN AND Less than or equal to 1.25 x ULN 175 mg/ m2 Less than 10 x ULN AND 1.26 to 2 x ULN 135 mg/ m2 Less than 10 x ULN AND 2.01 to 5 x ULN 90 mg/ m2 Greater than or equal to OR Greater than 5 x ULN Not recommended 10 x ULN ULN, upper limit of normal; mg, milligrams; m2, square meter

Subsequent paclitaxel doses and dose adjustments should be based on individual tolerance

Docetaxel: Docetaxel should not be administered to patients with any of the following altered laboratory values: (Prod Info TAXOTERE® injection concentrate IV infusion, 2010): - serum bilirubin greater than the upper limit of normal (Prod Info TAXOTERE® injection concentrate IV infusion, 2010) - serum glutamic-oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT) levels greater than 1.5 times the upper limit of normal in conjunction with alkaline phosphatase levels greater than 2.5 times the upper the limit of normal (Prod Info TAXOTERE® injection concentrate IV infusion, 2010)

Pediatric

The safety and effectiveness of paclitaxel and docetaxel have not been established in paediatric patients (Prod Info TAXOTERE® injection concentrate IV infusion, 2010- (Prod Info TAXOL® V injection, 2010)

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Dosage in Geriatric Patients Docetaxel Dosage adjustments are unnecessary in elderly patients; use caution secondary to decreased cardiac, hepatic, and renal function, concomitant diseases and other drug therapy (Prod Info TAXOTERE® injection concentrate IV infusion, 2010).

9.3 Duration of therapy

The duration of therapy, with paclitaxel or docetaxel, in adjuvant setting should comprise 6 cycles, in metastatic setting it could last until progression disease, in average it could be 4-6 cycles.

9.4 Reference to existing WHO and other clinical guidelines

WHO (EMRO) has produced a guidelines for management of breast cancer in 2006. Taxanes are recommended as first line therapy for metastatic cancer and in adjuvant systemic chemotherapy for endocrine resistant breast cancer: • World Health Organization. Regional Office for the Eastern Mediterranean. Guidelines for management of breast cancer. EMRO Technical Publications Series; 31. Cairo 2006 [79]

Other guidelines produced by international institution and professional medical associations are: • The 2009 NICE guidelines in early breast cancer prefer combinations of docetaxel rather than combinations of paclitaxel because the evidence of the latter is not based on combinations with standard UK treatments (DAC x 6c q3w). For patients with advanced breast cancer who are not suitable for anthracyclines (because they are contraindicated or because of prior anthracyclines treatment either in the adjuvant or metastatic setting) in first line systemic chemotherapy with single agent docetaxel should be offered [80].

• The CCO guidelines in early breast generally recommend taxane-containing regiments rather than those without taxanes. In advanced setting docetaxel is preferred, while in HER2 positive disease paclitaxel+trastuzumab is indicated [81].

• The ESMO guidelines recommend taxanes both in adjuvant and in advanced breast cancer. In adjuvant setting recommend chemotherapy for medium and high-risk patients. They included anthracyclines for all patients, regimens with taxanes for subgroups who are not candidates for anthracyclines (e.g. elderly patients, cardiac patients, those with contraindications, etc..) and taxanes limited to high-risk patients [82].

• The NCCN guidelines recommend taxanes both in adjuvant and in advanced breast cancer. In adjuvant setting the guidelines differentiate between preferential and other regimens, some with docetaxel and others with paclitaxel. In patients with positive nodes, preferential schedules are those that contains anthracyclines [83].

Taxanes are also included in National essential medicines lists of various WHO countries and region, as SEARO, Egypt, Trinidad and Tobago http://www.searo.who.int/LinkFiles/Essential_Drugs_and_Medicines_MMR.pdf http://www.who.int/selection_medicines/country_lists/TTO_VEN_ListByClass.pdf http://www.who.int/selection_medicines/country_lists/EGY_EML_2006.pdf

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9.5 Need for special diagnostic or treatment facilities and skills

Side effects monitoring is based on weekly-fortnightly clinical examination plus hematological profile. Since the recommended dosage proposed is weekly, clinical examination and laboratory tests can be done at the time of the treatment administration.

10. Summary of comparative effectiveness in a variety of clinical settings

The available evidence seems to be consistent across various populations although most of the trials have been performed in western countries.

10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)

The databases Medline and EMBASE have been searched for randomized controlled trials.

Search strategy: the following free terms have been used (advanced breast cancer OR adjuvant breast cancer OR early breast cancer) AND (neoadjuvant treatment OR treatment OR therapy OR taxanes) AND (paclitaxel OR docetaxel).

Limits: human, randomized controlled trial, metaanalysis, language english. No time restriction have been applied.

The search has retrieved 105 references. Seventies references have been selected based on title and abstract assessment.

10.2 Summary of available estimates of comparative effectiveness (appraisal of quality, outcome measures, summary of results)

Available evidence (systematic review with meta-analysis) have been synthesized in table of evidence for effectiveness and safety data (see Table 1, Table 2 and GRADE profile in Annex C)

11. Summary of comparative evidence on safety

The overall safety of taxanes is fairly good, especially at weekly regimen (see paragraph 11.2 for detailed description). The most frequent side effects are: • bone marrow suppression with neutropenia, leukopenia, anemia, • hypersensitivity reaction, • peripheral neuropathy, • myalgia/arthralgia, • alopecia.

11.1 Estimate of total patient exposure to date

Since they were first introduced at the end of the nineties, taxanes have been widely used all over the world.

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11.2 Description of adverse effects/reactions

The following adverse reaction related to taxanes, involving several districts, are most frequently reported (from MICROMEDEX®): cardiovascular effects, dermatologic effects, endocrine/metabolic effects gastrointestinal effects, hematologic effects, hepatic effects, immunologic effects, musculoskeletal effects, neurologic effects, ophthalmic effects, otic effects, renal effects, respiratory effects, other.

From FDA: The adverse reactions related to paclitaxel described by the FDA (available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_Approv alHistory) are reported below.

Pooled Analysis of Adverse Event Experiences from Single-Agent Studies Data in the following table are based on the experience of 812 patients (493 with ovarian carcinoma and 319 with breast carcinoma) enrolled in 10 studies who received single-agent TAXOL [Taxol FDA label]. Two hundred and seventy- five patients were treated in 8, Phase 2 studies with TAXOL doses ranging from 135 to 300 mg/m2 administered over 24 hours (in 4 of these studies, G-CSF was administered as hematopoietic support). Three hundred and one patients were treated in the randomized Phase 3 ovarian carcinoma study which compared 2 doses (135 or 175 mg/m2) and 2 schedules (3 or 24 hours) of TAXOL. Two hundred and thirty-six patients with breast carcinoma received TAXOL (135 or 175 mg/m2) administered over 3 hours in a controlled study.

Adverse event Percentage of patient % (812) Bone marrow Neutropenia <2.000/mm3 90 <500/mm3 52 Leukopenia <4.000/mm3 90 <1.000/mm3 17 Trombocytopenia <100.000/mm3 20 <50.000/mm3 7 Anemia <11 g/dl 78 <8 g/dl 16 Infections 30 Bleeding 14 Red cell transfusions 25 Platelet transfusions 2 Hypersensitivity reaction All 41 Severe 2 Cardiovascular Bradycardia (n=537) 3 Hypotension (n=532) 12 Significant cardiovascular events 1 Abnormal ECG All pts 23 Pts with normal baseline (n=559) 14 Peripheral neuropathy Any symptoms 60 Severe symptoms 3 Myalgia/Arthralgia Any symptoms 60 Severe symptoms 8

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Adverse event Percentage of patient % (812) Gastrointestinal Nausea and Vomiting 52 Diarrhea 38 Mucositis 31 Alopecia 87 Hepatic (pts with normal baseline and on study data) Bilirubin elevations (n=765) 7 Alkaline phosphatase elevations 22 (n=575) AST (SGOT) elevations (n=591) 19 Injection site reaction 13 Table 4. Summary of adverse events in patients with solid tumors receiving single-agent taxol. (based: on Taxol FDA label, , 08/13/2010)

11.3 Identification of variation in safety due to health systems and patient factors

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Weekly or fortnightly (every two weeks) monitoring is recommended.

11.4 Summary of comparative safety against comparators

Adjuvant Breast: the following table shows the incidence of important severe adverse events for the 3121 patients (total population of the Phase 3 adjuvant breast carcinoma study) who were evaluated for safety as well as for a group of 325 patients (early population) who, in the analysis per protocol, were monitored more intensively than other patients [Taxol FDA label, 08/13/2010].

Percent of patients Early population Total population Adverse event AC % (n=166) AC followed by T AC % (n=1551) AC followed by T % (n=159) % (n=1570)

Bone marrow Neutropenia <500/mm3 79 76 48 50 Trombocytopenia <50.000/mm3 27 25 11 11 Anemia <8g/dl 17 21 8 8 Infections 6 14 5 6 Fever without infections - 3 <1 1 Hypersensitivity reaction 1 4 1 2 Cardiovascular events 1 2 1 2 Neuromotor toxicity 1 1 <1 1 Neurosensory toxicity - 3 <1 3 Myalgia/Arthralgia - 2 <1 2 Nausea and Vomiting 13 18 8 9 Mucositis 13 4 6 5 Table 5. Frequency of important severe adverse events in the phase 3 adjuvant breast cancer study. (based: on Taxol FDA label, 08/13/2010)

The incidence of an adverse event for the total population likely represents an underestimation of the actual incidence given that safety data were collected differently based on enrolment cohort.

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However, since safety data were collected consistently across regimens, the safety of the sequential addition of TAXOL (paclitaxel) following AC therapy may be compared with AC therapy alone. Compared to patients who received AC alone, patients who received AC followed by TAXOL experienced more: • Grade III/IV neurosensory toxicity, • Grade III/IV myalgia/arthralgia, • Grade III/IV neurologic pain (5% vs 1%), • Grade III/IV flu-like symptoms (5% vs 3%), • Grade III/IV hyperglycemia (3% vs 1%).

During the additional 4 courses of treatment with TAXOL, 2 deaths (0.1%) were attributed to treatment. During TAXOL treatment, Grade IV neutropenia was reported for 15% of patients, Grade II/III neurosensory toxicity for 15%, Grade II/III myalgias for 23%, and alopecia for 46%. The incidences of severe hematologic toxicities, infections, mucositis, and cardiovascular events increased with higher doses of doxorubicin.

Breast Cancer After Failure of Initial Chemotherapy: for the 458 patients who received single- agent TAXOL in the Phase 3 breast carcinoma study, the following table shows the incidence of important adverse events by treatment arm (each arm was administered by a 3-hour infusion). Myelosuppression and peripheral neuropathy were dose related. There was one severe hypersensitivity reaction (HSR) observed at the dose of 135 mg/m2 [Taxol FDA label, 08/13/2010].

Adverse event Percentage of Percentage of patient % patient % 135/3 175/3(n=229) (n=229) Bone marrow Neutropenia <2.000/mm3 90 81 <500/mm3 28 19 Trombocytopenia <100.000/mm3 11 7 <50.000/mm3 3 2 Anemia <11 g/dl 55 47 <8 g/dl 4 2 Infections 23 15 Febrile neutropenia 2 2 Hypersensitivity reaction All 36 31 Severe 0 <1 Peripheral neuropathy Any symptoms 70 46 Severe symptoms 7 3 Mucositis Any symptoms 23 17 Severe symptoms 3 <1 Table 6. Frequency of important adverse events in the phase 3 study of breast cancer after failure of initial chemotherapy or within 6 months of adjuvant chemotherapy. (based on: Taxol FDA label, 08/13/2010)

Other safety data derived from secondary studies (systematic review of RCT) have been synthesized in table of evidence for effectiveness and safety data (Annex C)

DOCETAXEL ADVERSE REACTIONS

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The adverse reactions related to docetaxel described by the FDA (available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails)

Monotherapy with TAXOTERE for locally advanced or metastatic breast cancer after failure of prior chemotherapy 2 TAXOTERE 100 mg/m : Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received TAXOTERE administered at 100 mg/ m2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to TAXOTERE. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving TAXOTERE for the treatment of breast cancer and in patients with other tumor types.

Adverse Reaction All Tumor Types Normal All Tumor Types Elevated Breast Cancer Normal LFTs* n=2045 % LFTs** n=61 % LFTs* n=965 % Hematologic Neutropenia <2000 cells/mm3 96 96 99 <500 cells/mm3 75 88 86 Leukopenia <4000 cells/mm3 96 98 99 <1000 cells/mm3 32 47 44 Thrombocytopenia <100,000 cells/mm3 8 25 9 Anemia <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia*** 11 26 12 Septic Death 2 5 1 Non-Septic Death 1 7 1 Infections Any 22 33 22 Severe 6 16 6 Fever in Absence of Infection Any 31 41 35 Severe 2 8 2 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 7 8 9 With 3-day n=92 n=3 n=92 Premedication Any 64 67 64 Severe 7 33 7 Neurosensory Any 49 34 58 Severe 4 0 6

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Adverse Reaction All Tumor Types Normal All Tumor Types Elevated Breast Cancer Normal LFTs* n=2045 % LFTs** n=61 % LFTs* n=965 % Cutaneous Any 48 54 47 Severe 5 10 5 Nail Changes Any 31 23 41 Severe 3 5 4 Gastrointestinal Nausea 39 38 42 Vomiting 22 23 23 Diarrhea 39 33 43 Severe 5 5 6 Stomatitis Any 42 49 52 Severe 6 13 7 Alopecia 76 62 74 Asthenia Any 62 53 63 Severe 13 25 15 Myalgia Any 19 16 21 Severe 2 2 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 *Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Febrile Neutropenia: ANC grade 4 with fever >38oC with intravenous antibiotics and/or hospitalization Table 7. Summary of Adverse Reactions in Patients Receiving TAXOTERE at 100 mg/ m2 TAXOTERE 100 mg/m2 TAXOTERE 60 mg/m2 Adverse Reaction Normal LFTs* n=730 % Elevated LFTs** n=18 % Normal LFTs* n=174 % Neutropenia Any <2000 cells/mm3 98 100 95 Grade 4 <500 cells/mm3 84 94 75 Thrombocytopenia Any 11 44 14 <100,000 cells/mm3 Grade 4 <500 cells/mm3 1 17 1 Anemia <11 g/dL 95 94 65 Infection*** Any 23 39 1 Grade 3 and 4 7 33 0 Febrile Neutropenia**** By Patient 12 33 0 By Course 2 9 0 Septic Death 2 6 1 Non Septic Death 1 11 0 *Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN **Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia. ****Febrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever >38°C with intravenous antibiotics and/or hospitalization; for 60 mg/ m2, ANC grade 3/4 and fever >38.1°C

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Table 8. Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at TAXOTERE 100 mg/ m2 with Normal or Elevated Liver Function Tests or 60 mg/m2 with Normal Liver Function Tests

TAXOTERE 100 mg/m2 TAXOTERE 60 mg/m2 Adverse Reaction Normal LFTs* Elevated LFTs** n=18 Normal LFTs* n=730 % % n=174 % Acute Hypersensitivity Reaction Regardless of Premedication Any 13 6 1 Severe 1 0 0 Fluid Retention*** Regardless of Premedication Any 56 61 13 Severe 8 17 0 Neurosensory Any 57 50 20 Severe 6 0 0 Myalgia 23 33 3 Cutaneous Any 45 61 31 Severe 5 17 0 Asthenia Any 65 44 66 Severe 17 22 0 Diarrhea Any 42 28 NA Severe 6 11 Stomatitis Any 53 67 19 Severe 8 39 1 *Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN ** Elevated Baseline Liver Function: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ***Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m2 dose NA = not available

Table 9. Non-Hematologic Adverse Reactions in Breast Cancer Patients Previously Treated with Chemotherapy Treated at TAXOTERE 100 mg/m2 with Normal or Elevated Liver Function Tests or 60 mg/ m2with Normal Liver Function Tests

Combination therapy with TAXOTERE in the adjuvant treatment of breast cancer The following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with TAXOTERE 75 mg/m² every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 10).

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TAXOTERE 75 mg/m2+ Fluorouracil 500 mg/m2+ Doxorubicin 50 mg/m2+ Doxorubicin 50 mg/m2+ Cyclophosphamide 500 mg/m2 Cyclophosphamide 500 mg/m2 Adverse Reaction (TAC) (FAC) n=744 % n=736 % Any Grade 3/4 Any Grade 3/4 Anemia 92 4 72 2 Neutropenia 71 66 82 49 Fever in absence of infection 47 1 17 0 Infection 39 4 36 2 Thrombocytopenia 39 2 28 1 Febrile neutropenia 25 N/A 3 N/A Neutropenic infection 12 N/A 6 N/A Hypersensitivity reactions 13 1 4 0 Lymphedema 4 0 1 0 Fluid Retention* 35 1 15 0 Peripheral edema 27 0 7 0 Weight gain 13 0 9 0 Neuropathy sensory 26 0 10 0 Neuro-cortical 5 1 6 1 Neuropathy motor 4 0 2 0 Neuro-cerebellar 2 0 2 0 Syncope 2 1 1 0 Alopecia 98 N/A 97 N/A Skin toxicity 27 1 18 0 Nail disorders 19 0 14 0 Nausea 81 5 88 10 Stomatitis 69 7 53 2 Vomiting 45 4 59 7 Diarrhea 35 4 28 2 Constipation 34 1 32 1 Taste perversion 28 1 15 0 Anorexia 22 2 18 1 Abdominal Pain 11 1 5 0 Amenorrhea 62 N/A 52 N/A Cough 14 0 10 0 Cardiac dysrhythmias 8 0 6 0 Vasodilatation 27 1 21 1 Hypotension 2 0 1 0 Phlebitis 1 0 1 0 Asthenia 81 11 71 6 Myalgia 27 1 10 0 Arthralgia 19 1 9 0 Lacrimation disorder 11 0 7 0 Conjunctivitis 5 0 7 0 Table 10. Clinically important treatment emergent adverse reactions regardless of causal relationship in patients receiving TAXOTERE in combination with doxorubicin and cyclophosphamide (TAX316).

Of the 744 patients treated with TAC, 36.3% experienced severe treatment emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most

28 DRAFT October 12, 2010 common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs

12. Summary of available data on comparative costs and cost-effectiveness

The cost of taxanes, available in most cases also as generic formulations, is not an issue in term of access and availability.

12.1 Range of cost of the proposed medicine

Range of prices from the International Drug Price Indicator Guide published by Management Sciences for Health (MSH) in collaboration with WHO are available only for paclitaxel

Paclitaxel (1 vial 5 ml) Lowest price (Perù) US $ 6.29 Highest price (South Africa) US $ 9.54

12.2 Comparative cost-effectiveness presented as range of cost per routine outcome

No cost effective data are available for different settings or for different outcomes.

13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well)

Paclitaxel and docetaxel are approved in many countries (Arg, Austral, Austria, Belg, Braz, Canad, Denm, Fin, FR, Ger, Gr, Hong Kong, India, Irl, Israel, Ital, Jpn, Malaysia, Mex, Neth, Norw, NZ, Port, S.Afr, Singapore, Spain, Swed, Switz, Thai, UK, USA). From Martindale 13° edition 2005 A list of FDA-approved products is available in Annex A.

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopeia)

Paclitaxel and docetaxel are available in the following pharmacopoeias:

• British Pharmacopeia: Yes • US Pharmacopeia: Yes • European Pharmacopeia: Yes

15. Proposed (new/adapted) text for the WHO Model Formulary

Both taxanes should be available for breast cancer treatment; since at the present, their use, based on available evidence, is different according to specific subgroups of patient and concomitant treatments associated. However, their similarities prevail and could also be considered interchangeable to support a choice of either one of the other.

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Paclitaxel, based on available evidence, should be available for ovarian cancer.

For a detailed description of the product characteristics to be used in the WHO model formulary, it is suggested to refer to the BNF.

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39. Batista N et al. Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced/metastatic breastcancer. Br J Cancer 2004; 90: 1740-6. 40. Lueck H et al. Epirubicin/paclitaxel (EP) vs capecitabine/paclitaxel (XP) in first line metastatic breast cancer: a prospectine, randomized multiucentre phase III study of the AGO Breast Cancer Study Group. [abstract] J Clin Oncol 2006; 24 (18s):517. 41. Soto C et al. Capecitabine (X) and taxanes in patients with anthracycline-pretreated metastatic breast cancer: sequential versus combined therapy results from a MOSG randomized phase III trial [abstract]. J Clin Oncol 2006; 24:20s. 42. Blum JL et al. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2006; 24: 4384-90. 43. O’Shaughnessy J et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20:2812-23. 44. Albain KS et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2008; 26: 3950-7. 45. Chan S et al. Gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) for anthracycline-pretreated metastatic breast cancer (mBC) patients: results of a European phase III study [abstract]. J Clin Oncol 2005;23(16s):581. 46. Slamon DJ et al. Use of chemotherapy plus a monoclonal antibody against HER-2 for metastatic breast cancer that overespresses HER2. N Engl J Med 2001; 344:783-92. 47. Seidman AD et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19: 2587-95. 48. Gori S et al. Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxanes-pretreated patients with HER2-overespressing metastatic breast cancer. Br J Cancer 2004; 90: 36-40. 49. Marty M et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23: 4265-74. 50. Miller KD et al. Paclitaxel plu bevacizumab versus paclitaxel alone for metastatic breast cancer. N Eng J Med 2007; 357: 2666-76. 51. Miles D et al. Randomized, double-blind, placebo controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO [abstract] J Clin Oncol 2008;26 (20s): LBA1011. 52. Bedard PL et al. Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer. Nat Rev 2010;7:22-36. 53. Herdenson IC et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node- positive primary breast cancer. J Clin Oncol 2003;21:976-83. 54. Buzdar AU et al. Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer; preliminary data of a prospective randomized trial. Clin Cancer Res 2002; 8: 1073-79. 55. Joensuu H et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006; 354: 809-20. 56. Mamounas E et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP b-28. J Clin Oncol 2005;23: 3686-3696. 57. Martin M et al. Adjuvant docetaxel for node-positive breast cancer. N Engl. J. Med. 2005; 352: 2302-2313

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58. Evans TR et al. 5-year outcome for women randomized in a phase III trial comparing doxorubicin (A) and cyclophosphamide (C) with doxorubicin and docetaxel (D) as primary medical therapy of breast cancer: an Anglo-Celtic Cooperative Oncology Group Study [abstract] J Clin Oncol 2008; 2006:a540. 59. Mavroudis D et al. Randomized phase III trial comparing the sequential administration of docetaxel followed by epirubicin plus cyclophosphamide versus FEC5C as adjuvant chemotherapy in axillary lymph node-positive breast cancer [abstract] J Clin Oncol 2008; 26:a521. 60. Bear HD et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project protocol B-27. J Clin Oncol. 2003; 21:4165-74. 61. Goldstein LJ et al. Concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 or 3 positive axillary nodes: North American Brest Cancer Intergroup Trial E 2197. 2008; 26:4092-99. 62. Del Mastro L et al. Cyclophosphamide, epirubucin plus paclitaxel in node-positive early breast cancer patients: a randomized, phase III study of Gruppo Oncologico Nord Ovest- Mammella Intergruppo Group [abstract] J Clin Oncol 2008; 26s: a516. 63. Martin M et al. Multicenter, randomized phase III study of adjuvant chemotherapy for high- risk, node-negative breast cancer comparing TAC with FAC: 5-year efficacy analysis of the GEICAM 9805 trial [abstract] J Clin Oncol 2008; 26s: a542 64. Jones S et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow up of US oncology research trial 9735. J Clin Oncol 2009; 27:1177-83. 65. Ellis P et al. Preliminary results of the UK taxotere as adjuvant chemotherapy (TACT) trial.Abstract #78 presented at the San Antonio Breast Cancer symposium.2007 66. Gianni L et al. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer 2009. J Clin Oncol; 27:2474-81. 67. Francis P et al. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst 2008; 100:121-33. 68. Niltz U et al. Interim results of Intergroup EC-Doc Trial: a randomised multicenter phase III trial comparing adjuvant CEF/CMF to EC-docetaxel in patients with1-3 positive lymph nodes [abstract] J Clin Oncol 2008 26s: a515. 69. Foutzilas G et al. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomised phase III conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 2005;16:1762-1771. 70. Burnell M et al. Cyclophosphamode, epirubicin and fluorouracil versus dose-dense epirubicin and cyclophosfamide followed by paclitaxel versus doxorubicin and cyclophophamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol 2009.doi:10.1200. 71. Cognetti F et al. Sequential epirubicin-docetaxel-CMF as adjuvant therapy for node-positive early stage breast cancer: updated results of the TAXit216 randomized trial [abstract] Ann Oncol.2008; 19s: a1820. 72. Roche HH et al. Prognostic and predictive value of HER2, PR, ER, and ki67 in the PACS01 trial comparing epirubicin-based chemotherapy to sequential epirubicin followed by docetaxel [abstract] J Clin Oncol 2005;23s: a605.

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73. Martin M et al. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst 2008;100:805- 814. 74. Sparano JA et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Eng J Med 2008; 16:1663-71. 75. Bria E et al. Benefit of taxanes as adjuvant chemotherapy for early breast cancer: pooled analysis of 15,500 patients. Cancer 2006; 106: 2337-44. 76. De Laurentiis M et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008; 26:44-56. 77. Ferguson T et al. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database of Systematic Reviews. 2007, Issue 4. 78. Cuppone F et al. Taxanes as primary chemotherapy for early breast cancer. Meta-analysis of randomized trials. Cancer 2008; 113:238-46. 79. World Health Organization. Regional Office for the Eastern Mediterranean. Guidelines for management of breast cancer. EMRO Technical Publications Series; 31. Cairo 2006 80. Harnett A et al. Guideline development group. Diagnosis, treatment of early breast cancer, including locally advanced disease – summary of NICE guidance. BMJ 2009; 338: 438. 81. Trudeau M et al. Adjuvant taxane therapy for women with early-stage, invasive breast cancer: a clinical practice guideline. CCO 2006 Practice Guideline. 82. Kataja V, Castiglione M. ESMO Guideline Working Group. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 4 (suppl):10-4. 83. NCCN Clinical practice guidelines in Oncology. V.2.2010.

Annexes Annex A

FDA Approved Drug Products for paclitaxel (as of November 12, 2010) FDA Active Dosage Drug Name Application Company Strength Marketing Status Approval Date Ingredients Form/Route Number PACLITAXEL ANDA TEVA PACLITAXEL INJECTABLE; 6MG/ML Prescription January 25, 2002 075184 PARENTERAL INJECTION

PACLITAXEL ANDA BEDFORD PACLITAXEL INJECTABLE; 6MG/ML Prescription January 28, 2002 075190 INJECTION

PACLITAXEL ANDA MYLAN PACLITAXEL INJECTABLE; 6MG/ML Prescription January 25, 2002 075278 INJECTION

PACLITAXEL ANDA ACCORD PACLITAXEL INJECTABLE; 6MG/ML Prescription November 12, 075436 HLTHCARE INJECTION 2004 INC PACLITAXEL ANDA HOSPIRA PACLITAXEL INJECTABLE; 6MG/ML Prescription May 8, 2002 076131 INJECTION

PACLITAXEL ANDA FRESENIUS PACLITAXEL INJECTABLE; 6MG/ML Prescription November 27, 077574 KABI ONCOL INJECTION 2006

PACLITAXEL ANDA EBEWE PACLITAXEL INJECTABLE; 6MG/ML Prescription December 26, 078167 PHARMA INJECTION 2007

PACLITAXEL ANDA ACTAVIS PACLITAXEL INJECTABLE; 6MG/ML Prescription December 9, 090130 TOTOWA INJECTION 2009

TAXOL NDA 020262 BRISTOL PACLITAXEL INJECTABLE; 6MG/ML Discontinued December 29, MYERS INJECTION 1992 SQUIBB ABRAXANE NDA 021660 ABRAXIS PACLITAXEL FOR 5 MG/ML Prescription January 7, 2005 BIOSCIENCE SUSPENSION; IV (INFUSION) Source: Drugs@FDA, FDA/Center for Drug Evaluation and Research

ANDA: Abbreviated New Drug Approvals (Generic) NDA: New Drug Application

FDA Approved Drug Products for docetaxel (as of November 12, 2010)

FDA Active Drug Name Application Dosage Approval Date Company Ingredients Strength Marketing Status Number Form/Route

INJECTABLE; EQ 40MG DOCETAXEL Prescription INJECTION BASE/ML NDA SANOFI TAXOTERE 020449 AVENTIS INJECTABLE; 20MG/ML May 14, 1996 DOCETAXEL Prescription US INJECTION (20MG/ML) INJECTABLE; 80MG/4ML DOCETAXEL Prescription INJECTION (20MG/ML) DOCETAXEL INJECTABLE 20MG/2ML NDA HOSPIRA None DOCETAXEL August 11, 2008 022234 INC DOCETAXEL INJECTABLE 80MG/8ML (Tentative Approval) DOCETAXEL INJECTABLE 160MG/16ML DOCETAXEL INJECTABLE; 20MG/VIAL SUN NDA INJECTION None DOCEFREZ PHARMA February 23, 2010 022534 (Tentative Approval) GLOBAL DOCETAXEL INJECTABLE; 80MG/VIAL INJECTION Source: Drugs@FDA, FDA/Center for Drug Evaluation and Research

i EMA Approved Drug Products for docetaxel (as of November 12, 2010)

EMA Active Drug Name Approval Date Product number Company Ingredients Dosage Form/Route Strength Marketing Status

Injectable for DOCETAXEL 20MG/0.5ML Prescription Intravenous use Injectable for 20MG/ML DOCETAXEL Prescription Intravenous use (20MG/ML) TAXOTERE Aventis Injectable for 80MG/2ML EMEA/H/C/000073 DOCETAXEL Prescription 27/11/1995 Pharma S.A Intravenous use (40MG/ML) DOCETAXEL Injectable for 80MG/4ML Prescription Intravenous use (20MG/ML) DOCETAXEL Injectable for 160MG/8ML Prescription Intravenous use (20MG/ML) Injectable for 20MG/2ML DOCETAXEL DOCETAXEL EMEA/H/C/001107 Teva Pharma Intravenous use Prescription 26/01/2010 TEVA Generic B.V. Injectable for 80MG/8ML DOCETAXEL Intravenous use Injectable for DOCETAXEL 20MG/0.5ML Intravenous use Injectable for DOCETAXEL 20MG/1ML Intravenous use DOCETAXEL EMEA/H/C/000808 Sanofi-Aventis Injectable for DOCETAXEL 80MG/2ML Prescription 20/04/2007 WINTHROP Pharma S.A. Intravenous use Injectable for DOCETAXEL 80MG/4ML Intravenous use Injectable for DOCETAXEL 160MG/8ML Intravenous use Sun DOCETAXEL Injectable for 20MG/ML EMEA/H/C/001074 Pharmaceutical Intravenous use DOCEFREZ Prescription 10/05/2010 Generic Industries DOCETAXEL Injectable for 80MG/4 ML Europe B.V. Intravenous use Source: European Public Assessment Reports (EPARs)

ii Annex B

Manufacturers for paclitaxel 3Q2010 ALLACTIVEEXCEL DMF # SUBMIT HOLDER COUNTRY SUBJECT DATE 11909 29/03/1996 YUNNAN HANDE BIO-TECH CHINA PACLITAXEL DRUG SUBSTANCE MANUFACTURED IN CO LTD KUNMING, PEOPLES REPUBLIC OF CHINA. 12294 27/12/1996 SERIPHARM SA FRANCE PACLITAXEL, MANUFACTURED IN LE MANS, FRANCE 12876 23/02/1998 INDENA SPA ITALY PACLITAXEL, MANUFACTURED IN SETTALA (MI)- ITALY 15079 06/10/2000 MAYNE PHARMA (USA) USA PACLITAXEL EXTRACT AS MFG IN BOULDER, COLORADO 15319 23/02/2001 YUNG SHIN CHINA PACLITAXEL AS MFG IN TAIWAN, REPUBLIC OF CHINA. PHARMACEUTICAL INDUSTRIES CO LTD 16242 13/11/2002 INDENA SPA ITALY PACLITAXEL P.I. AS MANUFACTURED IN SETTALA, ITALY. 16374 21/01/2003 NATURAL USA SEMI-SYNTHETIC PACLITAXEL API AS MANUFACTURED IN PHARMACEUTICALS INC GRAFTON, WI. 16676 30/06/2003 SCINOPHARM TAIWAN LTD TAIWAN PACLITAXEL AS MANUFACTURED IN TAINAN COUNTY, TAIWAN. 16701 08/07/2003 TEVA CZECH INDUSTRIES CZECH PACLITAXEL AS MANUFACTURED IN OPAVA, CZECH SRO REPUBLIC. 17045 01/12/2003 GUILIN HUIANG CHINA PACLITAXEL DRUG SUBSTANCE AS MANUFACTURED IN BIOCHEMISTRY GUANGXI, P.R.CHINA. PHARMACEUTICAL CO LTD 17650 02/09/2004 BIOXEL PHARMA INC SPAIN PACLITAXEL API AS MANUFACTURED IN RANCHO CORDOVA, CA FOR BIOXEL PHARMA INC 17966 30/12/2004 FRESENIUS KABI INDIA PACLITAXEL SEMISYNTHETIC AS MANUFACTURED IN ONCOLOGY LTD WEST BENGAL, INDIA. 18397 23/05/2005 POLYMED THERAPEUTICS CHINA PACLITAXEL DRUG SUBSTANCE AS MANUFACTURED IN INC CHONGQING, CHINA. 19111 12/01/2006 YUNNAN HANDE BIOTECH CHINA PACLITAXEL DRUG SUBSTANCE ISOLATED FROM TAXUS CO LTD CANADENSIS AS MANUFACTURED IN KUNMING, CHINA. 19159 30/01/2006 CHONGQING UNITED CHINA PACLITAXEL DRUG SUBSTANCE AS MANUFACTURED IN PHARMACEUTICAL CO LTD CHONGQING, CHINA. 19293 24/03/2006 SHANGHAI JINSHAN CHINA PACLITAXEL AS MANUFACTURED IN SHANGHAI, CHINA. BIOTECH CO LTD 19421 08/05/2006 BEIJING YI HE BIOTECH CO CHINA PACLITAXEL USP, NON-STERILE BULK AS MANUFACTURED LTD IN BEJING, CHINA. 19527 29/05/2006 CENWAY CHINA PACLITAXEL, NON-STERILE BULK FORM AS PHARMACEUTICALS LTD MANUFACTURED IN TIANJIN, CHINA. 20977 22/10/2007 INDENA S.P.A. ITALY PACLITAXEL AS MANUFACTURED IN SETTALA, ITALY 21174 17/12/2007 SHANGHAI TECHWELL CHINA SEMISYNTHETIC PACLITAXEL AS MANUFACTURED IN BIOPHARMACEUTICAL CO SHANGHAI, CHINA LTD 22839 01/06/2009 YUNNAN HANDE BIO TECH CHINA SEMI SYNTHETIC PACLITAXEL DRUG SUBSTANCE AS CO LTD MANUFACTURED IN KUNMING PR CHINA 23506 02/02/2010 TEVA CZECH INDUSTRIES CZECH PACLITAXEL SEMISYNTHETIC AS MANUFACTURED IN SRO OPAVA KOMAROV CZECH REPUBLIC 23558 19/02/2010 FUJIAN SOUTH CHINA PACLITAXEL (NATURAL) USP (NATURAL, NON-STERILE PHARMACEUTICAL CO LTD BULK DRUG SUBSTANCE) AS MANUFACTURED IN FUJIAN PR CHINA

Source: Drug Master File (DMF), Food and Drug Administration(as of Q3, 2010)

iii

Manufacturers for docetaxel 3Q2010 ALLACTIVEEXCEL DMF # SUBMIT HOLDER COUNTRY SUBJECT DATE 20021 08/12/2006 SCINOPHARM TAIWAN LTD TAIWAN DOCETAXEL AS MANUFACTURED IN TAINAN TAIWAN 20608 11/06/2007 ACCORD HEALTH CARE INC CANADA ANHYDROUS DOCETAXEL AS MANUFACTURED IN QUEBEC CANADA AND NORTH BRUNSWICK NJ 20942 12/10/2007 SCINOPHARM TAIWAN LTD TAINAN DOCETAXEL TRIHYDRATE DRUG SUBSTANCE AS MANUFACTURED IN TAINAN, TAIWAN R.O.C. 20961 22/10/2007 POLYMED THERAPEUTICS INC CHINA DOCETAXEL ANHYDROUS, NON-STERILE BULK DRUG SUBSTANCE AS MANUFACTURED IN CHONGQING, CHINA FOR POLYMED THERAPEUTICS INC 21040 15/11/2007 POLYMED THERAPEUTICS INC CHINA DOCETAXEL TRIHYDRATE DRUG SUBSTANCE AS MANUFACTURED IN CHONGQING, CHINA FOR POLYMED THERAPEUTICS INC 21517 09/04/2008 BIOVECTRA INC CANADA DOCETAXEL AS MANUFACTURED IN CHARLOTTETOWN, CANADA 21930 23/10/2008 BIOXEL PHARMA INC USA DOCETAXEL TRIHYDRATE API AS MANUFACTURED IN CHARLES CITY, IA FOR BIOXEL PHARMA INC 22562 26/02/2009 HUBEI HAOSUN CHINA DOCETAXEL ANHYDROUS AS MANUFACTURED IN PHARMACEUTICALS CO LTD HUBEI, CHINA 23054 19/08/2009 TEVA PHARMACEUTICAL MEXICO DOCETAXEL AS MANUFACTURED IN LERMA EDO INDUSTRIES LTD And DE MEXICO AND SANTHIA (VC) ITALY FOR TEVA ITALY PHARMACUETICAL INDUSTRIES LTD 23138 24/09/2009 APTUIT LAURUS PRIVATE LTD INDIA DOCETAXEL ANHYDROUS AS MANUFACTURED IN ANDHRA PRADESH INDIA 23362 11/12/2009 CBL - CHATHAM BIOTEC LTD CHINA SEMISYNTHETIC DOCETAXEL DRUG SUBSTANCE (API) AS MANUFACTURED IN SHANGHAI CHINA (MAINLAND) FOR CBL - CHATHAM BIOTEC LTD 23406 16/12/2009 CENWAY PHARMACEUTICALS CHINA DOCETAXEL AS MANUFACTURED IN TIANJIN PR CO LTD CHINA

23458 08/01/2010 QILU PHARMACEUTICAL CO LTD CHINA DOCETAXEL AS MANUFACTURED IN JINAN SHANDONG PROVINCE PEOPLES REPUBLIC OF CHINA 23884 08/06/2010 INDENA SPA ITALY N-DEBOC-DOCETAXEL (N-DEBENZOYL-10- DEACETYLPACLITAXEL INTERMEDIATE) AS MANUFACTURED IN SETTALA (MI), ITALY 23886 8/30/2010 INDENA SPA ITALY DOCETAXEL AS MANUFACTURED IN MILAN ITALY

JIANGSU HENGRUI MEDICINE CO DOCETAXEL TRIHYDRATE USP AS 24175 9/13/2010 LTD CHINA MANUFACTURED IN JIANGSU, P.R. CHINA Source: Drug Master File (DMF), Food and Drug Administration(as of Q3, 2010)

iv Annex C

GRADE profiles for one of the systematic review retrieved on effectiveness of taxanes in adjuvant setting for breast cancer [78] is reported here. Notes are provided for each limitation identified. Summary table of the two other systematic review described in the text are reported in the core document (pg 11 and pg 15).

Tables of evidence have been developed using the GRADE profile software (http://www.gradeworkinggroup.org/toolbox/index.htm) where a balance between benefits and harms of the intervention are analyzed [see related bibliography i-vi].

Each study is tabulated according to the selected outcome (e.g. overall survival, cardiotoxicity), and importance is rated in the last column (critical, important, not important).

Quality assessment of the study considered for each outcome takes into account study design, limitations, inconsistency, indirectness, and imprecision. Reasons for judging the quality of the study are reported in footnotes. In the column ‘quality’, a summary scoring of the study quality for the considered outcome is given: high, moderate, low, or very low.

A summary of findings is given with absolute numbers and estimate of relative (RR) and absolute effects (ARR) of the intervention considered.

Related bibliography i. GRADE working group. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490-1494 (available at: http://bmj.bmjjournals.com/cgi/content/full/328/7454/1490 last assessed 2008.06.06) ii. Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, Liberati A, Vist GE, Schünemann HJ; GRADE working group. Incorporating considerations of resources use into grading recommendations. BMJ. 2008;336:1170-3 iii. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, Schünemann HJ; GRADE Working Group. Going from evidence to recommendations. BMJ. 2008;336:1049-51 iv. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; GRADE Working Group. What is "quality of evidence" and why is it important to clinicians? BMJ. 2008;336:995-8

v. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-6 vi. Schünemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, Williams JW Jr, Kunz R, Craig J, Montori VM, Bossuyt P, Guyatt GH; GRADE Working Group. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336:1106- 10

Author(s): LM , SDM Date: 2010-11-11 Question: Should taxanes vs any chemotherapy not containing taxanes be used in women of any age with operable histologically confirmed breast cancer? Bibliography: Ferguson T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004421

Summary of findings Quality assessment No of patients Effect any Importance No of Other chemotherapy Relative Quality Design Limitations Inconsistency Indirectness Imprecision taxanes Absolute studies considerations not containing (95% CI) taxanes overall survival (follow-up 36 -69 months; number of deaths) 11 randomised no serious no serious no serious no serious none 26 fewer per trials limitations inconsistency indirectness imprecision 1360/9154 1000 (from (14.9%) 17 fewer to 35 fewer) HR 0.81 11 fewer per 1123/9150 1000 (from 7 ⊕⊕⊕⊕ 5.8% (0.75 to CRITICAL (12.3%) HIGH 0.88) fewer to 14 fewer) 43 fewer per 1000 (from 25.8% 27 fewer to 57 fewer) disease free survival (follow-up 36-69 months; second primary breast cancer, local or distant recurrences) 11 randomised no serious no serious no serious no serious none HR 0.81 44 fewer per 2312/10454 ⊕⊕⊕⊕ trials limitations inconsistency indirectness imprecision 2488/9488 (0.77 to 1000 (from CRITICAL (22.1%) HIGH (26.2%) 0.86) 32 fewer to 53 fewer) 25 fewer per 1000 (from 14% 18 fewer to 30 fewer)

vi Summary of findings Quality assessment No of patients Effect any Importance No of Other chemotherapy Relative Quality Design Limitations Inconsistency Indirectness Imprecision taxanes Absolute studies considerations not containing (95% CI) taxanes 57 fewer per 1000 (from 36% 41 fewer to 69 fewer) cardiotoxicity when same dose of anthracycline is used in both groups (follow-up 36-69 months; WHO/NCIC toxicity criteria) 3 randomised no serious no serious no serious no serious none 3 more per trials limitations inconsistency indirectness imprecision 1000 (from 2 47/3816 (1.2%) fewer to 10 more) OR 1.24 2 more per 59/3845 1000 (from 1 ⊕⊕⊕⊕ 0.7% (0.83 to CRITICAL (1.5%) HIGH 1.86) fewer to 6 more) 4 more per 1000 (from 3 1.7% fewer to 14 more) cardiotoxicity when anthracycline dose is reduced in taxanes group (follow-up 36-69 months; WHO/NCIC toxicity criteria) 2 randomised serious1 no serious no serious no serious none 7 fewer per trials inconsistency indirectness imprecision 1000 (from 0 17/1448 (1.2%) fewer to 10 fewer) OR 0.38 4 fewer per 6/1452 1000 (from 0 ⊕⊕⊕Ο 0.6% (0.15 to CRITICAL (0.4%) MODERATE 0.98) fewer to 5 fewer) 8 fewer per 1000 (from 0 1.3% fewer to 11 fewer)

vii Summary of findings Quality assessment No of patients Effect any Importance No of Other chemotherapy Relative Quality Design Limitations Inconsistency Indirectness Imprecision taxanes Absolute studies considerations not containing (95% CI) taxanes

febrile neutropaenia for sequential anthracycline and taxane treatment (follow-up 36-69 months; WHO/NCIC toxicity criteria) 4 randomised no serious serious3 no serious no serious none 35 more per trials limitations2 indirectness imprecision 1000 (from 167/2426 (6.9%) 35 fewer to 208 more) OR 1.57 15 more per 269/2413 1000 (from ⊕⊕⊕Ο 2.7% (0.48 to CRITICAL (11.1%) MODERATE 5.17) 14 fewer to 98 more) 46 more per 1000 (from 9.3% 46 fewer to 253 more) febrile neutropaenia for concurrent anthracycline and taxane treatment (follow-up 36-69 months; WHO/NCIC toxicity criteria) 2 randomised serious4 no serious no serious serious5 none 208 more per trials inconsistency indirectness 1000 (from 105/2181 (4.8%) 40 more to 502 more) OR 6.8 119 more per 458/2188 1000 (from ⊕⊕ΟΟ 2.4% (1.91 to CRITICAL (20.9%) LOW 24.15) 21 more to 349 more) 243 more per 1000 (from 6% 49 more to 547 more)

viii Summary of findings Quality assessment No of patients Effect any Importance No of Other chemotherapy Relative Quality Design Limitations Inconsistency Indirectness Imprecision taxanes Absolute studies considerations not containing (95% CI) taxanes

treatment related deaths (follow-up 36-69 months; WHO/NCIC toxicity criteria) 6 randomised no serious no serious no serious serious6 none 0 fewer per trials limitations inconsistency indirectness 1000 (from 1 7/5611 (0.1%) fewer to 3 more) OR 1 0 fewer per 7/5649 1000 (from 0 ⊕⊕⊕Ο 0.06% (0.33 to CRITICAL (0.1%) MODERATE 3.04) fewer to 1 more) 0 fewer per 1000 (from 2 0.3% fewer to 6 more)

Notes 1 Allocation concealment unclear in one of the two trials (ECTO study, Gianni 2005) 2 Allocation concealment unclear in one of the four trials (GEICAM 9906 study, Martin 2004) 3 One study shows reduced side effect in intervention arm, two studies show increased side effect in intervention arm and one study shows no differences 4 Allocation concealment unclear in one of the two trials (E2197 study, Goldstein 2005) 5 Large 95% confidence interval of risk estimate 6 Two out of six studies report no events both in intervention and treatment arms

ix Question: Should docetaxel vs any chemotherapy not containing taxanes be used in in women of any age with operable and histologically confirmed breast cancer? Bibliography: Ferguson T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004421

Summary of findings Quality assessment No of patients Effect any chemotherapy Relative Importance No of Other Quality Design Limitations InconsistencyIndirectnessImprecision docetaxel not (95% Absolute studies considerations containing CI) taxanes overall survival (follow-up 36-69 months; number of deaths) 6 randomised no serious no serious no serious no serious none 27 fewer trials limitations1 inconsistency indirectness imprecision per 1000 551/4691 (from 16 (11.7%) fewer to 37 fewer) 14 fewer per 1000 HR 0.76 (from 8 421/4686 5.9% ⊕⊕⊕⊕ (0.67 to fewer to CRITICAL (9%) HIGH 0.86) 19 fewer) 17.4% 39 fewer per 1000

(from 22 fewer to

54 fewer)

x Summary of findings Quality assessment No of patients Effect any chemotherapy Relative Importance No of Other Quality Design Limitations InconsistencyIndirectnessImprecision docetaxel not (95% Absolute studies considerations containing CI) taxanes disease free survival (follow-up 36-69 months; second primary breast cancer, local or distant recurrences) 7 randomised no serious no serious no serious no serious none 41 fewer trials limitations2 inconsistency indirectness imprecision per 1000 1273/5659 (from 26 (22.5%) fewer to 53 fewer) 26 fewer per 1000 HR 0.80 1267/6605 (from 17 ⊕⊕⊕⊕ 14% (00.74 CRITICAL (19.2%) fewer to HIGH to 0.87) 34 fewer) 52 fewer per 1000 (from 34 30.4% fewer to 69 fewer)

Notes

1 Allocation concealment unclear in one of the six trials (E2197 study, Goldstein 2005) 2 Allocation concealment unclear in one of the seven trials (E2197 study, Goldstein 2005)

xi Question: Should paclitaxel vs any chemotherapy not containing taxanes be used in women of any age with operable histologically confirmed breast cancer? Bibliography: Ferguson T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004421

Summary of findings Quality assessment No of patients Effect any chemotherapy Relative Importance No of Other Quality Design Limitations InconsistencyIndirectnessImprecision paclitaxel not (95% Absolute studies considerations containing CI) taxanes overall survival (follow-up 36-69 months; number of deaths) 5 randomised serious1 no serious no serious no serious none 25 fewer trials inconsistency indirectness imprecision per 1000 809/4463 (from 10 (18.1%) fewer to 40 fewer) 12 fewer per 1000 (from 5 8.2% HR 0.85 702/4464 fewer to ⊕⊕⊕Ο (0.76 to CRITICAL (15.7%) 19 MODERATE 0.94) fewer) 34 fewer per 1000 (from 13 fewer to 25.8% 55 fewer)

xii Summary of findings Quality assessment No of patients Effect any chemotherapy Relative Importance No of Other Quality Design Limitations InconsistencyIndirectnessImprecision paclitaxel not (95% Absolute studies considerations containing CI) taxanes disease free survival (follow-up 36-69 months; second primary breast cancer, local or distant recurrences) 4 randomised serious2 no serious no serious no serious none 49 fewer trials inconsistency indirectness imprecision per 1000 1215/3829 (from 29 (31.7%) fewer to 65 fewer) 33 fewer per 1000 HR 0.82 1045/3850 (from 20 ⊕⊕⊕Ο 20.1% (0.76 to CRITICAL (27.1%) fewer to MODERATE 0.89) 44 fewer) 54 fewer per 1000 (from 32 36.3% fewer to 73 fewer)

Notes

1 Allocation concealment unclear in two of the five trials (ECTO study, Gianni 2005; GEICAM 9906 study, Martin 2004) 2 Allocation concealment unclear in one of the four trials (ECTO study, Gianni 2005)

xiii Question: Should three cycles of taxane vs any chemotherapy not containing taxanes be used in women of any age with operable histologically confirmed? Bibliography: Ferguson T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004421

Summary of findings Quality assessment No of patients Effect any three chemotherapy Relative Importance No of Other Quality Design Limitations InconsistencyIndirectnessImprecision cycles of not (95% Absolute studies considerations taxane containing CI) taxanes overall survival (follow-up 36-69 months; number of deaths) 3 randomised no serious no serious no serious no serious none 31 fewer trials limitations inconsistency indirectness imprecision per 1000 226/1801 (from 11 (12.5%) fewer to 47 fewer) 15 fewer per 1000 (from 5 5.9% HR 0.74 173/1803 fewer to ⊕⊕⊕⊕ (0.61 to CRITICAL (9.6%) 23 HIGH 0.91) fewer) 49 fewer per 1000 (from 17 fewer to 20.5% 74 fewer)

xiv Summary of findings Quality assessment No of patients Effect any three chemotherapy Relative Importance No of Other Quality Design Limitations InconsistencyIndirectnessImprecision cycles of not (95% Absolute studies considerations taxane containing CI) taxanes disease free survival (follow-up 36-69 months; second primary breast cancer, local or distant recurrences) 3 randomised no serious no serious no serious no serious none 45 fewer trials limitations inconsistency indirectness imprecision per 1000 433/1801 (from 19 (24%) fewer to 70 fewer) 28 fewer per 1000 HR 0.79 351/1803 (from 12 ⊕⊕⊕⊕ 14% (0.68 to CRITICAL (19.5%) fewer to HIGH 0.91) 43 fewer) 59 fewer per 1000 (from 25 33% fewer to 92 fewer)

Question: Should four or more cycles of taxane vs any chemotherapy not containing taxanes be used in women of any age with operable histologically confirmed? Bibliography: Ferguson T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD004421

Summary of findings Quality assessment No of patients Effect any four or chemotherapy Relative Importance No of Other more Quality Design Limitations InconsistencyIndirectnessImprecision not (95% Absolute studies considerations cycles of containing CI) taxane taxanes overall survival (follow-up 36-69 months; number of deaths) 7 randomised no serious no serious no serious no serious none 25 fewer trials limitations1 inconsistency indirectness imprecision per 1000 1082/6719 (from 15 (16.1%) fewer to 36 fewer) 13 fewer per 1000 HR 0.83 (from 8 916/6733 7.8% ⊕⊕⊕⊕ (0.76 to fewer to CRITICAL (13.6%) HIGH 0.90) 18 fewer)

39 fewer per 1000 25.8% (from 22 fewer to

55 fewer)

xvi Summary of findings Quality assessment No of patients Effect any four or chemotherapy Relative Importance No of Other more Quality Design Limitations InconsistencyIndirectnessImprecision not (95% Absolute studies considerations cycles of containing CI) taxane taxanes disease free survival (follow-up 36-69 months; second primary breast cancer, local or distant recurrences) 7 randomised no serious no serious no serious no serious none 44 fewer trials limitations1 inconsistency indirectness imprecision per 1000 1789/6719 (from 30 (26.6%) fewer to 59 fewer) 26 fewer per 1000 HR 0.81 1495/6733 (from 18 ⊕⊕⊕⊕ 14.7% (0.75 to CRITICAL (22.2%) fewer to HIGH 0.87) 35 fewer) 57 fewer per 1000 (from 38 36.3% fewer to 76 fewer)

Notes

1 Allocation concealment unclear in two of seven trials (ECTO study, Gianni 2005; E2197study, Goldstein 2005)

xvii