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CHAPTER 16: USE OF ANTINEOPLASTIC AGENTS INCLUDING ENDOCRINE THERAPY Malaysian Statistics on Medicines 2006

Edited by: Lim YS1, Lim GC1, Goh AS2, Wan Ariffin 3A , M Roslan H4, Kamarun Neasa BMK1, Yuzlina MY5

1. Kuala Lumpur Hospital, 2. Pulau Pinang Hospital, 3. Universiti Malaya, 4. Sultan Ismail Hospital, Johor Bahru, 5. Putrajaya Hospital

Systemic therapy is part of the treatment for many cancer patients and for some malignancies they may be the only option. Systemic therapy in cancer is particularly complex and antineoplastic drugs are used either as monotherapy or in combination in different regimes. Antineoplastics can be used in first line or as treatment for relapse of disease.

Some of the antineoplastics have been around since 6 decades ago. came in use in 1992 followed by the molecular targeted agents such as Imatinib Mesylate in early 2000’s. Bevacizumab was the first clinically proven antiangiogenic agent for the treatment of colon cancer in 2004.

The top ten antineoplastics in terms of expenditure in 2006 by public hospitals were (RM5.3 million), (RM5.2 million), (RM2.8 million), Rituximab (RM2.5 million), (RM2.1 million), (RM2.0 million), (RM1.3 million), (RM 1.2 million), (RM1.1 million) and (RM1.0 million). Prices were quoted according to Hospital Kuala Lumpur catalog of drug prices for 2006.

Epirubicin was used mainly for as in the FEC regime which was a combination therapy with Flurouracil and . Docetaxel was used mainly in breast cancer for salvage therapy. This was also used in Non-Small Cell (NSCLC). Another taxane, Paclitaxel was used in ovarian cancer and NSCLC in combination with or . Then in 2006, government hospitals started using Paclitaxel for a new indication in Ministry of Health (MOH) Formulary in combination with Gemcitabine for breast cancer. The earlier indication of Gemcitabine that was approved by the Drug Control Authority (DCA) was for . Furthermore Gemcitabine was widely used for NSCLC in combination with Cisplatin, a platinum compound.

Irinotecan was frequently used for . On the other hand, Methotrexate, a folic acid analog was used for breast cancer in combination with Cyclophosphamide and Fluorouracil. This is the popularly known CMF regime which was the first line therapy in many breast cancer patients. Fluorouracil was mainly used for colorectal cancer, breast cancer, nasopharyngeal cancer, stomach and pancreatic cancer.

Capecitabine is an of pyrimidine analog. Capecitabine initially was used in public hospitals for colorectal cancer only, but not long afterwards was also indicated for breast cancer in metastatic setting. Tegafur was used in private hospitals exceeding ten fold more than in public hospitals. Tegafur was on case by case approval by Director General of Health until 2008 when it was indicated for NSCLC. However Tegafur found many more uses in private hospitals in addition to NSCLC such as and breast cancer. Hence the disparity between quantum of Tegafur used in private compared to public hospitals. The tyrosine kinase inhibitor Imatinib was included in the MOH Formulary in 2007. Imatinib was used for CML as well as for gastro-intestinal stromal tumour (GIST) which had been incompletely resected or unresectable. The usage of Imatinib was actually higher than captured in these procurement data due to the Glivec International Assistance Program (GIPAP) in CML and GIST in Malaysia.

The other molecular targeted therapy were the monoclonal antibodies Rituzimab and Trastuzumab. While Rituzimab was already in MOH Formulary since 2004, Trastuzumab was used on a named-patient basis in 2006. This accounted for the relatively low expenditure for Trastuzumab. In haematological malignancies, Rituximab and the proteosome inhibitor, are making real impact on patient survival and remission rates. Rituximab was already in the MOH Formulary in 2004 for Rituximab enhanced regime of Cyclophosphamide, Adriamycin, and Prednisolone (R-CHOP) in Non-Hodgkin’s Lymphoma whereas Bortezomib was not in the MOH Formulary until 2008. However, improvement in survival comes at a cost and the soaring price of new cancer regimes are adding to the financial burden of cancer patients and causing a strain to public hospitals’ budget.

77 CHAPTER 16: USE OF ANTINEOPLASTIC AGENTS Malaysian Statistics on Medicines 2006 INCLUDING ENDOCRINE THERAPY

Due to the exorbitant price of the newer drugs, only a selected number of patients may have access to these novel targeted agents. The newer drugs that are being focused on in government hospitals are those in whom overall survival benefit have been proven in published randomised controlled trials. Patients depend largely on insurance coverage in the private hospitals and adequacy of budget in individual government hospitals.

The usage of Rituximab was more in public than in private hospitals. The usage of Bortezomib was low in government, university hospitals and private hospitals. Many patients would go to public hospitals if they could get the monoclonal antibodies there since they would not need to worry about the exorbitant prices of the drugs that were heavily subsidised. Other non-formulary drugs such as and were little used in public hospitals and even less so in private hospitals.

Table 16.1: Use of Antineoplastic Agents by Drug Class and Agents, in total dosage/1000 population/day 2006 ATC Drug Class and Agents Unit 2006 L01A A analogues L01A A01 Cyclophosphamide mg Public 2.2612 Private 0.6601 Total 2.9212 L01A A02 mg Public 0.0062 Private 0.0009 Total 0.0071 L01A A03 mg Public 0.0036 Private <0.0001 Total 0.0036 L01A A06 Ifosfamide g Public 0.0009 Private 0.0001 Total 0.0011 L01A B Alkyl sulfonates L01A B01 mg Public 0.0093 Private <0.0001 Total 0.0095 L01A C Ethylene imines L01A C01 mg Public - Private <0.0001 Total <0.0001 L01A D Nitrosoureas L01A D01 Carmustine mg Public 0.003 Private <0.0001 Total 0.003 L01A D0 2 Lomustine mg Public 0.0008 Private 0.0003 Total 0.001 L01A X Other alkylating agents L01A X03 mg Public 0.0045 Private 0.022 Total 0.0265 L01A X04 mg Public 0.0631 Private 0.0198 Total 0.0829

78 CHAPTER 16: USE OF ANTINEOPLASTIC AGENTS INCLUDING ENDOCRINE THERAPY Malaysian Statistics on Medicines 2006

Table 16.2: Use of Antineoplastic Agents by Drug Class, in total dosage/1000population/day 2006 ATC Drug Class and Agents Unit 2006 L01B A Folic acid analogues L01B A01 Methotrexate mg Public 0.6852 Private 0.1102 Total 0.7954 L01B A04 mg Public - Private 0.0055 Total 0.0055 L01B B Purine analogues L01B B02 mg Public 0.6879 Private 0.0103 Total 0.6982 L01B B03 mg Public 0.0133 Private 0.0002 Total 0.0135 L01B B04 mg Public <0.0 001 Private - Total <0.0001 L01B B05 Fludarabine mg Public 0.001 Private 0.0018 Total 0.0028 L01B C Pyrimidine analogues L01B C01 mg Public 0.7999 Private 0.0436 Total 0.8435 L01B C02 Fluorouracil mg Public 4.8107 Private 1.4858 Total 6.2965 L01B C05 Gemcitabine mg Public 0.2908 Private 0.121 Total 0.4118 L01B C06 Capecitabine mg Public 7.5826 Private 8.9727 Total 16.5553 L01B C53 Tegafur, combinations mg Public 0.0272 Private 0.326 Total 0.3533

Table 16.3: Use of Antineoplastic Agents by Drug Class and Agents, in total dosage/1000 population/day 2006 ATC Drug Class and Agents Unit 2006 L01C A Vinca alkaloids and analogues L01C A01 mg Public 0.00 11 Private 0.00 03 Total 0.0014 L01C A02 Vincristine mg Public 0.0018 Private 0.00 02 Total 0.002 L01C A04 mg Public 0.00 62 Private 0.00 51 Total 0.0113

79 CHAPTER 16: USE OF ANTINEOPLASTIC AGENTS Malaysian Statistics on Medicines 2006 INCLUDING ENDOCRINE THERAPY

ATC Drug Class and Agents Unit 2006 L01C B Podophyllotoxin derivatives L01C B01 mg Public 0.1511 Private 0.0293 Total 0.1804 L01C B02 mg Public 0.0015 Private <0.0001 Total 0.0015 L01C D Taxanes L01C D01 Paclitaxel mg Public 0.0687 Private 0.0464 Total 0.1151 L01C D02 Docetaxel mg Public 0.0152 Private 0.0158 Total 0.031

Table 16.4: Use of Antineoplastic Agents by Drug Class, in total dosage/1000 population/day 2006 ATC Drug Class and Agents Unit 2006 L01D A Actinomycines L01D A01 mg Public <0.0001 Private <0.0001 Total <0.0001 L01D B Anthracyclines and related substances L01D B01 mg Public 0.0426 Private 0.0274 Total 0.0701 L01D B02 mg Public 0.0085 Private 0.0008 Total 0.0093 L01D B03 Epirubicin mg Public 0.0771 Private 0.0123 Total 0.0893 L01D B06 mg Public 0.0008 Private <0.0001 Total 0.0009 L01D B07 Mitoxantrone mg Public 0.0003 Private 0.0001 Total 0.0004 L01D C Other cytotoxic antibiotics L01D C01 mg Public 0.0074 Private 0.0031 Total 0.0105 L01D C03 Mitomycin mg Public 0.002 Private 0.001 Total 0.003

80 CHAPTER 16: USE OF ANTINEOPLASTIC AGENTS INCLUDING ENDOCRINE THERAPY Malaysian Statistics on Medicines 2006

Table 16.5: Use of Antineoplastic Agents by Drug Class and Agents, in total dosage/1000 population/day 2006 ATC Drug Class and Agents Unit 2006 L01X A Platinum compounds L01X A01 Cisplatin mg Public 0.0817 Private 0.0462 Total 0.1278 L01X A02 Carboplatin mg Public 0.3832 Private 0.1088 Total 0.4919 L01X A03 Oxaliplatin mg Public 0.0123 Private 0.0281 Total 0.0404 L01X B Methylhydrazines L01X B01 mg Public 0.0269 Private <0.0001 Total 0.0269 L01X C Monoclonal antibodies L01X C02 Rituximab mg Public 0.0377 Private 0.0242 Total 0.0619 L01X C0 3 Trastuzumab mg Public 0.0008 Private 0.0058 Total 0.0065 L01X C06 Cetuximab mg Public 0.0017 Private 0.0335 Total 0.0352 L01X C07 Bevacizumab mg Public - Private 0.0128 Total 0.0128 L01X E01 Imatinib mg Public 0.0942 Private 0.2025 Total 0.2966 L01X E02 Gefitinib mg Public 0.0086 Private 0.1336 Total 0.1422 L01X X Other antineoplastic agents L01X X02 mg Public 5.2422 Private 0.2473 Total 5.4895 L01X X05 mg Publ ic 23.5787 Private 5.4791 Total 29.0578 L01X X11 Estramustine mg Public - Private <0.0001 Total <0.0001 L01X X14 Tretinoin mg Public 0.0301 Private 0.0046 Total 0.0347 L01X X17 mg Public - Private - Total -

81 CHAPTER 16: USE OF ANTINEOPLASTIC AGENTS Malaysian Statistics on Medicines 2006 INCLUDING ENDOCRINE THERAPY

ATC Drug Class and Agents Unit 2006 L01X X19 Irinotecan mg Public 0.0202 Private 0.0097 Total 0.03 L01X X27 Arsenic trioxide mg Public 0.0007 Private - Total 0.0007 L01X X32 Bortezomib mg Public <0.0001 Private <0.0001 Total <0.0001 L01X X35 Anagrelide mg Public 0.0037 Private 0.0005 Total 0.0042 References: 1. Australia Department of Health and Ageing, Australian Statistics On Medicine 2003. 2. Statistics on Drug use in Australia 2006.

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