proposal for the inclusion of imatinib mesylate for … · malini aisola, msc...

PROPOSAL FOR THE INCLUSION OF IMATINIB MESYLATE

FOR THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA IN

THE WHO MODEL LIST OF ESSENTIAL MEDICINES FOR ADULTS

Authors:

Sandeep P. Kishore, PhD

[email protected]

Malini Aisola, MSc

[email protected]

Ruth Lopert, BMed, FAFPHM

[email protected]

Nii Koney, MD, MBA

[email protected]

Advisor:

Marcus M. Reidenberg, MD

Weill Cornell Medical College

Person to Contact:

Dr Sandeep P. Kishore

Weill Cornell / Rockefeller/ Sloan-Kettering

Tri-Institutional MD-PhD Program

1230 York Avenue, Box 292

New York, New York 10065

[email protected]

+1 917-733-1973

1st January 2013

mailto:[email protected]

Proposal for inclusion of imatinib in the WHO Model List

2

Table of Contents

1. Summary statement of the proposal for inclusion .............................................................. 3

2. Name of the focal point in WHO submitting or supporting the application ........................ 3

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

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

5. Formulation proposed for inclusion ................................................................................... 4

6. International availability - sources, if possible manufacturers and trade names .................. 4

7. Whether listing requested as an individual medicine or example of a therapeutic group ..... 4

8. Information supporting the public health relevance ............................................................ 4

9. Treatment details ............................................................................................................... 5

Chronic phase ............................................................................................................. 5

Accelerated phase ....................................................................................................... 5

Blast phase .................................................................................................................. 5

10. Summary of comparative effectiveness in a variety of clinical settings ............................ 6

Compared with pre-existing treatments ....................................................................... 6

In the elderly ............................................................................................................... 8

In different settings ..................................................................................................... 8

11. Summary of comparative evidence on safety ................................................................... 8

Common adverse effects ............................................................................................. 8

Safety in Pregnancy .................................................................................................... 9

12. Summary of available data on comparative costs and cost-effectiveness ........................ 10

Costs ......................................................................................................................... 10

Comparative effectiveness ........................................................................................ 10

Cost effectiveness ..................................................................................................... 10

13. Summary of regulatory status of the medicine ............................................................... 11

14. Availability of pharmacopoeial standards ...................................................................... 11

15. Proposed (new/adapted) text for the WHO Model Formulary ........................................ 12

Definitions of terms used to describe clinical responses to imatinib ..................................... 13


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1. Summary statement of the proposal for inclusion, change or deletion

Effective treatments for chronic myeloid leukemia (CML) have now been available for nearly

a decade. The chromosomal translocation found in 95% of CML that yields an aberrant

tyrosine kinase (BCR-ABL) that drives the chronic ablation of myeloproliferative cells, can

be addressed with the tyrosine kinase inhibitor, imatinib mesylate. With this medicine, 5-year

survival rates have increased by over 35%. Complete cytogenetic response is seen in 75 -

80% of patients, with a Number Needed to Treat (NNT) of 1.6 patients to achieve a complete

cytogenetic response at 18 months. Evidence from low- and middle-income countries,

including South Africa, Mexico, China, and India, demonstrates the utility of this therapy in a

variety of clinical and geographic contexts. Moreover, individual nations are already adding

imatinib to their national Essential Medicines Lists (EMLs), exemplified by India in its

national EML revision of 2011, prompting the question of whether the WHO Model List

should be similarly amended.

This submission surveys recent efficacy, effectiveness, and safety data on imatinib gathered

over the past decade. We have also reviewed the cost-effectiveness of imatinib and our

analysis shows that not only is imatinib an effective treatment, but that at current generic

product prices it dominates pre-existing treatment options over a plausible range of prices for

the comparators.

Based on our assessment and consultations with experts in this field, including practitioners

in resource-poor settings, we conclude that imatinib meets the definition of an Essential

Medicine. While the international partnership, the Glivec International Patient Assistance

Program (GIPAP), has provided the medicine to over 18,000 patients free of charge in over

15 countries (and in doing so provided a model for managing CML in resource-poor settings),

a more structured and comprehensive effort is urgently needed for appropriate scale-up in the

public sector.

Recognizing this, we have reviewed the regulatory landscape for imatinib, particularly noting

the recent grant of marketing authorization for the first generic version of the drug by the

European Medicines Agency (EMA). We have catalogued the various generic suppliers of

imatinib globally and note the wide impact generic competition will have on making the

medicine affordable globally. The cost of the medicine is now as low as $3.5 - $18 per gram

in some settings because of generic competition. Taken together, based on our review of

patent status, availability worldwide by global manufacturers, clinical efficacy, cost and cost

effectiveness, we propose that imatinib be added to the WHO EML as an individual medicine.

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

(where relevant)

N/A

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

Third World Network (TWN)


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Universities Allied for Essential Medicines (UAEM)

Individuals:

Sakhtivel Selvaraj, Health Economist, Public Health Foundation of India

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

imatinib mesylate

5. Formulation proposed for inclusion

imatinib mesylate (400, 600, 800 mg), oral tablet

6. International availability - sources, if possible manufacturers and trade names

Appendix A provides a list of suppliers of imatinib mesylate in several countries. The

original manufacturer, Novartis, markets imatinib mesylate under the trade names Glivec and

Gleevec worldwide. Imatinib is also available through generic manufacturers in several

countries. For example, Teva Pharmaceuticals is a supplier of the medicine in Russia. There

are a number of firms manufacturing imatinib mesylate in India noted in the list.

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

therapeutic group

As an individual medicine.

8. Information supporting the public health relevance (epidemiological

information on disease burden, assessment of current use, target population)

Chronic myelogenous leukemia constitutes 15% of all adult leukemia cases and 5% of all

childhood leukemias.1 The incidence in crude terms is estimated at 1 to 1.5 per 100,000

people globally. In developed countries, the estimated 5-year survival rate of patients

diagnosed between 2001 and 2007 was 57%.2 The average patient is diagnosed at 66 years

and males are affected slightly more than females.3

The diagnosis of CML is typically made by laboratory testing including bone marrow tests,

complete blood count and cytogenetic studies to detected chromosomal changes. There are

three stages of CML: chronic (5-6 years), accelerated and blast phase. The blast phase is

normally fatal within 3-6 months. Use of the medicine is targeted towards chronic or

accelerated phases. Complete cytogenetic response or complete hematologic response are

often used as surrogates for progression-free and overall survival.

Notably, the Glivec International Patient Assistance Program, GIPAP, has provided imatinib

free of charge to nearly 18,000 patients in over 15 countries including Kenya, Nigeria, South

Africa, Sudan, Argentina, Chile, El Salvador, Mexico, Russia, Georgia, China, India,

Malaysia, Pakistan and Thailand.4 Notably, none of the participants have come from high-


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income settings. Here, the average age of diagnosis has been 38.7 years, significantly lower

than in developed country settings, and the dominant age cohort is 31-40 years. At diagnosis,

over 11,000 of the 18,000 patients were in the chronic phase, just over 1,200 were in the

accelerated phase and just under 1,000 were in blast crisis. Among these patients, imatinib

has produced an 8-year event free survival of 81%.5

While large RCTs have not been undertaken in low and middle income countries, small trials

and observational studies from India, Mexico, China, Brazil and South Africa indicate that

responses to imatinib in developing country settings are consistent with those in

industrialized countries where the major RCTs were conducted. This suggests that imatinib

response does not vary widely by ethnicity or race. Relevant sources, reviewed in the section

on comparative effectiveness, also point to the increasing uptake of CML therapy in resource-

poor settings, including India and Mexico.6,7

9. Treatment details

Treatment recommendations from the European LeukemiaNET and adapted for South Africa

are provided here.8 The recommendations are as published in Louw VJ et al.

9

Chronic phase

First line - imatinib at 400 mg/day PO

Second line -

1. imatinib dose escalation to 600 mg/day (can be increased to 800 mg/day);

2. nilotinib (400 mg/twice a day PO; preferred if pleural effusions, congestive cardiac

failure, COPD, chest wall injury, asthma, GI bleeding or autoimmune disease are

present);

3. dasatinib 100 mg/day PO preferred if there history of pancreatitis or diabetes.

Accelerated phase

First line: imatinib 600 mg/day or 800 mg/day or allogeneic stem cell transplantation

Alternative first-line or second-line: second-generation tyrosine kinase inhibitor or stem

cell transplantation

Blast phase

First line: imatinib 800 mg/day or allogeneic stem cell transplantation

Alternative first-line and second-line:

Lymphoid: dasatanib or chemotherapy + dasatinib

Myeloid: second-generation tyrosine kinase inhibitor, chemotherapy + tyrosine kinase

inhibitor or allogeneic stem cell transplant


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

[See Note at end of application for definition of terms]

Compared with pre-existing treatments

Data sources included MEDLINE, EMBASE, Current Controlled Trials, ClinicalTrials.gov,

and the US FDA website and European Medicines Agency websites searched from October

2002 to September 2012.

In a phase II trial in 454 patients late-stage chronic CML patients in whom interferon had

failed Kantarijan (2002) reported imatinib-induced major cytogenetic responses in 60 percent

and complete cytogenetic responses in 41 percent.10

Subsequently, the International Randomized Study of Interferon vs STI571i (IRIS) clearly

demonstrated the efficacy of imatinib 400 mg daily compared with interferon alpha and low

dose cytarabine (Ara-C), as measured by hematologic response, complete cytogenetic

response, progression-free survival and overall survival.11,12

Complete hematologic responses

were seen in 95 percent, with estimated progression-free survival at 18 months of nearly 90

percent and a 6-year overall survival rate of 88%.13 Imatinib was associated with complete

remission at 12 months follow-up in 68% patients compared with 20% for interferon-alpha

plus Ara-C. The estimated proportion of patients taking imatinib who had not progressed to

accelerated or blast phase at 12 months was 98.5% compared with 93.1% for interferon-alpha

plus Ara-C. Withdrawal due to side effects was 2% for imatinib vs 5.6% for interferon-alpha

plus Ara-C.13

Number Needed to Treat (NNT) in the IRIS trial

The NNTs for imatinib vs interferon-alpha/Ara-C) for chronic phase CML during median

follow-up of 19 months, from the IRIS trial:

1.9 for major cytogenetic response (52% absolute risk reduction)

1.6 for complete cytogenetic response (62% absolute risk reduction)

A 2003 NICE technology appraisal14

summarized the IRIS data as follows:

For chronic phase:

An intention to treat analysis at 18 months in IRIS indicated that the disease had not

progressed in estimated 92% of the people in the imatinib arm (n=553) compared with

74% in the interferon-alpha and Ara-C arm (n=553). Importantly, at 18 months, complete

remission was achieved more often in people in the imatinib group versus the interferon-

alpha/Ara-C group (76% vs 15&, respectively). In cases where interferon-alpha failed to

achieve a response for late stage chronic CML, major or partial cytogenetic response (CR)

was observed in 60% of people. At 31-months follow-up 74% remained on imatinib and

______________________________ i STI571 = imatinib


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48% maintained the CR. Progression-free survival was estimated at 87% at 24 months

with overall survival of 92% at 24 months.14

For accelerated phase:

Two groups were followed in accelerated phase. One with a median follow-up time of 9.9

months (400mg imatinib, n=77) and 11 months (600 mg, n = 158). When both groups

were combined, 53% achieved complete hematogenic response (HR) and 19% retverted to

the chronic phase. Major CR was reported in 24% of the population. Overall survival (OS)

was estimated at 65% at 12 months for the 400mg group and 78% for the 600mg group;

progress-free survival was 44% at 12 months for the 400mg group and 67% for the 600mg

group. A 36 month follow-up for the 600mg group showed a 66% survival rate.

For blast crisis:

Sustained HR (lasting for 4 weeks) was observed for 31% of people. 8% of people had

complete HR and 18% had returned to the chronic phase. At 4 months people with 600mg

treatment, 16% of people achieved major CR with 7% with complete CR. The OS for 12

months was 32%.

Six-year follow up of the imatinib arm in IRIS indicated an EFS of 83% at 6 years. A 95%

OS was reported with only CML-related deaths identified. The cumulative complete CR was

82% with over 60% of patients randomized to receive imatinib still on the medicine. This

follow-up study found that the level of complete CR at 6 months was an important prognostic

factor for freedom from progression with 6-year EFS of 91% in patients achieving complete

CR at the 6-month landmark, 85% in those with a partial cytogenetic response and 58% in

those with a minor cytogenetic response.13

A recent systematic review by Ferdinand et al also examined the clinical effectiveness, safety

and effect on quality of life of tyrosine kinase inhibitors for the management of chronic-,

accelerated-, or blast-phase CML patients.15

The authors found only one RCT demonstrating

the long-term efficacy of imatinib, the IRIS trial discussed above.

A recent Health Technology Assessment from the UK National Health Service compared

imatinib with the 2nd

generation tyrosine kinase inhibitors dasatinib and nilotinib. The review

found that although rates of complete cytogenetic response and major molecular response

were higher for patients receiving dasatanib than those treated with imatinib (83% vs 72% for

complete cytogenetic response and 46% vs 28% for major molecular response) overall

survival was not significantly different for the newer agents at 24-months follow-up. 16

A 2012 systematic review and meta-analysis by Gurion et al also examined 2nd-generation

TKIs vs imatinib as first-line treatment for CML.17

A total of 2120 patients were included. At

12 months, patients treated with second-generation TKIs had higher rates of complete

cytogenetic response and major molecular response (HR: 1.16, 95% CI 1.09 to 1.23 and RR

1.68, 5% CI, 1.48 to 1.91, respectively). Progression to accelerated phase/blast crisis was also

significantly lower with the newer tyrosine kinase inhibitors at all time points.


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In the elderly

A systematic review by Breccia reviewed the effectiveness of tyrosine kinase inhibitors for

CML in the elderly (>65).18

A summary of the results appears in the following table.

Trial No. patients Elderly cohort Complete CR Overall Survival

Sapienza 117 40 85% 82% (5yr)

Spanish 36 36 72% NR

GIMEMA 559 115 87% 55% (5yr)

The authors concluded that imatinib has similar efficacy in the elderly as in younger patients,

but with more frequent toxicity that leads to higher rates of discontinuation and dose

reduction. A direct comparison was made in the German Study IV in which the imatinib

standard dose group (223 patients) included 58 patients aged >65 years (median 69 years).

The discontinuation rate among this subgroup was 12%, and 8.6% died, whereas in the

younger cohort only 8.4% discontinued and 2.4% died. Older patients also took longer to

achieve a complete cytogenetic response than the younger group (mean 12.3 months vs 10.7

months). This study included second-generation tyrosine kinase inhibitors as well, but the

data shown above are specific to imatinib.

In different settings

The use of imatinib in low and middle-income countries has been documented using a variety

study designs. The rates of complete CR, OS and adverse reactions are similar to those

reported in industrialized countries, indicating that global use is justified and that the

effectiveness is constant across different ethnic and geographic contexts. The chart below

provides a snapshot of the studies:

Location Complete CR Overall Survival Follow-Up (months)

China 19

70% 75% 60

India7 56% 95% 30

Pakistan20

39.4% 92% 18

Mexico6 NR 84% 60

Cuba21

91% 96% 39

11. Summary of comparative evidence on safety

Common adverse effects

Imatinib is generally well tolerated in diverse patient populations. The most common side

effects include gastrointestinal discomfort due to nausea, vomiting, diarrhea as well as

superficial fluid retention and skin rashes. Rare, but severe and sometimes fatal, side effects


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such as Steven Johnson syndrome have also been reported. The table below summarizes the

list of common adverse events reported with use of imatinib mesylate.

Studies performed in China, India, South Africa, Taiwan Mexico and Pakistan all show

similar adverse event profiles as those observed in the US and European countries. The

pharmacokinetic profile of the drug appears to be the primary driver of adverse effects.

Adverse Events Reported in Association with use of imatinib mesylate

Adverse Events

Cardiovascular Congestive heart failure, edema*

Respiratory Interstitial pneumonitis

Gastrointestinal Nausea*, vomiting*, diarrhea*

Renal Acute renal failure, SIADH

Dermatologic Hypopigmentation*, epidermal necrolysis, Stevens Johnson syndrome

Hematologic Anemia, neutropenia, thrombocytopenia, splenic rupture

Gynecologic Premature ovarian failure

Endocrine Hypophosphatemia

Musculoskeletal Myalgia*, arthralgia

Genito-urinary Oligospermia

*Most common adverse events

The drug exhibits 98% bioavailability with a half-life of 18 hours for the parent drug and 40

hours for its major metabolite.22

Cytochrome P450 isoenzyme 3A4 is the main enzyme

responsible for elimination. Concomitant use of drugs that inhibit this enzyme such as the

azole antifungals and macrolide anti-bacterials lead to increased plasma levels of imatinib

and thus may increase the risk of adverse effects. Drugs that induce this isoenzyme such as

carbamezapine and phenobarbital can cause decreased plasma levels and potentially reduced

drug efficacy.

Larson et al performed a study to monitor the effect of trough drug levels on efficacy and

safety.23

Efficacy and safety were monitored during the first three months of drug

administration and within the first 5 years. Patients were divided into quartiles based on

trough levels of the drug. Patients with the highest trough levels of the drug demonstrated

significantly higher cytogenetic response and major molecular response rates, as well as

longer event free survival. Adverse events were similar across the high and low trough levels

except for edema, myalgia, rash and anemia.

Safety in Pregnancy

Imatinib is classified as a Class D drug, meaning it should only be used in life threatening

emergency when no safer drug is available, as there is positive evidence of human fetal risk.

The drug has also been shown to be present in breast milk and is thus not recommended

during lactation.24,25


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

the pharmacological class or therapeutic group:

Costs

A catalogue of surveyed prices from several countries and listing of manufacturers, including

several generic firms, is provided in Appendix A. The price per gram and cost of a year's

treatment with imatinib according to treatment guidelines for chronic phase CML were

estimated. Prices available through generic manufacturers were generally lower than via

Novartis. In India, where no product patent has been granted for imatinib, stiff generic

competition has resulted in private sector prices as low as $3.5-$18 per gram (including the

branded product), and even lower in instances of public sector procurement. In the case of

speciality drug procurement by the Tamil Nadu Medical Services Corporation, for example,

the cost of imatinib was as low as $0.90 per gram ($130.75 per year). Using a survey of

Indian retail prices, costs per year of treatment range from $454 to $2,623 (6-year costs of

$2726 - $15,738). A similar downward trend in prices is expected in several regions as

patents on Novartis' product expire and cheaper generic alternatives penetrate markets. In

comparison, the US Federal Supply Schedule price is $240-$330 per gram and the reported

price in Bahrain is >$400 per gram. International reference prices are reported in Appendix

B.

Comparative effectiveness

Reed et al (2008) used 60-month survival data from the IRIS trial to model cost-effectiveness

of imatinib vs interferon-alpha/cytarabine. The study reported average life expectancy with

first line imatinib as 19.1 life years (15.25 QALYs) and with interferon-alpha/cytarabine as

9.1 life years (6.3 QALYs). The study thus showed an average incremental benefit of

imatinib over interferon-alpha/cytarabine of slightly less than 9 QALYs.26

Cost effectiveness

Given the dynamic modern regulatory environment on imatinib, we sought to analyze cost-

effectiveness with current generic products (using Indian retail prices). Using data from the

IRIS trial and prices from our survey in Appendices C & D, we calculated incremental cost

effectiveness ratios (ICERs) for imatinib vs IFN/ARA-C over a plausible range of cost

estimates. We found that for compete cytogenetic response at 18 months follow-up imatinib

was dominant over IFN/ARA-C (see spreadsheet at Appendix C and D for costs and

Appendix E for model details). Our analysis shows that not only is imatinib a superior first-

line treatment for CML, but that at current generic product prices it dominates preexisting

treatment options over a plausible range of prices for the alternatives. Using data from

Hochhaus13

in the following table we also report costs and absolute cost effectiveness ratios

for treatment outcomes at 6 years follow-up.


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Cost Effectiveness Ratios*

Cost of 6 years treatment with imatinib $13,512 (2,726 - 15,738)

Estimated event-free survival at 6 years 83%

*Cost per patient surviving event free at 6 years $16,280 (3,284 - 18,961)

Estimated rate of freedom from progression to accelerated phase

/blast-crisis at 6 years 93%

*Cost per patient avoiding progression at 6 years $14,529 (2,931 - 16,922)

Estimated overall survival at 6 years: 88%

*Cost per patient surviving at 6 years $15,355 (3,097 - 17,884)

13. Summary of regulatory status of the medicine

Imatinib mesylate was approved by the FDA on May 11, 2001 via an expedited review.

According to the FDA Orange Book, imatinib is covered by patents extending to May 23,

2019 and orphan drug exclusivity that expires in Dec 2015. However, the compound patent

on imatinib will expire in 2015. Glivec has been authorized in the European Union since

November 2001.

We draw the committee’s attention to the fact that on October 18, 2012 Teva Pharmaceuticals

received the first marketing authorization by the European Medicines Agency (EMA) for

generic imatinib (100 mg and 400 mg forms).27

The medicine (branded and generic) is currently registered in over 90 countries including:

Argentina, Australia, Bulgaria, Canada, Chile, Columbia, Dominican Republic, Ecuador, El

Salvador, Guatemala, India, Israel, Indonesia, Japan, Jordan, Kuwait, Malta, Mexico, New

Zealand, Nicaragua, Palestine, Peru, Romania, Russia, South Korea, Switzerland, Syria,

United States, Uruguay, Venezuela.28

14. Availability of pharmacopoeial standards (British Pharmacopoeia,

International Pharmacopoeia, United States Pharmacopoeia)

The medicine is listed in the 2012 British National Formulary.

According to the International Pharmacopoeia, imatinib is listed in the ‘work in progress’

column as of May 2012 and has a scientific liaison assigned.

The medicine is listed in the Indian pharmacopoeia.


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

Imatinib mesylate (400, 600, 800 mg), oral tablet

Imatinib mesylate is a member of the class of tyrosine kinase inhibitor (TKI) that inhibit activity of the bcr-abl fusion protein, resulting in both hematologic response (ie normal

cell counts in the peripheral blood and normal bone marrow morphology), as well as cytogenetic response (ie disappearance or reduction of the Philadelphia [Ph] chromosome)

Uses:

Chronic phase chronic myeloid leukemia

Accelerated phase and blast crisis chronic myeloid leukemia

Contraindications: None.

Precautions: cardiac disease; risk factors for heart failure; history of renal failure;

monitor for fluid retention; monitor liver; monitor growth in children (may cause growth retardation); interactions:

Hepatic impairment: max. 400 mg daily; reduce dose further if not tolerated

Renal impairment: max. starting dose 400 mg daily if creatinine clearance less than 60 mL/minute; reduce dose further if not tolerated

Use in Pregnancy: avoid unless potential benefit outweighs risk; effective contraception

required during treatment.

Breast-feeding: discontinue breast-feeding

Dosage:

Chronic phase chronic myeloid leukaemia, adult 400 mg once daily, increased if necessary to max. 800 mg daily (in 2 divided doses); child (chronic and advanced phase) 2–18 years 340 mg/m2 (max. 800 mg) daily (in 1–2 divided doses), increased to 570 mg/m2 (max. 800 mg) daily if necessary

Accelerated phase and blast crisis chronic myeloid leukaemia, adult 600 mg once daily, increased if necessary to max. 800 mg daily (in 2 divided doses)

Monitoring: At 3 months, examine leukocyte and platelet counts for complete

hematologic response, at 6 months for partial cytogenetic response and 12 months for complete cytogenetic response and 18 months for a major molecular response.

Adverse effects: Edema, neutropenia, nausea, muscle cramps, musculoskeletal pain,

thromopocytopenia, rash, fatigue, diarrhea, headache, arthralgia, abdominal pain, myalgia, nasopharyngitis, hemorrhage, vomiting, dyspepsia, cough, dizziness, URT infection, fever, weight gain, hepatotoxicity and insomnia.


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Definitions of terms used to describe clinical responses to imatinib

Ph+ Philadelphia chromosome positive

Hematologic Response

Complete Hematologic Response WBC < 10 x 10^9/L

Basophils <5%

No myelocytes, promyelocytes or myeloblasts

Spleen non-palpable

Cytogenetic Response

Complete cytogenetic response No Ph+ metaphases

Partial cytogenetic response 1 – 35% Ph+ metaphases

Minor cytogenetic response 36 – 56% Ph+ metaphases

Minimal cytogenetic response 66 – 95% Ph+ metaphases

Non response > 95% Ph+ metaphases

Molecular Response

Complete response Undetectable BCR-ABL mRNA transcripts

by RT-PCR and/or two consecutive blood

samples of adequate quality

Major response Ratio of BCR-ABL to ABL <0.1% on

international scale


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22 Cohen MH, Williams G, Johnson JR, Duan J et al. Approval summary for imatinib

mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res

2002;8(5):935-42.

23 Larson RA, Druker BJ, Guilhot F, O'Brien SG et al. Imatinib pharmacokinetics and its

correlation with response and safety in chronic-phase chronic myeloid leukemia: a

subanalysis of the IRIS study. Blood 2008;111(8):4022-8.

24 Pye SM, Cortes J, Ault P, Hatfield A et al. The effects of imatinib on pregnancy outcome.

Blood 2008;111(12):5505-8.

25 Ault P, Kantarjian H, O'Brien S, Faderl S et al. Pregnancy among patients with chronic

myeloid leukemia treated with imatinib. J Clin Onc 2006;24(7):1204-8.

26 Reed SD, Anstrom KJ, Li Y, Schulman KA. Updated estimates of survival and cost

effectiveness for imatinib versus interferon-alpha plus low-dose cytarabine for newly

diagnosed chronic-phase chronic myeloid leukaemia. Pharmacoeconomics

2008;26(5):435-46.

27 European Medicines Agency. Summary of opinion: Imatinib Teva. Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-

_Initial_ authorisation/human/002585/WC500134083.pdf, October, 18, 2012.

28 Martindale: The Complete Drug Reference, 37th Edition

Appendix A. Prices of imatinib mesylate and cost of treatment in several countries

Country Date Brand Company Strength Pack sizePrice (local currency) Currency

Price (USD)*

Price per gram (USD)

Price per patient per year** (USD) Price detail Source

*Based on exchange rates of 30 November 2012, http://www.oanda.com**Based on a chronic phase CML treatment regimen of 400 mg per day (e.g., NICE Guidance on the use of imatinib for chronic myeloid leukaemia)

Australia Nov, 2012 Glivec Novartis 400 mg 30 tabs 3,863.70 AUD 4,039.38 336.62 49,145.79 PBS base dispensed price http://www.pbs.gov.au/pbsNov, 2012 Glivec Novartis 100 mg 60 tabs 2,005.08 AUD 2,096.25 349.38 51,008.75 PBS base dispensed price http://www.pbs.gov.au/pbs

Bahrain Nov, 2012 Glivec Novartis 100 mg 60 tabs 948.52 BHD 2,501.24 416.87 60,863.51 Government approved retail price http://www.moh.gov.bh/EN/Nov, 2012 Glivec Novartis 400 mg 30 tabs 1,897.04 BHD 5,002.48 416.87 60,863.51 Government approved retail price http://www.moh.gov.bh/EN/Nov, 2012 Glivec Novartis 100 mg 120 tabs 1,987.04 BHD 5,239.81 436.65 63,751.02 Government approved retail price http://www.moh.gov.bh/EN/

Belgium Nov, 2012 Glivec Novartis 400 mg tab 85.46 EUR 110.80 277.01 40,443.10 Hospital reimbursement rate; ex-‐factory = 80.62 Euros http://www.inami.fgov.be

Nov, 2012 Glivec Novartis 400 mg tab 85.70 EUR 111.11 277.79 40,556.61 Ambulatory reimbursement rate; ex-‐factory = 80.62 Euros http://www.inami.fgov.be

Nov, 2012 Glivec Novartis 100 mg tab 21.82 EUR 28.29 282.91 41,304.42 Hospital reimbursement rate; ex-‐factory = 20.59 Euros http://www.inami.fgov.be

Nov, 2012 Glivec Novartis 100 mg tab 21.88 EUR 28.37 283.72 41,423.27 Ambulatory reimbursement rate; ex-‐factory =20.59 Euros http://www.inami.fgov.be

Canada Nov, 2012 Gleevec Novartis 100 mg tab 26.48 CAD 26.69 266.91 38,968.71 Price reimbursed to pharmacist from provincial government Ontario Drug Benefit Formulary

Nov, 2012 Gleevec Novartis 400 mg tab 105.94 CAD 106.76 266.91 38,968.86 Price reimbursed to pharmacist from provincial government Ontario Drug Benefit Formulary

Czech Republic Nov, 2012 Glivec Novartis 400 mg 30 tabs 71,526.25 CZK 3,674.82 306.24 44,710.31

Estimate of retail price using capped ex-‐factory price+max permitted profit margin+VAT; max ex-‐fact.=59600.31 CZK http://www.sukl.eu/

Nov, 2012 Glivec Novartis 100 mg 60 tabs 36,158.91 CZK 1,857.74 309.62 45,205.01

Estimate of retail price using capped ex-‐factory price+max permitted profit margin+VAT; max ex-‐fact.=29769.56 CZK http://www.sukl.eu/

Denmark Nov, 2012 Glivec Novartis 400 mg tab 800.20 DK 139.08 347.69 50,763.11 http://www.medicinpriser.dkNov, 2012 Glivec Novartis 100 mg tab 200.22 DK 34.80 347.99 50,806.25 http://www.medicinpriser.dk

India 2012-‐2013 ImatinibUnited Biotech (P) Ltd. 400 mg 100 tabs 1,974.00 INR 35.82 0.90 130.75

Tamil Nadu Medical Services Corporation Ltd. procurement price

http://www.tnmsc.com/tnmsc/new/index.php

2010-‐2011 ImatinibNaprod Life Sciences (P) Ltd. 400 mg 100 tabs 7,156.86 INR 129.87 3.25 474.04

Tamil Nadu Medical Services Corporation Ltd. procurement price

www.tnmsc.com/tnmsc/new/html/pdf/spldrug.pdf

2010-‐2011 ImatinibNaprod Life Sciences (P) Ltd. 100 mg 100 tabs 1,862.75 INR 33.80 3.38 493.52

Tamil Nadu Medical Services Corporation Ltd. Procurement

www.tnmsc.com/tnmsc/new/html/pdf/spldrug.pdf

Oct, 2011 Imat

Biochem Pharmaceutical Industries Ltd. 400 mg 10 tabs 540.00 INR 9.80 2.45 357.67

Procurement price excluding 4% taxes

South Central Railway annual medical indent 2011-‐12

Oct, 2011 Imat

Biochem Pharmaceutical Industries Ltd. 100 mg 10 tabs 185.00 INR 3.36 3.36 490.15

Procurement price excluding 4% taxes

South Central Railway annual medical indent 2011-‐12

Nov, 2012 Glivec Novartis India 100 mg 60 tabs 1,028.80 INR 18.67 3.11 454.29 Retail Price http://www.mims.com/IndiaNov, 2012 Glivec Novartis India 400 mg 30 tabs 4,115.20 INR 74.68 6.22 908.58 Retail Price http://www.mims.com/IndiaNov, 2012 Celonib Celon (Vivilon) 400 mg 10 tabs 3,200.00 INR 58.07 14.52 2,119.55 Retail Price http://www.mims.com/IndiaNov, 2012 Celonib Celon (Vivilon) 100 mg 10 tabs 900.00 INR 16.33 16.33 2,384.50 Retail Price http://www.mims.com/India

Nov, 2012 ImalekSun Pharmaceuticals 400 mg 6 tabs 2,029.00 INR 36.82 15.34 2,239.88 Retail Price http://www.mims.com/India

Nov, 2012 ImalekSun Pharmaceuticals 100 mg 10 tabs 850.00 INR 15.42 15.42 2,252.02 Retail Price http://www.mims.com/India

Nov, 2012 Mesylonib Miracalus 400 mg 10 tabs 3,000.00 INR 54.44 13.61 1,987.08 Retail Price http://www.mims.com/IndiaNov, 2012 Mesylonib Miracalus 100 mg 10 tabs 950.00 INR 17.24 17.24 2,516.97 Retail Price http://www.mims.com/India

Nov, 2012 MitinibGlenmark (Onkos) 400 mg 6 tabs 1,800.00 INR 32.66 13.61 1,987.08 Retail Price http://www.mims.com/India

Nov, 2012 MitinibGlenmark (Onkos) 100 mg 10 tabs 900.00 INR 16.33 16.33 2,384.50 Retail Price http://www.mims.com/India

Nov, 2012 Shantinib Shantha Biotech 100 mg 10 tabs 990.00 INR 17.97 17.97 2,622.95 Retail Price http://www.mims.com/IndiaNov, 2012 Veenat Natco 400 mg 10 tabs 3,520.00 INR 63.88 15.97 2,331.51 Retail Price http://www.mims.com/IndiaNov, 2012 Veenat Natco 100 mg 10 tabs 950.00 INR 17.24 17.24 2,516.97 Retail Price http://www.mims.com/India

Lebanon Nov, 2012 Glivec Novartis 100 mg 120 tabs 5,906,814.00 LBP 3,875.48 322.96 47,151.67 Public price of imported drug; Pharmacist margin = 19.35 LBP http://www.moph.gov.lb

Nov, 2012 Glivec Novartis 100 mg 60 tabs 3,108,857.00 LBP 2,039.73 339.96 49,633.43 Public price of imported drug; Pharmacist margin = 19.35 LBP http://www.moph.gov.lb

Nov, 2012 Glivec Novartis 400 mg 30 tabs 6,217,713.00 LBP 4,079.46 339.96 49,633.43 Public price of imported drug; Pharmacist margin = 19.35 LBP http://www.moph.gov.lb

Morocco Nov, 2012 Imatec 100 mg 120 tabs 3,500.00 MAD 407.15 33.93 4,953.67 Hospital price; maximum reimbursement price = 3,500 MAD http://www.moph.gov.lb

Nov, 2012 Imatinib Cooper 100 mg 120 tabs 3,500.00 MAD 407.15 33.93 4,953.67 Hospital price; maximum reimbursement price = 3,500 MAD http://www.moph.gov.lb

Nov, 2012 Glivec Novartis 100 mg 120 tabs 25,735.00 MAD 2,993.73 249.48 36,423.72 Hospital price; maximum reimbursement price = 3,500 MAD http://www.moph.gov.lb

Nov, 2012 Glivec Novartis 400 mg 30 tabs 26,000.00 MAD 3,024.55 252.05 36,798.69 Hospital price; not reimburseable http://www.moph.gov.lb

Nov, 2012 Glivec Novartis 100 mg 60 tabs 13,200.00 MAD 1,535.54 255.92 37,364.81 Hospital price; maximum reimbursement price = 3,500 MAD http://www.moph.gov.lb

Netherlands Nov, 2012 Glivec Novartis 400 mg 15 tabs 1,266.93 EUR 1,642.64 273.77 39,970.91

Reimbursement price including VAT and delivery rate; parallel import price =1248.99 http://www.medicijnkosten.nl/

Nov, 2012 Glivec Novartis 100 mg 15 tabs 317.54 EUR 411.71 274.47 40,072.72 Reimbursement price including VAT and delivery rate http://www.medicijnkosten.nl/

New Zealand Nov, 2012 Glivec Novartis 100 mg 60 tabs 2,400.00 NZD 1,977.41 329.57 48,116.98 Pharmaceutical Schedule price http://www.pharmac.govt.nz

Norway Nov, 2012 Glivec Novartis 100 mg 120 tabs 22,416.20 NOK 3,952.66 329.39 48,090.70

Maximum retail price Including VAT; max wholesale price excluding VAT= NOK 17,216.33 http://www.legemiddelverket.no

Nov, 2012 Glivec Novartis 100 mg 60 tabs 11,225.60 NOK 1,979.42 329.90 48,165.89


Nov, 2012 Glivec Novartis 400 mg 30 tabs 22,878.40 NOK 4,034.16 336.18 49,082.28


Oman Sep, 2012 Glivec Novartis 100 mg 60 tabs 881.92 OMR 2,283.82 380.64 55,572.95 Retail price controlled by Ministry of Health http://www.moh.gov.om

Sep, 2012 Glivec Novartis 400 mg 30 tabs 1,763.83 OMR 4,567.61 380.63 55,572.59 Retail price controlled by Ministry of Health http://www.moh.gov.om

Portugal Nov, 2012 Glivec Novartis 400 mg 30 tabs 2,469.08 EUR 3,201.29 266.77 38,949.03 http://www.infarmed.ptNov, 2012 Glivec Novartis 100 mg 60 tabs 1,247.58 EUR 1,617.55 269.59 39,360.38 http://www.infarmed.pt

Russia Nov, 2012 Imatinib Teva 100 mg 120 tabs 54,021.00 RUB 1,743.70 145.31 21,215.02 State Maximum Release Pricehttp://grls.rosminzdrav.ru/pricelims.aspx?s=

Nov, 2012 Imatinib Teva 400 mg 30 tabs 84,167.00 RUB 2,716.76 226.40 33,053.91 State Maximum Release Pricehttp://grls.rosminzdrav.ru/pricelims.aspx?s=

Nov, 2012 Gleevec Novartis 100 mg 120 tabs 60,368.57 RUB 1,948.59 162.38 23,707.85 State Maximum Release Pricehttp://grls.rosminzdrav.ru/pricelims.aspx?s=



Spain Nov, 2012 Glivec Novartis 400 mg 30 tabs 2,520.61 EUR 3,268.10 272.34 39,761.88 Retail price; seller's price = 2,367.75 EUR http://www.vademecum.es/

Nov, 2012 Glivec Novartis 100 mg 60 tabs 1,289.75 EUR 1,672.23 278.71 40,690.93 Retail price; seller's price = 1,184.23 EUR http://www.vademecum.es/

Sweden Nov, 2012 Glivec Novartis 400 mg 30 tabs 23,339.00 SEK 3,507.42 292.29 42,673.61

Reimbursement price including pharmacy margin -‐ public health insurance system http://www.fass.se

Nov, 2012 Glivec Novartis 100 mg 60 tabs 11,753.00 SEK 1,766.26 294.38 42,978.99

Reimbursement price including pharmacy margin -‐ public health insurance system http://www.fass.se

UK Nov, 2012 Glivec Novartis 100 mg 60 tabs 862.19 GBP 1,381.38 230.23 33,613.58 Net price not including VAT and other fees http://www.mims.co.uk/

Nov, 2012 Glivec Novartis 400 mg 30 tabs 1,724.39 GBP 2,762.78 230.23 33,613.82 Net price not including VAT and other fees http://www.mims.co.uk/

USAJan, 2012 -‐ Nov, 2012 Gleevec Novartis 400 mg 30 tabs 2,859.96 USD 2,859.96 238.33 34,796.18

U.S. Federal Supply Schedule contract price; reflects discounting practices through private health insurance http://www.pbm.va.gov

Jan, 2012 -‐ Nov, 2012 Gleevec Novartis 100 mg 90 tabs 2,975.03 USD 2,975.03 330.56 48,261.60

U.S. Federal Supply Schedule contract price; reflects discounting practices through private health insurance http://www.pbm.va.gov

Appendix B. International Reference Prices for imatinib mesylate

MSH International Drug Price Indicator Guide

Price USD 2010

Price USD 2011

Price per gram (USD)

Price per patient per year (USD) Source

imatinib 100 mg 19.38 193.83 28299.62 Caja Costarricense de Seguro Social (CRSS)imatinib 100 mg 3.24 32.39 4729.38 Barbados Drug Service (BDS)imatinib 100 mg 8.15 81.50 11899.00 The System of Central American Integration (SICA)imatinib 400 mg 62.50 625.00 91250.00 The System of Central American Integration (SICA)

Appendix C. Estimated costs of treatment of CML with Interferon-‐Alpha + Cytarabine using Indian retail prices

Source: CIMS India (http://www.mims.com/India); retail prices as of December 2012

INTERFERON-‐ALPHA 2a (IFN)

Brand Company Strength Price (INR) Price (USD)

Price per patient for 18 months of treatment* (USD)

Median cost (USD) min-‐max

Alferon Zydus 3MU 1,190.00 21.60 18,959.70 15,901.14 7,752.77 -‐ 21,684.16Inron-‐A Bio E 3MU 970.00 17.61 15,454.55 Intalfa PF Intas 3MU 603.00 10.94 9,607.31 Intalfa PF Intas 5MU 811.00 14.72 7,752.77 LG Intermax Alpha LGLSI 3MU 1,150.00 20.87 18,322.40 LG Intermax Alpha LGLSI 6MU 2,000.00 36.30 15,932.52 Roferon-‐A AHPL 3MU 1,361.00 24.70 21,684.16 Zavinex Zydus Cadila 3MU 998.03 18.11 15,901.14 Zavinex Zydus Cadila 5MU 1,498.03 27.19 14,320.44

CYTARABINE (ARA-‐C)

Brand Company Strength** Price (INR) Price (USD)

Price per patient for 18 months of treatment* (USD)

Median cost (USD) min-‐max

Arasid Intas 100 mg 176.00 3.19 230.00 230.65 222.16 -‐ 241.76Biobin Biochem 100 mg 180.00 3.27 235.22 Cancyt Miracalus 100 mg 175.00 3.18 228.69 Cybin-‐PF VHB 100 mg 185.00 3.36 241.76 Cytabin Zydus Cadila 100 mg 175.00 3.18 228.69 Cytalon Celon 100 mg 177.00 3.21 231.30 Cytaraside Chandra Bhagat 100 mg 175.00 3.18 228.69 Cytarine Dabur 100 mg 184.00 3.34 240.45 Cytrostar VHB 100 mg 184.00 3.34 240.45 Remcyta Alkem 100 mg 170.00 3.09 222.16

Cost of treatment of IFN/ARA-‐C 16,131.79 (7,974.92 -‐ 21,925.92)

*average dose of 4.81 MU of IFN per day; 40 mg daily dose of cytarabine for 10 days per month (Reed et al., 2004)**alternate strengths (e.g., 1g, 500mg) are also available

Appendix D. Estimated costs of treatment of CML with imatinib mesylate using Indian retail prices

IMATINIBSource: CIMS India (http://www.mims.com/India); retail prices as of December 2012

Brand Company Strength Pack size Price (INR)Price per g (USD)

Price per patient for 18 months of treatment (USD)

Price per patient for 6 years of treatment (USD)

Glivec Novartis India 100 mg 60 tabs 1,028.80 3.11 681.44 2,725.75 Glivec Novartis India 400 mg 30 tabs 4,115.20 6.22 1,362.87 5,451.49 Celonib Celon (Vivilon) 400 mg 10 tabs 3,200.00 14.52 3,179.33 12,717.31 Celonib Celon (Vivilon) 100 mg 10 tabs 900.00 16.33 3,576.75 14,307.01 Imalek Sun Pharmaceuticals 400 mg 6 tabs 2,029.00 15.34 3,359.82 13,439.26 Imalek Sun Pharmaceuticals 100 mg 10 tabs 850.00 15.42 3,378.03 13,512.12 Mesylonib Miracalus 400 mg 10 tabs 3,000.00 13.61 2,980.62 11,922.47 Mesylonib Miracalus 100 mg 10 tabs 950.00 17.24 3,775.45 15,101.80 Mitinib Glenmark (Onkos) 400 mg 6 tabs 1,800.00 13.61 2,980.62 11,922.47 Mitinib Glenmark (Onkos) 100 mg 10 tabs 900.00 16.33 3,576.75 14,307.01 Shantinib Shantha Biotech 100 mg 10 tabs 990.00 17.97 3,934.42 15,737.69 Veenat Natco 400 mg 10 tabs 3,520.00 15.97 3,497.26 13,989.04 Veenat Natco 100 mg 10 tabs 950.00 17.24 3,775.45 15,101.80

median 3,378.03 13,512.12 min-‐max 681.44 -‐ 3,934.42 2,725.75 -‐ 15,737.69

Appendix E. Illustration of potential costs per treatment outcome using an Indian context

Source Additional clinical benefit

O'Brien et al., 2003 -‐ IRIS trial

Complete cytogenetic response (CCR) at 18 months (Kaplan-‐Meier estimates)

point estimate range

imatinib: 76.2% (95% CI: 72.5 -‐ 79.9) 0.617 (0.69-‐0.54)interferon-‐alpha/cytarabine: 14.5% (95% CI: 10.5-‐18.5)

O'Brien et al., 2003 -‐ IRIS trial Freedom from progresson to accelerated/blast-‐crisis at 18 monthsimatinib: 96.7% 0.052interferon-‐alpha/cytarabine: 91.5%

USD (min-‐max)See Appendix D for details Cost of 18 month treatment with imatinib* 3,378.03 (681.44 -‐ 3,934.42)See Appendix C for details Cost of 18 month treatment with IFN/ARA-‐C 16,131.79 (7,974.92 -‐ 21,925.92)

*assuming still receving treatment at 18 months

Incremental cost per patient achieving CCR at 18 months IMATINIB DOMINANT

Absolute Cost-‐Effectiveness RatiosUSD (min-‐max)

See Appendix D for details Cost of 6 years treatment with imatinib 13,512.12 (2,725.75-‐15,737.69)

Hochhaus et al., 2009 Estimated event-‐free survival at 6 years with imatinib: 83%Cost per patient surviving event free at 6 years 16,279.67 (3,284.03 -‐ 18,961.07)

Hochhaus et al., 2009 Estimated rate of freedom from progression to accelerated/blast-‐crisis at 6 years with imatinib: 93%Cost per patient avoiding progression at 6 years 14,529.17 (2,930.91 -‐ 16,922.25)

Hochhaus et al., 2009 Estimated overall survival at 6 years: 88%Cost per patient surviving at 6 years 15,354.69 (3,097.44 -‐ 17,883.74)

proposal for the inclusion of imatinib mesylate for … · malini aisola, msc...

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