PROPOSAL FOR THE INCLUSION OF IMATINIB MESYLATE FOR … · Malini Aisola, MSc...
Transcript of 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
Malini Aisola, MSc
Ruth Lopert, BMed, FAFPHM
Nii Koney, MD, MBA
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
+1 917-733-1973
1st January 2013
Proposal for inclusion of imatinib in the WHO Model List
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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.
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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
Proposal for inclusion of imatinib in the WHO Model List
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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.
Proposal for inclusion of imatinib in the WHO Model List
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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.
Proposal for inclusion of imatinib in the WHO Model List
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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.
Proposal for inclusion of imatinib in the WHO Model List
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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
Proposal for inclusion of imatinib in the WHO Model List
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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
Maximum retail price Including VAT; max wholesale price excluding VAT= NOK 8,608.16 http://www.legemiddelverket.no
Nov, 2012 Glivec Novartis 400 mg 30 tabs 22,878.40 NOK 4,034.16 336.18 49,082.28
Maximum retail price Including VAT; max wholesale price excluding VAT= NOK 17,571.81 http://www.legemiddelverket.no
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=
Nov, 2012 Gleevec Novartis 400 mg 30 tabs 93,830.39 RUB 3,028.68 252.39 36,848.94 State Maximum Release Pricehttp://grls.rosminzdrav.ru/pricelims.aspx?s=
Nov, 2012 Gleevec Novartis 100 mg 60 tabs 48,616.12 RUB 1,569.24 261.54 38,184.84 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)