Transcript One Year Post Exclusivity Adverse Event Review: Topotecan

One Year Post Exclusivity Adverse
Event Review:
Topotecan
Pediatric Subcommittee of the
Anti-infective Drugs Advisory Committee Meeting
June 9, 2004
Susan McCune, MD, MA Ed
Medical Officer
Division of Pediatric Drug Development
Center for Drug Evaluation and Research
Food and Drug Administration
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Background Drug Information
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Moiety: Hycamtin® (topotecan)
Therapeutic Category: Anti-tumor oncologic agent
Sponsor: GlaxoSmithKline
Indications:
– Adults
• Metastatic carcinoma of the ovary after failure of initial or subsequent
chemotherapy
• Small cell cancer sensitive disease after failure of first-line
chemotherapy
– Pediatrics
• There are NO approved pediatric indications
• Original Market Approval: May 28, 1996
• Pediatric Exclusivity Granted: November 20, 2002
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Clinical Studies for Exclusivity Efficacy
• Summaries of studies previously performed by the Pediatric
Oncology Group that were initiated in 1992 and 1993.
• Phase 2 study in pediatric solid tumors enrolled 108 patients
less than 16 years of age.
• Tumor types were Ewing’s sarcoma/Peripheral
Neuroectodermal tumor, Neuroblastoma, Osteoblastoma, and
Rhabdomyosarcoma.
• Study endpoint was tumor response rate.
• 86% of patients died with 10% dying within 30 days of the last
dose of topotecan.
• Overall response rate was 8% but the response rates for
patients with neuroblastoma was 18% (alternative regimen
using combinations of available drugs in patients with relapsed
neuroblastoma are 35-50%).
• No patients less than 2 years of age had a response.
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Clinical Studies for Exclusivity –
Safety and Dosing
• Eight of the 11 patients that died within 30 days of
the last dose of topotecan had progressive disease and
3 died with infection, a known complication.
• 44% of patients were hospitalized with adverse
events, primarily febrile neutropenia, fever or sepsis.
• Pediatric Phase 2 dose was determined to be different
from adults
– Daily infusion for 5 consecutive days every 21 days
– 1.4mg/m2/d without Granulocyte-Colony Stimulating
Factor (G-CSF)
– 2mg/m2/d with G-CSF
– Adult dose 1.5mg/m2/d
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Drug Use Trends in Inpatient
Settings: Topotecan
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Nationally projected hospital discharge data from Premier’s™ network of
approximately 450 hospitals revealed pediatric use accounted for approximately 10.6%
of discharges (425 of 4,001) between 7/01 and 6/03.1
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Pediatric topotecan use increased annually between 7/01 and 6/03 (6.3% to 18.6% of
projected discharges).1
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Topotecan accounted for 407 discharges from 29 CHCA™ freestanding pediatric
hospitals.2
– Most frequent diagnosis was chemotherapy encounter followed by malignant
neoplasm of the adrenal gland
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A significant limitation of our analysis is that FDA does not currently access data to
capture use in the outpatient hospital clinic setting where most chemotherapy is
administered
1Premier
2Child
Perspective™, Jul 2001 - Jun 2003
Health Corporation of America™: Pediatric Health Information System (PHIS) Jul 2001 - June 2003
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Adverse Event Reports:
Topotecan
11/20/02 - 12/20/03
• Total number of reports, all ages:
– 29 reports (18 U.S.)
• Pediatric reports:
– No pediatric reports were submitted during this time period.
• Unlabeled pediatric reports from 5/96 to 11/02
– Convulsion, hypotension, edema, speech disorder, arachnoiditis,
ascites, Budd Chiari Syndrome, caecitis, confusional state
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Comments
• The FDA will continue its routine monitoring of
adverse events in all populations.
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One Year Post Exclusivity Adverse
Event Review:
Temozolomide
Pediatric Subcommittee of the
Anti-infective Drugs Advisory Committee Meeting
June 9, 2004
Susan McCune, MD, MA Ed
Medical Officer
Division of Pediatric Drug Development
Center for Drug Evaluation and Research
Food and Drug Administration
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Background Drug Information
• Moiety: Temodar® (temozolomide)
• Therapeutic Category: Anti-tumor oncologic agent
• Sponsor: Schering-Plough Research Institute
• Indication:
− Adults: Temozolomide capsules are indicated for the
treatment of adult patients with refractory anaplastic
astrocytoma, ie., patients at first relapse who have
experienced disease progression on a drug regimen
containing a nitrosourea and procarbazine.
− Pediatrics: There are NO approved pediatric indications
• Original Market Approval: August 11, 1999
• Pediatric Exclusivity Granted: November 20, 2002
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Clinical Studies for Exclusivity
• One Phase 1 and two Phase 2 open-label multicenter
studies
• Phase 1 dose escalation study in 27 pediatric patients
with advanced non-CNS and CNS cancers
• Phase 2 study in 63 pediatric patients with recurrent
brain stem glioma and high grade astrocytoma
• Phase 2 study (Cooperative Group Sponsored Study) in
122 pediatric patients with various recurrent CNS
tumors
• Patients ranged in age from 1 to 23 years of age with
the majority of patients between 3 and 17 years of age
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Results of the Clinical Studies
for Exclusivity - Efficacy
• The primary endpoint was tumor response rate
• In the first study, there was 1 complete response
(CR) and 3 partial responses (PR) among 27
patients
• In the second study, there were no CR or PR in the
brain stem glioma patients, and no CR and 12%PR
in the high grade astrocytoma patients
• In the third study, the overall response rate
(CR+PR) was 5%. Only 1 patient achieved CR
and 5 patients had PRs.
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Results of the Clinical Studies
for Exclusivity - Safety
• Safety was assessed in 204 patients at doses of
100-240mg/m2 daily for 5 days every 28 days
• Toxicity profile was similar to adults
• Most common adverse events
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Dizziness
Neuropathy
Paresthesia
Nausea/vomiting
Constipation
Myelosuppression
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Drug Use Trends in Outpatient
Settings: Temozolomide
• The total number of prescriptions dispensed for
temozolomide in the U.S. has nearly doubled over
the past 3 years, from 50,000 prescriptions
dispensed in 2001 to 93,000 in 2003.1
• The top prescribers for temozolomide in 2003
were oncology/neoplastic, neurology, and
hematology. Only 1% of temozolomide
prescriptions were written by pediatricians.1
1 IMS
Health, National Prescription Audit Plus™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004
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Drug Use Trends in Outpatient
Settings: Temozolomide
• The pediatric population (1-16 years of age)
accounted for approximately 2,223 temozolomide
prescriptions (3.1%) in 2002 and approximately
3,649 prescriptions (3.9%) in 2003.1,2*
• The most frequent diagnosis associated with
temozolomide use in both the adult and pediatric
populations was “malignant neoplasm of the brain
(unspecified sites).”3
Health, National Prescription Audit Plus™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004
Dimension Rx, January 2002 to Dec 2003
3IMS Health, National Disease and Therapeutic Index™, CD-ROM 3-Year Jan 2001 – Dec 2003, Data Extracted Jan 2004
*Calculation based on application of proportions of pediatric temozolomide prescriptions in AdvancePCS to IMS Health,
National Prescription Audit Plus to estimate number of temozolomide prescriptions dispensed nationwide to pediatric
population
1IMS
2AdvancePCS™,
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Drug Use Trends in Outpatient
Settings (Sales): Temozolomide
• Sales in the U.S. have been on the rise, increasing
from an estimated 1.8 million capsules sold in 2002
to over 2.2 million capsules sold in 2003.1
• The majority sales in the U.S. were to retail channels
(80%), including chain and independent pharmacies,
food stores with pharmacies, mail service, and longterm care pharmacies.1
1IMS
Health, National Sales Perspectives™, On-line, Source Year 2001 – 2003, Data Extracted Jan 2004
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Drug Use Trends in Inpatient
Settings: Temozolomide
• CHCA™ data demonstrated that from July 2002 to
June 2003, there were 17 pediatric discharges
associated with temozolomide.1
1Child
Health Corporation of AmericaTM: Pediatric Health Information System (PHIS), Jul 2002 - Jun 2003
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Limitations to Drug Use Data
in Outpatient Settings:
• Currently, outpatient data sources available to FDA do not
capture drug use data in outpatient hospital clinics where
considerable chemotherapy treatments are provided.
• However, the sales data do capture products sold to
outpatient clinic settings through number of temozolomide
capsules sold to the various sales distribution channels.
• These data suggest that approximately 20% of
temozolomide is purchased by hospitals and clinics. The
number of chemotherapy treatment centers in the sales
audit is unknown at this time.1
• Therefore, it appears that the majority of temozolomide use
is captured through this assessment of outpatient use.
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Adverse Event Reports:
Temozolomide
11/20/02 - 12/20/03
• Total number of reports, all ages:
– 250 reports (160 U.S.)
• Pediatric reports:
– 5 unduplicated pediatric reports (2 U.S.)
– All with serious outcomes and one death
– Gender: Female (4), Male (1)
– Age: 2-5 years (3), 6-11 years (2)
– Diagnosis: Blastoma (1), Adrenal metastatic
neuroblastoma (1), Anaplastic astrocytoma (1),
Medulloblastoma (1), Brain stem tumor (1)
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Adverse Event Reports:
Temozolomide
11/20/02 - 12/20/03
Clinically Significant Unlabeled Adverse Events
• Brain edema
• Concomitant radiation therapy
• Death
• Potentially due to underlying condition
• Hemangioma acquired
• Potentially related to underlying condition, concomitant
medications or radiation therapy
• ITP
• Potentially labeled event or secondary to underlying condition
• Myelodysplastic syndrome
• Potentially labeled event or secondary to underlying condition
Although not specifically delineated in the label, these are all potentially related to
a labeled process or the underlying disease state.
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Adverse Events: Temozolomide
n=5
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A three year old started temozolomide to treat pineal blastoma
and subsequently (unknown relation to drug treatment) died
of an unspecified cause. The event was reported by the
patient’s father.
A six year old was treated with temozolomide (90mg/m2/d)
for recurrent anaplastic astrocytoma. Concomitant
medications included a flu vaccine, Bactrim, and radiation
therapy. Following temozolomide use, a cavernous
hemangioma was noted on MRI (not previously seen on
MRI). Following temozolomide treatment, the patient was
admitted with thrombocytopenia requiring platelet
transfusions, IVIG infusions, prednisone and monitoring of
the hemangioma. This was diagnosed as ITP and subsequent
bone marrow analysis revealed a myelodysplastic syndrome.
The patient was discharged with an improved clinical status
18 days after admission.
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Adverse Events: Temozolomide
(cont.)
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A four year old started temozolomide for treatment of
medulloblastoma. An infection (disseminated Fusariosis) was
reported but there was no outcome of the event documented.
A four year old was treated with temozolomide (120mg/m2/d)
for adrenal metastatic neuroblastoma. She developed
thrombocytopenia, anemia and fever which were managed
with blood transfusions and antibiotics. One month after
temozolomide treatment, she recovered without sequelae and
was given a second cycle of temozolomide without
recurrence.
An eight year old was treated with temozolomide (140mg
reduced to 60mg) for a brainstem tumor. Concomitant
therapy included radiation therapy. A routine MRI revealed
“radiation-induced cerebellum edema” requiring
hospitalization for intracranial drainage. She was
subsequently discharged in stable condition.
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Comments
• Labeled and unlabeled adverse events reported
• The unlabeled events have also been reported in adults
and are not unique to pediatrics
• The FDA will continue its routine monitoring of
adverse events in all populations.
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