One Year Post-Exclusivity Adverse Event Review: Sirolimus Pediatric Advisory Committee Meeting November 16, 2006

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One Year Post-Exclusivity Adverse Event
ReviewSirolimusPediatric Advisory Committee
Meeting November 16, 2006
Alan M. Shapiro, MD, PhD, FAAP Medical
Officer Pediatric and Maternal Health
Staff Office of New Drugs Center for Drug
Evaluation and Research Food and Drug
Administration
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Background Drug Information

• Drug Rapamune (sirolimus)
• Therapeutic Category immune suppressant
• Sponsor Wyeth Pharmaceuticals
• Indications Prophylaxis of organ rejection in
  patients aged 13 years or older receiving renal
  transplants
• Original Market Approval September 15, 1999
• Pediatric Exclusivity Granted November 17, 2004

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Drug Use Trends in Outpatient Settings Sirolimus

• Pediatric patients (0-16 years) accounted for
  4.3 (7,100) of the 165,000 Rapamune
  prescriptions dispensed in the U.S. (Dec 2004
  to Nov 2005) 1
• The pediatric use of Rapamune increased from
  4,900 prescriptions in the year prior to
  exclusivity (Dec 2003 to Nov 2004 ) to 7,100
  prescriptions in the year following exclusivity
  (Dec 2004 to Nov 2005) 1
• Patients in the 12-16 year old subgroup accounted
  for the majority of prescriptions dispensed to
  pediatrics in the post-exclusivity period, with
  almost 60 of the annual Rapamune prescriptions
  dispensed to this group of pediatric patients 1

1 Verispan, LLC, December 2002 November 2005,
Data Extracted 1/06
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Pediatric Exclusivity Studies Sirolimus

• Study 1 Randomized study in high immunologic
  risk pediatric renal allograft recipients that
  compared the following regimens for safety and
  efficacy
• Sirolimus plus calcineurin inhibitor
  (cyclosporine or tacrolimus) and corticosteroids
• Double therapy calcineurin inhibitor and
  corticosteroids
• Triple therapy calcineurin inhibitor plus
  azathioprine or mycophenolate mofetil and
  corticosteroids
• Study 2 A Double-Blind Randomized Trial of
  Steroid Withdrawal in Sirolimus and
  Cyclosporine-Treated Primary Transplant
  Recipients
• Pharmacokinetic data collected from both studies

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Results of Pediatric Exclusivity Studies

• Efficacy failure in the intention-to-treat (ITT)
  population (n102) was numerically more
  frequent in patients randomly assigned to receive
  the combination of sirolimus and a calcineurin
  inhibitor than in the subjects allocated to
  standard therapy (29/65, 44.6 versus 12/37,
  32.4, respectively)
• When comparing only patients 18 years old or
  younger (24/53, 45.3 versus 11/25, 44.0,
  respectively) efficacy failure rates were similar

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Results of Pediatric Exclusivity Studies (cont.)

• Adverse events such as abdominal pain, fever,
  abnormal renal function, and urinary tract
  infection (UTI) were significantly more common in
  the sirolimus treatment cohort compared with
  standard therapy
• UTI rates were 15 versus 1 in the sirolimus
  combination group versus the control group,
  respectively

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Results of Pediatric Exclusivity Studies (cont.)

• Pharmacokinetics of Sirolimus and Cyclosporine
  Regimen
• Younger children had overall lower sirolimus dose
  normalized to exposure apparently due to higher
  clearance
• A strong correlation at steady-state between
  whole blood sirolimus pharmacokinetic values were
  observed for all treatments and regimens
• Sirolimus trough concentrations were adequate
  surrogates for sirolimus exposure

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Resultant Labeling from Exclusivity Studies

• Information on pharmacokinetic parameters
• Safety and efficacy of sirolimus established in
  children 13 years or older judged to be at low to
  moderate immunologic risk
• In pediatric (lt18 years of age) renal transplant
  recipients considered high immunologic risk the
  use of sirolimus in combination with calcineurin
  inhibitors and corticosteroids was associated
  with
• an increased risk of deterioration of renal
  function
• lipid abnormalities
• urinary tract infections
• Safety and efficacy have not been established in
  pediatric patients less than 13 years old or in
  pediatric renal transplant recipients considered
  at high immunologic risk

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Adverse Event Reports since Market Approval
(December 2005) Sirolimus
Raw counts All reports (US) Serious (US) Death (US)
All Ages 3712 (1415) 2981 (1231) 375 (160)
Adults (gt 17) 2254 (1011) 2471 (931) 322 (133)
Pediatrics (0-16) 88 (57) 82 (51) 6 (5)
may include duplicates and unknown ages
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Adverse Event Reports 1 Year Post Exclusivity
Period Sirolimus
Raw counts All reports (US) Serious (US) Death (US)
All ages 862 (342) 845 (325) 86 (36)
Adults (gt 17) 713 (273) 706 (266) 66 (26)
Pediatrics (0-16) 19 (10) 19 (10) 0
may include duplicates and unknown ages
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Pediatric Deaths in Post-Marketing Period (n6)

• 15 year old recurrence of hepatoblastoma with
  fatal complications following liver transplant
• This is a high risk of cancer recurrence in
  transplanted hepatoblastoma patients
• 10 year old renal transplant patient with
  subsequent renal vein thrombosis and infarction
  of donor kidney
• Developed respiratory failure and cardiac arrest
• Known transplant complication of renal vein
  thrombosis versus sirolimus related thrombosis

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Pediatric Deaths in Post-Marketing Period (n6)
(cont.)

• 9 year old with renal and cardiac transplant
• Developed severe thrombocytopenia and leukopenia
  three weeks after transplant
• Died three weeks later
• Sirolimus associated with bone marrow suppression
• 2.5 year old study patient with congenital
  genitourinary abnormalities status post renal
  transplant
• Died of complications of aspergillus pneumonia
  and gastrointestinal bleeding
• Aspergillus pneumonitis and CMV colitis known
  complication of immunosuppression

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Pediatric Deaths in Post-Marketing Period (n6)
(cont.)

• 6 year old with short bowel syndrome status post
  intestinal transplant
• Developed progressive encephalitis with elevated
  liver enzymes due to Hepatitis A along with
  primary EBV and HHV-6 infection
• Graft removed and immunosupression discontinued
• Subsequently developed erythroderma with severe
  edema and adenopathy followed by cytolytic
  hepatitis and eosinophillia
• Died of multi-organ failure
• Exacerbations of EBV and HHV-6 infections are
  known complications of immunosuppression

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Pediatric Deaths in Post-Marketing Period (n6)
(cont.)

• 12 year old with end-stage renal disease,
  post-transplant diabetes mellitus, hypertension
  and renal hyperplasia status post renal
  transplant
• 5 months after transplant hospitalized with viral
  lower respiratory infection with subglottic edema
  
• Died following discharge
• Death thought to be due to laryngeal inflammation
  and airway obstruction
• Likely exacerbation of viral infection due to
  immune suppression

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Serious Pediatric Adverse Events

• 19 unduplicated pediatric reports in patients on
  sirolimus during the One-Year Post-Exclusivity
  Period
• Transplant Complications/Rejection (n8)
• Gastrointestinal Events (n3)
• Drug Interactions / Drug Level Fluctuations (n3)
  
• Possible Interaction with Azithromycin (n2)
• Cardiac Events (n2)
• Infection (n1)
• Panniculitis (n1)
• Intracranial bleeding (n1)

Underlined events Unlabeled events paralytic
ileus and haematochezia are not specifically
mentioned, but the related events of ileus,
rectal disorder and hemorrhage are mentioned
Some drug interactions are labeled, others are not
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Pediatric Adverse Event Possible Drug
Interactions with Azithromycin (n2)

• 6 year old renal transplant patient on sirolimus,
  tacrolimus, prednisone, and co-trimoxazole
• On azithromycin for pneumonia
• Overdose of tacrolimus due to a medication error
• increased tacrolimus and sirolimus levels and
  neurological side-effects
• Sirolimus levels continued to be elevated even
  though tacrolimus stopped
• Only when azithromycin was stopped, did the
  sirolimus level decrease

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Pediatric Adverse Event Possible Drug
Interactions with Azithromycin (n2) (cont.)

• 5 year old renal transplant patient on sirolimus,
  tacrolimus, atorvastatin, ferrous sulfate
• On azithromycin for pneumonia
• Developed increased sirolimus and tacrolimus
  levels with neurotoxicity despite having the
  sirolimus dose reduced
• These 2 cases are confounded by tacrolimus
  overexposure
• Sirolimus label does not have any warnings about
  interactions with azithromycin
• Compared to other drugs including but not limited
  to ketoconazole and erythromycin, azithromycin is
  a weak CYP3A inhibitor which are labeled

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Pediatric Adverse Event Possible Drug Cardiac
Adverse Events (n2)

• 3 year old renal transplant patient on tacrolimus
  and sirolimus with iron deficiency
• Fever and 3 month history of cough
• X-ray showed massive cardiomegally and lung
  infiltrate
• Echo showed moderate to large pericardial
  effusion
• Viral work-up only revealed Adenovirus type 2 in
  stool
• Had pericardiocentesis and the effusion
  stabilized and did not recur

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Pediatric Adverse Event Drug Cardiac Adverse
Events (n2) (cont.)

• 2 year old renal transplant patient with
  hypertension and a prior history of pericardial
  effusion on tacrolimus, prednisone and sirolimus
• Subsequent development of persistent pericardial
  effusion
• Pericardial effusion increased in size despite
  decrease in sirolimus dose and was hospitalized
  twice for this condition
• During second hospitalization, noted to have
  upper respiratory infection associated with
  fever, nausea and emesis
• Following the second hospitalization, the
  pericardial effusion resolved on its own while on
  the reduced sirolimus dose
• Office of Safety and Epidemiology is currently
  evaluating the association of sirolimus use with
  pericardial effusion

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Pediatric Adverse Event Panniculitis (n1)
(foreign report)

• 14 year old renal transplant patient on
  azathioprine, prednisolone, sirolimus,
  nitrofurantoin and enalapril
• Developed lower limb panniculitis 2 months after
  starting sirolimus and was hospitalized
• Continued sirolimus for another 7 months
• Recovered following the discontinuation of
  sirolimus therapy
• Not enough information to make any conclusions
  about this AE

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Pediatric Adverse Event Intracranial Bleed (n1)
(foreign report)

• 2 year old liver transplant patient with
  concurrent short-bowel syndrome on tacrolimus,
  prednisolone, sirolimus, loperamide and
  gentamicin
• Treated with 2mg of sirolimus for 28 days
• Day after stopping sirolimus developed
  intracranial hemorrhage
• One and two weeks after the event, brain scan
  still indicated new bleeding
• Patient recovered from event
• Interval between transplant and intracranial
  hemorrhage not known
• Hemorrhage is a labeled AE
• Not clear if bleeding related to sirolimus since
  it occurred after it was discontinued

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Summary Sirolimus

• OSE and the DSPTP are evaluating the association
  of sirolimus with pericardial effusion
• DSPTP is in discussions with the Sponsor about
  potential labeling changes
• This completes the one-year post-exclusivity AE
  reporting as mandated by BPCA
• FDA recommends routine monitoring of sirolimus
  for AEs in all populations
• Does the Advisory Committee concur?

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Acknowledgements

• OND
• Hui-Hsing Wong
• Marc Cavaille Coll
• Hyun Son
• OCP
• Gerlie Gieser

• OSE
• Evelyn Farinas
• Rosemary Johann-Liang
• Mark Avigan
• Laura Governale
• Toni Piazza-Hepp