Cancidas - FDA Presentation Slides - PDF by mjy20742

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									      Pediatric Safety Review
           Caspofungin

      Pediatric Advisory Committee Meeting

         Amy M. Taylor, MD, MHS, FAAP
Medical Officer, Pediatric and Maternal Health Staff,
        Office of New Drugs, CDER, FDA
                 December 8, 2009
                                                        1
 Background Drug Information
• Drug: Cancidas® (caspofungin acetate) for
  injection
• Therapeutic Category: echinocandin
  antifungal
• Sponsor: Merck and Co., Inc.
• Original Market Approval: January 26, 2001
• Pediatric Exclusivity Granted: April 15, 2008

                                             2
    Background Drug Information
Indications:
Indicated in adults and pediatric patients (3 months and older) for:
• Empirical therapy for presumed fungal infections in febrile,
   neutropenic patients.
• Treatment of candidemia and the following Candida infections:
   intra-abdominal abscesses, peritonitis and pleural space
   infections.
• Treatment of esophageal candidiasis.
• Treatment of invasive aspergillosis in patients who are refractory
   to or intolerant of other therapies (e.g., amphotericin B, lipid
   formulations of amphotericin B, itraconazole).
                                                                  3
Background Drug Information
Dosage
  Recommended dosing in pediatric patients [3 months to 17 years
  of age] via infusion for all indications
   – Dosing based on body surface area
   – Loading dose 70 mg/m2 on Day 1
   – Maintenance dose 50 mg/m2 once daily
       • May be increase to maximum dose of 70 mg/m2 depending on
         clinical response
   – maximum dose: 70 mg
   – Duration of treatment: individualized to the indication



                                                                    4
                            Drug Use Trends
                       June 1, 2006 – May 31, 2009
Caspofungin pediatric use (0-16 years old)1
   – Inpatient setting
            • total discharges 34,000 (~600 pediatric)
            • total patients 31,000 (~500 pediatric)
   – Pediatric discharges and patients associated with a hospital
     billing for caspofungin accounted for less than 2% of the total
     share
   – For the most recent 12-month period ending May 2009:
            • pediatric patients age 0-2 months old accounted for 24 discharges
              and patients
            • pediatric patients age 3 months to 16 years old accounted for 165
              discharges and 124 patients
   1
       Source:Premier Healthcare Informatics, RxMarket Advisor™, Data Extracted 09-2009

                                                                                          5
               Exclusivity Studies
5 studies were conducted:

Pharmacokinetic Studies (n=3)
• Sequential, dose-escalation pharmacokinetic study in pediatric
  patients with fever and neutropenia (2 to 17 years)
• Multiple dose pharmacokinetic study in pediatric patients with fever
  and neutropenia (3 to 24 months)
• Multiple dose pharmacokinetic study in pediatric patients with
  documented or suspected cases of invasive candidiasis (0 to 3
  months)

Results:
  Systemic exposure was comparable between pediatric patients age
  3 months to 17 years and adults.
                                                                         6
              Exclusivity Studies

Efficacy was extrapolated from evidence in adult patients
and supported by studies in pediatric patients

Safety and Efficacy Studies (n=2)
– Prospective, randomized, double-blind, comparator controlled
  (amphotericin B) empiric therapy safety, tolerability, and efficacy
  study in pediatric patients with persistent fever and neutropenia
  (2 to 17 years)
– Prospective, open label, non-comparative safety, and efficacy
  study in pediatric patients with candidemia and other Candida
  infections, esophageal candidiasis and invasive aspergillosis (3
  months to 17 years)
                                                                        7
            Exclusivity Studies
Safety and Efficacy Study Results
• The safety and efficacy profiles of caspofungin in
  pediatric patients 3 months to 17 years were
  comparable to that seen in adults.
• The most common adverse events in pediatric
  patients were pyrexia (29%), blood potassium
  decreased (15%), diarrhea (14%), increased
  aspartate aminotransferase (12%), rash (12%),
  increased alanine aminotransferase (11%),
  hypotension (11%) and chills (11%)
                                                   8
             Exclusivity Studies
Results for neonates and infants less than 3 months
• The efficacy and safety of Cancidas® has not been
  adequately studied in prospective clinical trials.
• Although limited pharmacokinetic data were collected,
  these data are insufficient to establish a safe and
  effective dose of caspofungin in the treatment of
  neonatal candidiasis
• Invasive candidiasis in neonates has a higher rate of
  CNS and multi-organ involvement than in older patients;
  the ability of Cancidas® to penetrate the blood-brain
  barrier and to treat patients with meningitis and
  endocarditis is unknown.
                                                            9
 Exclusivity Studies Labeling Changes
Labeling Sections Changed
Highlights Section
   –   Indications and Usage
   –   Dosage and Administration
   –   Adverse Reactions
   –   Use in Specific Populations
Section 1     Indications and Usage
Section 2     Dosage and Administration
Section 6     Adverse Reactions
Section 8     Use in Specific Populations
Section 12    Clinical Pharmacology
Section 14    Clinical Studies
                                            10
 Exclusivity Studies Labeling Changes
Details of Specific Labeling Changes
Section 1 Indications and Usage
  – Patient population expanded to include pediatric
    patients 3 months and older
Section 2.3 Dosage and Administration
  – Recommended dosing in pediatric patients age 3
    months to 17 years
Section 6.2 Adverse Reactions/ Clinical Trials
  Experience in Pediatric Patients
  – Safety information from clinical trials in pediatric
    patients 3 months to 17 years                          11
 Exclusivity Studies Labeling Changes
Section 8.4 Use in Specific Populations/ Pediatric Use
   – Safety and effectiveness established in pediatric patients 3
     months to 17 years
   – Efficacy and safety not adequately studied in neonates and
     infants under 3 months of age.
   – Limited pharmacokinetic data collected; insufficient to establish a
     dose.
   – Ability of Cancidas® to penetrate the blood brain barrier and to
     treat meningitis and endocarditis is unknown
   – Has not been studied in pediatric patients with endocarditis,
     osteomyelitis, and meningitis due to Candida or as initial therapy
     for invasive aspergillosis.
   – Summary of clinical trial and adverse event data.
                                                                      12
Exclusivity Studies Labeling Changes

Section 12.3 Pharmacokinetics/Special
Populations/ Pediatric Patients
 – Results of three pediatric pharmacokinetic
   studies in patients aged 3 months to 17 years
   are presented
Section 14.5 Clinical Studies/ Pediatric
Patients
 – Results of two safety and efficacy studies in
   pediatric patients age 3 months to 17 years
   are presented
                                                   13
           Pediatric Adverse Events Since
                Marketing Approval
            Crude Counts1 of AERS Reports for All Sources from
    Marketing Approval Date to January 26, 2001 through August 14, 2009
                                                All reports (US)2               Serious3 (US) Death (US)

Adults (≥ 17 yrs)                                     730 (265)                     686 (226)                358 (75)

Pediatrics (0-16 yrs.)                                 101 (31)                      100 (30)                  51 (9)

Age unknown (Null                                      231 (99)                      185 (64)                100 (14)
values)
Total                                                1062 (395)                     971 (320)                509 (98)
1
  May include duplicates
2
  US counts in parentheses
3
  Serious adverse drug experience per regulatory definition (CFR 314.80), which includes death, life threatening,
hospitalization (initial or prolonged), disability, and congenital anomaly                                          14
            Case Selection
• 101 cases met search criteria
• 84 non duplicated reports
  – 52 eligible reports for case series
  – 31 cases no adverse event reported
  – 1 adult case miscoded as pediatric




                                          15
       Most Common Pediatric Uses Reported with
       Adverse Events Since Marketing Approval1

•   Aspergillus unspecified (9)
•   Pulmonary aspergillosis (7)
•   Candidal sepsis (4)
•   Neutropenia-empiric treatment (4)
•   Anti-fungal prophylaxis (3)
•   Unknown (3)
1Not   a complete list

                                                  16
  Factors Affecting Assessment of
             Causation
• In these reports, patients had serious
  underlying conditions
• Patients were treated with multiple drugs
  with known toxicity




                                              17
  Pediatric Deaths Since Market Approval
                  (N=17)
Hepatic (n=7)
Neurologic (n=4)
Hematologic (n=2)
Other (n=4)



                                           18
    Pediatric Deaths Since Market Approval

Hepatic (n=7)
•   13 y/o with ALL on Amphotericin B for 3 years for aspergillosis.
    Patient was treated with caspofungin for neutropenia and developed
    signs of liver failure including elevated bilirubin (14) and ammonia
    (83) after 7 days. Caspofungin was discontinued. 3 days later the
    patient developed a coagulation disorder, a probable pulmonary
    embolism, and increased encephalopathy. Support was withdrawn
    two days later and the patient died.

•   14 y/o with ALL, s/p allogeneic stem cell transplant with graft failure
    treated for suspected mycosis developed fulminant hepatic failure
    with coagulopathy and acute renal failure after 9 days. The patient
    died 7 days later.
                                                                          19
    Pediatric Deaths Since Market Approval

Hepatic continued
•   26 d/o with esophageal atresia, anal and rectum abnormalities,
    hydrocephalus and respiratory insufficiency treated for systemic
    candida parapsilosis infection developed slight elevation in GGT and
    ALP. Patient died at 8 months from multiple congenital
    abnormalities.

•   4 y/o with AML and macrophage activation syndrome treated for
    pulmonary aspergillus infection developed hepatitis and pancreatitis.
    Also on voriconazole. Adverse events resolved after discontinuing
    caspofungin and voriconazole. Patient died from complications of
    underlying leukemia.

•   5 y/o with idiopathic medullaris aplasia s/p bone marrow transplant
    treated empirically for neutropenia developed 5-fold increase in
    bilirubinemia and transaminase levels. The patient died from acute
    GVHD, CMV infection and multi-organ failure.                        20
   Pediatric Deaths Since Market Approval

Hepatic continued
• 7 y/o with ALL s/p bone marrow transplant treated for
  pulmonary aspergilloma developed elevated liver
  functions which improved with discontinuation of
  caspofungin. The patient subsequently died 1 month
  later from leukemia, aspergillosis pneumonia and
  multisystem organ failure.

• 16 y/o with common variable immunodeficiency treated
  for candidemia and fungal pneumonia developed
  hyperbilirubinemia which improved upon discontinuation
  of caspofungin. The patient died of gastrointestinal
  bleeding refractory to octreotide infusion.           21
   Pediatric Deaths Since Market Approval
Neurologic (n=4)
• 12 y/o with ALL and sepsis treated for oral mucositis and
  myelosuppression developed convulsions and
  respiratory distress after one day of treatment. The
  patient died from sustained convulsions and respiratory
  distress
• 16 y/o with AML treated for pulmonary aspergillosis
  developed confusion and cerebellar syndrome two days
  after stopping voriconazole and starting caspofungin.
  The patient died of an arrhythmia leading to cardiac
  arrest and cerebellar syndrome.


                                                         22
   Pediatric Deaths Since Market Approval

Neurologic continued
• 7 y/o with autoimmune hemolytic anemia treated for
  brain and renal aspergillus fumigatus abscess developed
  neurologic deficits. The patient was reported to have
  failed treatment with caspofungin and other antifungals
  and died of disseminated aspergillosis
• 12 y/o with lymphoma and a perforated appendicitis
  treated for candidal infection developed a cerebral
  aneurysm. The cause of death is unknown

                                                        23
   Pediatric Deaths Since Market Approval

Other (n=6)
• 1 y/o with familial hemophagocytic reticulosis, diabetes, HTN,
   nephropathy and bone marrow transplant treated for cerebral
   asperillosis developed thrombotic microangiopathy 6 months later.
   The patient died less than one month later.
• 9 y/o with chronic myelogenous leukemia, s/p bone marrow
   transplant, GVHD, and CMV, HSV and EBV infections treated with
   caspofungin for antifungal prophylaxis developed leukocytosis and
   an increase in CRP. The patient was found to have a nasal septum
   abscess containing Fusarium verticillioides. The patient was placed
   on amphotericin B and improved. Later the patient developed
   pleural lesions containing aspergillus fumigatus. The patient
   subsequently died of CMV interstitial pneumonia.
                                                                    24
    Pediatric Deaths Since Market Approval

Other continued
•   10 y/o with AML, acute renal insufficiency, and respiratory
    insufficiency treated for neutropenia died from a perforation of the
    cecum 6 days later.
•   13 y/o with myelodysplasia, refractory anemia and GVHD treated for
    aspergillus of the lung and CNS developed renal insufficiency,
    hepatic deterioration and cerebral hemorrhage from which she died
•   15 y/o with cystic fibrosis, diabetes, s/p liver transplant, cholangitis
    and de novo autoimmune hepatitis treated for cavitating lung
    disease (aspergillus) developed tension pneumothoraces and died 7
    days later of destructive lung disease
•   16 y/o with unknown underlying conditions treated for aspergillosis
    developed metabolic acidosis and subsequently died of
    aspergillosis.                                                           25
 Serious Pediatric Adverse Events Since Market
 Approval (includes cases with outcome of death)
     (event sum ≠ 52 due to more than one event per case)
Hepatic (n=18)
Neurologic (n=8)
Hypersensitivity (n=6)
Gastrointestinal (n=5)
Renal (n=5)
Electrolyte Abnormality (n=4)
Other (n=12)
                                                        26
     Serious Pediatric Adverse Events Since Market
    Approval*(includes cases with outcome of death)
Neurologic Adverse Events (n=8)
•    Seizures (n=2)
•    Paresthesias (n=2)
•    Brain atrophy (n=1)
•    Cerebral aneurysm (n=1)
•    Confusion and cerebellar syndrome (n=1)
•    Unspecified neurologic deficits associated with a
     right frontal brain abscess containing Aspergillus
     fumigatus (n=1)                                  27
*Unlabeled adverse events are underlined
     Serious Pediatric Adverse Events Since Market
    Approval*(includes cases with outcome of death)
Hypersensitivity adverse events (n=6)
•    Difficulty breathing, flushing (n=3)
•    Periorbital edema (n=1)
•    Formication (n=1)
•    Vomiting, fever, and rash (n=1)
Gastrointestinal adverse events (n=5)
• Pancreatitis (n=4)
• Cecum perforation (n=1)
*Unlabeled adverse events are underlined
                                                  28
   Serious Pediatric Adverse Events Since Market
  Approval*(includes cases with outcome of death)
Renal Adverse Events (n=5)
• Renal insufficiency (n=2)
• Renal failure (n=1)
• Increased creatinine (n=1)
• Nephrotic syndrome (n=1)
Electrolyte Abnormality Adverse Events (n=4)
• Hypercalcemia (n=2; including one case with
  hyperphosphatemia)
• Hypernatremia (n=1)
• Hypokalemia (n=1)
*Unlabeled adverse events are underlined        29
  Serious Pediatric Adverse Events Since Market
 Approval*(includes cases with outcome of death)
Other Adverse events (n=12)
•   Metabolic acidosis (n=2)
•   Neutropenia (n=1)
•   Injection site hematoma (n=1)
•   Hypotension (n=1)
•   Polyserositis and myositis ossificans (n=1)
•   Thrombotic microangiopathy (n=1)
•   Delayed engraftment and prolonged immunosuppression
    (n=1)
•   Leukocytosis and increase CRP (n=1)
•   Tension pneumothoraces (n=1)
•   Hemolysis (n=1)
•   Leukopenia, neutropenia, and thrombocytopenia (n=1)
                                                          30
*Unlabeled adverse events are underlined
 Serious Pediatric Adverse Events Since Market
 Approval (includes cases with outcome of death)
Hepatic adverse events (n=18)
• Elevated LFTs without evidence of hepatic injury (n=7)
• Hepatic failure (n=3)
• Hyperbilirubinemia (n=3)
• Cholestatic hepatitis (n=2)
• Hepatic function abnormality (n=1)
• Hepatic insufficiency (n=1)
• Hepatic ascites (n=1)


                                                           31
 Serious Pediatric Adverse Events Since Market
 Approval (includes cases with outcome of death)
Summary of hepatic case characteristics
• Primarily in very ill patients with competing causes for
  hepatotoxicity (e.g. underlying condition and concomitant
  medications)
• Seven cases of positive dechallenge reported
   – Most confounded by simultaneous change in other
     drug therapy
• No cases of positive rechallenge
• One case of negative rechallenge

                                                         32
                   Current labeling
Warnings and Precautions

5.2 Hepatic Effects
   Laboratory abnormalities in liver function tests have been seen in
   healthy volunteers and patients treated with CANCIDAS. In some
   patients with serious underlying conditions who were receiving
   multiple concomitant medications with CANCIDAS, isolated cases of
   clinically significant hepatic dysfunction, hepatitis, and hepatic failure
   have been reported; a causal relationship to CANCIDAS has not
   been established. Patients who develop abnormal liver function
   tests during CANCIDAS therapy should be monitored for evidence
   of worsening hepatic function and evaluated for risk/benefit of
   continuing CANCIDAS therapy.



                                                                           33
                  Current labeling
Adverse Reactions

6.4 Postmarketing Experience
The following additional adverse reactions have been identified during
   the post-approval use of CANCIDAS. Because these reactions are
   reported voluntarily from a population of uncertain size, it is not
   always possible to reliably estimate their frequency or establish a
   causal relationship to drug exposure.
    – Gastrointestinal disorders: pancreatitis
    – Hepatobiliary disorders: hepatic necrosis
    – Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-
      Johnson, skin exfoliation
    – Renal and urinary disorders: clinically significant renal dysfunction
    – General disorders and administration site conditions: swelling and
      peripheral edema
                                                                         34
                  Summary
• Pediatric use accounted for less than 2% of total
  share
• Assessment of reported adverse events complicated
  by serious underlying illnesses and use of multiple
  concomitant drugs
• The number of reported pediatric hepatobiliary
  events is notable
   – FDA recommends an update to the labeling to
     clarify that hepatobiliary events have been
     reported in pediatric as well as adult patients
                                                   35
  Question for the Committee
• FDA recommends an update to the
  labeling to clarify that hepatobiliary events
  have been reported in pediatric as well as
  adult patients
• FDA will continue its standard, ongoing
  safety monitoring for caspofungin
• Does the Advisory Committee concur?

                                              36
                Acknowledgments
OSE                                 PMHS
•   Patty Greene, PharmD            •   Denise Pica-Branco, PhD
•   S. Christopher Jones, PharmD,   •   Hari Cheryl Sachs, MD
    MS                              •   Lisa Mathis, MD
•   Laura Governale, PharmD, MBA
•   Melissa M Truffa, RPh
•   Ann McMahon, MD, MS
DSPTP                               OPT
•   Hala Shamsuddin, MD             •   Debbie Avant, RPh
•   Yuliya Yasinskaya, MD           •   Suzanne Malli, BA, BSN
•   Renata Albrecht, MD             •   Judith Cope, MD, MPH
                                    •   Dianne Murphy, MD
                                                                  37

								
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