# Presentation: 951402

## One Year Post-Exclusivity Adverse Event Review:SirolimusPediatric 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**

## 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

## 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

## 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

## 

Efficacy failure in the intention-to-treat (ITT) population   (n=102) 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

- Efficacy failure in the intention-to-treat (ITT) population   (n=102) 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

**Results of Pediatric Exclusivity Studies**

## 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

## 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

## 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 (<18 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

## 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 (> 17) | 2254 (1011) | 2471 (931) | 322 (133) |
| Pediatrics (0-16) | 88 (57) | 82 (51) | 6 (5) |

- *may include duplicates and unknown ages

## 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 (> 17) | 713 (273) | 706 (266) | 66 (26) |
| Pediatrics (0-16) | 19 (10) | 19 (10) | 0 |

- * may include duplicates and unknown ages

## Pediatric Deaths in Post-Marketing Period (n=6)

- 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

## Pediatric Deaths in Post-Marketing Period (n=6) (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

## Pediatric Deaths in Post-Marketing Period (n=6) (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

## Pediatric Deaths in Post-Marketing Period (n=6) (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

## Serious Pediatric Adverse Events

- 	**19 unduplicated pediatric reports in patients on sirolimus during the One-Year Post-Exclusivity Period**
- Transplant Complications/Rejection (n=8)
- Gastrointestinal Events (n=3) *
- Drug Interactions / Drug Level Fluctuations (n=3) **
- _Possible Interaction with Azithromycin (n=2)_
- _Cardiac Events (n=2)_
- Infection (n=1)
- _Panniculitis (n=1)_
- _Intracranial bleeding (n=1)_

- 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

## Pediatric Adverse Event: Possible Drug Interactions with  Azithromycin (n=2) 

- 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

## Pediatric Adverse Event: Possible Drug Interactions with Azithromycin (n=2) (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

## Pediatric Adverse Event: Possible Drug Cardiac Adverse Events (n=2) 

- 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

## Pediatric Adverse Event: Drug Cardiac Adverse Events (n=2) (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

## Pediatric Adverse Event: Panniculitis (n=1) (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

## Pediatric Adverse Event: Intracranial Bleed (n=1) (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

## 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?

## Acknowledgements

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

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