# Presentation: 081666

## One Year Post-Exclusivity Adverse Event Review:Ritonavir  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: **Norvir® (Ritonavir)
**Therapeutic Category: **HIV protease inhibitor
**Sponsor:  **Abbott Laboratories
**Indication: **Treatment of HIV-infection in combination with other antiretroviral agents patients ≥ 2 years of age (prior to exclusivity)
**Original Market Approval: **March 1, 1996
**Pediatric Exclusivity Granted: **June 14, 2005

## Boosting Regimens

- Resistance has been reported with all protease inhibitors (PIs) when used as monotherapy, and can develop rapidly even with combination therapy in which drug levels are subtherapeutic1
- inadequate dosing, poor drug absorption, rapid drug clearance and inadequate adherence
- Ritonavir is mainly used now to increase the serum concentrations and decrease the dosage frequency of other PIs2

- 1 Excerpted from _Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection_;
- National Resource Center (NRC), HRSA, NIH November 3, 2005
-  2 _Treatment Guidelines: Drugs for HIV Infection_ The Medical Letter 4(50) October 2006

## Boosting Regimens (cont.)

- “Boosted” therapeutic regimens consisting of two PIs (e.g., low dose ritonavir plus saquinavir or lopinavir/ritonavir (LPV/RTV, KaletraTM) and combined with one or two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 1
- With the exception of LPV/RTV
- limited data on safety and dosing of combination PI regimens in children1

- 1 Excerpted from _Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection_;
- National Resource Center (NRC), HRSA, NIH November 3, 2005

## Ritonavir Pediatric Exclusivity Trials

- Phase I/II, dose-finding, open-label study [pivotal] of two different doses of ritonavir used alone and in combination with lamivudine (3TC) and zidovudine (ZDV) in HIV-1 infected infants and children (n=50)
- Safety and tolerance
- Pharmacokinetics
- Activity of  ritonavir
- Phase I/II, open-label, management study in HIV patients  6 months to 21 years of age with rapidly progressive/advanced disease failing current therapy
-     (n=164 )

## Exclusivity Trials Results

- No statistically significant differences were noted  in this small non-randomized study between the 350mg/ m2 and the 450mg/m2 twice daily doses during the first 104 weeks of follow-up with respect to HIV-1 RNA levels, CD4 cell count or CD4 percentage
- Overall, the toxicity profile of ritonavir seen during the clinical trial appeared similar to that observed in adults
- Ritonavir was a part of combination antiretroviral therapy
- Therefore difficult to determine the exact contribution of  ritonavir to any clinical or laboratory toxicities
- Many of the approved antiretroviral drugs have overlapping toxicities

## Labeling Changes Resulting from Exclusivity Studies: Ritonavir

- Indication: extended age range from 2 years down to 1 month
- Safety: AE profile in the pediatric population was similar to that for adults
- PK / Dosing: Information was added for pediatric patients less than 2 years of age

## Adverse Event Reports since Market Approval (March 1996): Ritonavir 

| Raw counts* | All reports (US) | Serious (US) | Death (US) |
| --- | --- | --- | --- |
| All Ages | 6511 (3003) | 6026  (2680) | 703 (210) |
| Adults (> 17) | 5055 (2149) | 4726  (1931) | 562  (153) |
| Pediatrics (0-16) | 417  (205) | 380 (185) | 39  (23) |

- *may include duplicates and unknown ages

## Adverse Event Reports 13 Month Post Exclusivity Period: Ritonavir

| Raw counts* | All reports (US) | Serious (US) | Death (US) |
| --- | --- | --- | --- |
| All ages | 984 (335) | 953 (309) | 183 (69) |
| Adults (> 17) | 780 (238) | 766 (225) | 148 (53) |
| Pediatrics (0-16) | 68 (39) | 63 (37) | 5  (3)** |

- * may include duplicates and unknown ages
- ** 3 unduplicated pediatric deaths

## Adverse Events by Types of Ritonavir Exposure

**Direct: Treatment of HIV-infected pediatric patients**
- Used in combination with other anti-retroviral agents for HIV treatment, so difficult to assign causality to reported adverse events
**Indirect: Used during pregnancy by HIV****+**** mothers for maternal health and prevention of perinatal HIV**
- Exposed infants may or may not be HIV infected
- Possible association of combination antiretroviral (ARV) therapy and premature delivery
- Newborns receive ARV therapy postpartum, which may complicate interpretation of  adverse events associated with in utero exposure

## Deaths (n=3)
Hepatic Events (n=7)
Drug Interaction with fluticasone propionate: 
	Cushing Syndrome (n=5)
Pancreatitis (n=2)
Gastrointestinal (GI) symptoms (n=2)
Drug Ineffective (n=3)
Skin reactions (n=3)
Miscellaneous (n=8)
anemia, Pseudomonas aeruginosa sepsis, epistaxis, arthropathy, convulsion associated with pyrexia, alopecia, nystagmus with photophobia and strabismus  and spontaneous abortion

- Hepatic Events (n=7)
- Drug Interaction with fluticasone propionate:
- 	Cushing Syndrome (n=5)
- Pancreatitis (n=2)
- Gastrointestinal (GI) symptoms (n=2)
- Drug Ineffective (n=3)
- Skin reactions (n=3)
- Miscellaneous (n=8)
- anemia, *Pseudomonas aeruginosa* sepsis, epistaxis, arthropathy, convulsion associated with pyrexia, _alopecia_, _nystagmus_ with photophobia and _strabismus_  and _spontaneous abortion_

- AEs from Direct Exposure during the One-Year Post-Exclusivity Period (n=33)**

- Underlined events = Unlabeled events     ** 4 reports due to use of  lopinavir /ritonavir

## Pediatric Deaths- Direct Exposure during the One-Year Post-Exclusivity Period (n=3)

- 16-year old HIV infected female on lopinavir/ritonavir, stavudine, and lamivudine  died of cryptococcal meningitis
- 21-month old HIV infected patient on lopinavir/ritonavir, lamivudine, stavudine died of cardio-respiratory complications secondary to disseminated cytomegalovirus infection
- A 2-year-old male patient died due to hemorrhagic pneumonia, ruptured porencephalic cyst, medication error, bronchospasm and deterioration of renal function while enrolled in a clinical trial of atazanavir, stavudine, lamivudine and ritonavir therapies

## In Utero Exposure Adverse Events (n=17)* 

- Most commonly reported AEs
- _Fetal / Intrauterine growth retardation (n=3)_
- Neutropenia (n=3)
- Anemia (n=2)
- Hypertriglyceridemia (n=2)
- _Blood lactate or lactic acid increased (n=3_)**
- CPK increased (n=2)

- * Most patients had more than one listed adverse event
- ** All three patients exposed to nucleoside reverse transcriptase inhibitors both in utero and post-partum known to be associated with lactic acidosis
-    Underlined = unlabeled event

## In Utero Exposure Adverse Events (cont.)

- Congenital anomalies (n=7)
- _Ventricular septal defect _
- _Micrognathia and cardiac murmur_
- _DiGeorge syndrome, _
- _Hypospadias_
- _Congenital pyelocaliectasis_
- _Polydactyly_
- _Trisomy 15_
- The interpretation of congenital anomalies in ritonavir exposed patients complicated by the health of the mother (HIV) and the use of multiple antiretrovirals during pregnancy
- One intrauterine death at 34 weeks gestation in a 35 year old female on saquinavir, ritonavir, zidovidine and lamivudine with severe endometriosis.  Fetus delivered following demise and nuchal cord noted but no apparent birth defects

- Underlined = unlabeled event

## Ritonavir Drug Use1

- Pediatric patients accounted for approximately 0.8% of Norvir® (ritonavir) prescriptions.
- Number of patients receiving Norvir® over the pre to post-exclusivity years increased 20% for adults and decreased 31% for pediatric patients aged 0-16 years.
- In the post exclusivity year, an estimated 765 pediatric patients and over 94,000 adult patients received a Norvir® prescription.
- Projected number of unique pediatric patients (aged 0 through 16 years) who received a dispensed prescription for Kaletra® (lopinavir/ritonavir) decreased by 8% from 2,600 in the pre-exclusivity year to 2,383 in the post-exclusivity year.

-  1Verispan, LLC, Vector One National (VONA) Data extracted 8-8-2006

## Summary

- There are no concerning safety signals
- HIV is a serious frequently fatal disease and antiretroviral therapy has many known serious adverse events
- Causality interpretation also confounded by concomitant medications
- This completes the one-year post-exclusivity AE reporting as mandated by BPCA
- The FDA recommends routine monitoring of ritonavir for AEs in all populations
- Does the Advisory Committee concur?

## Acknowledgements

_**OSE**_
- Melissa Truffa
- Mark Avigan
- Kendra Worthy
- Andrea Feight
- Solomon Iyasu

_**DAVP**_
- Andreas Pikis
- Kim Struble