FDA Approves Dosing Recommendations for Ritonavir in Pediatric
Patients
On
October 6, 2006 the Food and Drug Administration (FDA) approved
dosing recommendations for ritonavir
(Norvir)
in pediatric patients one month to two years of age. The major
revisions to the package insert include the following:
CLINICAL
PHARMACOLOGY
This section was modified to include pharmacokinetic data
in children 1 month to 2 years of age. The new Clinical
Pharmacology section for Pediatric Patients reads as follows:
Pediatric
Patients
Steady-state pharmacokinetics were evaluated
in 37 HIV infected patients ages 2 to 14 years receiving doses
ranging from 250 mg/m2 twice-daily to 400 mg/m2 twice daily in
PACTG Study 310, and in 41 HIV-infected patients ages 1 month
to 2 years at doses 350 and 450 mg/m2 twice daily in PACTG Study
345.
Across dose groups, ritonavir steady-state
oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster
in pediatric patients than in adult subjects.
Ritonavir concentrations obtained after 350
to 400 mg/m2 twice daily in pediatric patients > 2 years were
comparable to those obtained in adults receiving 600 mg (approximately
330 mg/m2) twice daily.
The following observations were seen regarding
ritonavir concentrations after administration with 350 or 450
mg/m2 twice daily in children < 2 years of age.
Higher ritonavir exposures were not evident
with 450 mg/m2 twice daily compared to the 350 mg/m2 twice daily.
Ritonavir trough concentrations were somewhat lower than those
obtained in adults receiving 600 mg twice daily.
The area under the ritonavir plasma concentration-time
curve and trough concentrations obtained after administration
with 350 or 450 mg/m2 twice daily were approximately 16% and 60%
lower, respectively, than that obtained in adults receiving 600
mg twice daily.
PRECAUTIONS
The following information was added under
the section of Pediatric Use subsection:
Pediatric
Use
In HIV-infected patients age > 1 month
to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through post-marketing experience
were similar to that for adult patients.
ADVERSE
REACTIONS
The following information was added under
the section of Pediatric Use subsection. Of note, the treatment-emergent
adverse events and laboratory abnormalities shown in the label
reflect the summary of the adverse events and laboratory abnormalities
observed in pediatric studies M95-310, PACTG 366, and PACTG 345.
Pediatrics:
Treatment-emergent Adverse Events
NORVIR has been studied in 265 pediatric
patients > 1 month to 21 years of age. The adverse event profile
observed during pediatric clinical trials was similar to that
for adult patients.
Vomiting, diarrhea, and skin
rash/allergy were the only drug-related clinical adverse events of moderate to
severe intensity observed in = 2% of pediatric patients enrolled
in NORVIR clinical trials.
Laboratory
Abnormalities
The following Grade 3-4 laboratory abnormalities
occurred in = 3% of pediatric patients who received treatment
with NORVIR either alone or in combination with reverse
transcriptase inhibitors: neutropenia
(9%), hyperamylasemia (7%), thrombocytopenia
(5%),
anemia (4%), and elevated AST (3%).
DOSAGE
AND ADMINISTRATION
The section of Pediatric Patients has been
modified to include dosing recommendations for children > 1
month to 2 years of age. The new Dosage and Administration section
for Pediatric Patients is:
Pediatric
Patients
Ritonavir should be used in combination with
other antiretroviral agents (see General Dosing Guidelines). The
recommended dosage of ritonavir in children > 1 month is 350
to 400 mg/m2 twice daily by mouth and should not exceed 600 mg
twice daily.
Ritonavir should be started at 250 mg/m2
and increased at 2 to 3 day intervals by 50 mg/m2 twice daily.
If patients do not tolerate 400 mg/m2 twice daily due to adverse
events, the highest tolerated dose may be used for maintenance
therapy in combination with other antiretroviral agents, however,
alternative therapy should be considered.
When possible, dose should be administered
using a calibrated dosing syringe.
10/26/05
Sources
Richard Klein (Office of Special Health Issues
Food and Drug Administration)
Kimberly Struble (Division of Antiviral Drug
Products Food and Drug Administration)
Norvir Articles on HIVandHepatitis.com
Ritonavir-based
HAART in HIV Positive Infants Younger Than 24 Months of Age - 9/19/05
Reduced
Susceptibility to Protease Inhibitors (PI) in the Absence of Primary
PI Resistance-associated Mutations - 6/15/05
Switch
from Ritonavir to Indinavir in Combination Therapy for
Children with HIV - 4/06/05
Development and Validation of
a Population Pharmacokinetic Model for Ritonavir -
2/04/05
Buffalo
Hump Seen in HIV-Associated Lipodystrophy Is Associated with Hyperinsulinemia
But Not Dyslipidemia
-
1/28/05
HIV
Protease Inhibitors Impair Muscle Repair and Remodeling
-
11/29/04
HIV
Protease Inhibitor Ritonavir Enhances the Anticancer Effects
of Docetaxel in Prostate Cancer Cells in vitro and in vivo - 10/29/04
Comparison
of Two Indinavir/Ritonavir Regimens in Patients Failing
Their First Protease Inhibitor-based Regimen - 10/25/04
NIH Rejects
Request to Override Abbott's Norvir Patent - 08/06/04
Interactions
Between Atazanavir/Ritonavir and Tenofovir in Heavily Pretreated
HIV Patients
-
07/28/04
Updates
on Antiretroviral Drug Interactions
-
07/28/04
Once
Daily Ritonavir-boosted Fosamprenavir Continues to Perform
Well: 96 Weeks of the SOLO Trial -
07/16/04
Indinavir
Plus Ritonavir and Efavirenz: Is Tolerability the issue?
-
07/16/04
Ritonavir-boosted
Atazanavir Is Safe and Well Tolerated in Patients Commencing HAART
-
07/16/04
Abbott Norvir Price Claims
Were Misleading - FDA 06/11/04
Abbott Defends Ritonavir
Price Rise to Panel 05/26/04
Once Daily
Dosing of Saquinavir Soft-gel Capsules and Ritonavir Combination - 05/21/04
PI Monotherapy
Tested in Patients with Well-controlled HIV Infection - 05/21/04
Pharmacokinetics and Safety of
Fosamprenavir and Ritonavir, with and without Efavirenz
-
4/13/04
Once-daily
Saquinavir and Ritonavir in Treatment-experienced HIV-infected
Individuals -
3/29/04
A
Regimen of Amprenavir/ Ritonavir/ Lopinavir Produced Low
Tolerance and Did Not Prevent Decrease in Amprenavir Levels
-
3/29/04
Fosamprenavir/ Ritonavir
Once Daily in Treatment-naive HIV Patients Shows No PI Resistance
at 48 Weeks
- 3/26/04
Abbott
Sends Second Letter to Physicians Regarding Re-pricing of Norvir
02/13/04
Reyataz
Enhances Invirase Concentrations in a Norvir-boosted Once
Daily Regimen 02/11/04
Saquinavir-Ritonavir
Dual PI Regimen at 800/100 mg B.I.D. Is a Reasonable Treatment
Option for HIV Positive Pregnant Women 02/04/04
Pharmacologic
Enhancement in Protease Inhibitor-based HAART: The Role of Ritonavir
02/02/04
By Stephen L. Becker,
MD, and Lorna Thornton, MD
Effect
of Lopinavir on Agenerase (amprenavir) Concentrations Boosted
by Norvir (ritonavir) 01/23/04
In
vitro-in vivo Model for Evaluating the Antiviral Activity of Agenerase
(amprenavir) in Combination with Norvir (ritonavir)
01/23/04
Ritonavir-based
Therapy Confers No Advantages Compared to Other Regimens in Preventing
Kaposi's Sarcoma
01/12/04
FDA Approves Roche Protease
Inhibitor Invirase Boosted with Norvir
01/07/04
Should Boosted Norvir Regimens
Be Among the First Options Considered for Use in HIV Clinical
Practice? 01/07/04
Abbott Increases Price
of Norvir 400%, Causing Furor Among AIDS Advocates
By Vanessa Fuhrmans / Wall Street Journal
01/05/04
Abbott Sends Letter
to HIV Treating Physicians Concerning Norvir Price Increase
01/05/04
A randomized clinical trial
to compare the effectiveness of indinavir, ritonavir and
saquinavir.
11/10/03
Saquinavir/Ritonavir
(SQV/r) Pharmacokinetics in HIV Patients: 1000/100mg Twice Daily
vs 1600/100 and 2000/100mg Once Daily
09/15/03
Predictive
Value of Drug Levels, HIV Genotyping, and the Genotypic Inhibitory
Quotient (GIQ) at Different Time-Points Along 48 Weeks Using A
SQV/RTV Salvage Therapy
PDF
09/15/03
The
Pharmacokinetic (PK) Interaction of GW433908 (908) with Atorvastatin
(ATO) and 908/Ritonavir (RTV) with ATO (APV10013)
PDF
09/15/03
Multicentre
Trial in Naïve HIV Patients, Comparing ZDV/3TC vs d4T/ddI
Plus Efavirenz, Nevirapine or Indinavir/Ritonavir
09/26/03
Difficulties in
Understanding the Metabolic Complications of AIDS
09/11/03
Evaluation of Indinavir/Ritonavir
Versus Saquinavir/Ritonavir in HIV Patients: The MaxCmin-1 Trial
09/10/03
Administration of
Indinavir (Crixivan) and low-dose Norvir (ritonavir) 800/100
mg Twice Daily with Food Reduces Nephrotoxicity of Indinavir
09/03/03
Indinavir/Ritonavir-based
Regimens May Be Able to Overcome Resistance in Patients with Multiple
Prior Protease Inhibitor Failures
08/27/03
Effect of Simultaneous Versus
Staggered Dosing on Pharmacokinetic Interactions of Protease Inhibitors
08/04/03
Use of Lower-Dose
Indinavir Boosted with Ritonavir Maintains Potency and
Improves Tolerability
08/01/03
Rescriptor (delavirdine) Treatment
Increases Norvir (ritonavir) Concentrations
06/16/03
Viread (tenofovir) Is As Potent
as Norvir (ritonavir) in Monotherapy Study
05/23/03
Norvir (Ritonavir) Damage
to Endothelial Cells May Explain Its Adverse Vascular Effects
10/28/02
Sustiva (Efavirenz)
Outperforms Fortovase (Saquinavir) + Norvir (Ritonavir)
Dosed Once Daily
10/11/02
Study Examines Lipid
Safety Profile of Norvir (Ritonavir) Boosted Fortovase (Saquinavir)
vs. Norvir Boosted Crixivan (Indinavir)
10/02/02
Saquinavir-Ritonavir
Combination for HIV Therapy Gets European Approval
09/20/02
Norvir
(Ritonavir) Blocks Plasma Membrane Efflux Pump Present in Blood-Brain
Barrier
09/18/02
