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On June 24,
2008, FDA approved labeling changes to the Viramune (nevirapine)
oral solution and tablets to reflect various updates, including:
Dosing recommendations for
pediatric patients 15 days to 2 months of age.
Dose recommendations for all
pediatric age groups are now based on body surface area (BSA)
instead of weight-based dosing. Studies were conducted
comparing weight-based dosing and BSA-based dosing. While
comparable drug concentrations are achieved with either method,
BSA dosing allows for smoother dose transitions between
pediatric age groups and is therefore preferred.
Addition of data from a
pharmacokinetic hepatic impairment study
Revision of the recommendation that
nevirapine not be administered to patients with severe hepatic
impairment to a recommendation that nevirapine not be
administered to patients with moderate (Childs Pugh B) or severe
(Childs Pugh C) hepatic impairment
Revision of recommendations for the
occurrence of rash during the once daily lead-in phase of
dosing. The label now states that lead-in dosing should not be
extended beyond 28 days of dosing
Important
changes made to the product label include the following:
Under
Dosage and Administrations (2.0)
Pediatric
Patients (2.2)
The recommended
oral dose for pediatric patients 15 days and older is 150 mg/m2
once daily for 14 days followed by 150 mg/m2 twice daily
thereafter. The total daily dose should not exceed 400 mg for
any patient.
Table 1
Calculation of the Volume of VIRAMUNE Oral Suspension (50 mg/5
mL) Required for Pediatric Dosing Based on Body Surface and a
Dose of 150 mg/m2
BSA range (m2) Volume (mL)
0.06 –
0.12 1.25
0.12 –
0.25 2.5
0.25 –
0.42 5
0.42 –
0.58 7.5
0.58 –
0.75 10
0.75 –
0.92 12.5
0.92 –
1.08 15
1.08 –
1.25 17.5
1.25+ 20
Dosage
Adjustment (2.4)
Patients with
Rash
VIRAMUNE should
be discontinued if a patient experiences severe rash or any rash
accompanied by constitutional findings [see Boxed Warning,
Warnings and Precautions (5.2), and Patient Counseling
Information (17.1)]. A patient experiencing mild to moderate
rash without constitutional symptoms during the 14-day lead-in
period of 200 mg/day (150 mg/m2/day in pediatric patients)
should not have their VIRAMUNE dose increased until the rash has
resolved [see Warnings and Precautions (5.2) and Patient
Counseling Information (17.1)]. The total duration of the once
daily lead-in dosing period should not exceed 28 days at which
point an alternative regimen should be sought.
Under
Use in Specific Populations (8.0)
Hepatic
Impairment (8.7)
Because
increased nevirapine levels and nevirapine accumulation may be
observed in patients with serious liver disease, do not
administer VIRAMUNE to patients with moderate or severe (Child
Pugh Class B or C, respectively) hepatic impairment [see
Contraindications (4), Warnings and Precautions (5.1), and
Clinical Pharmacology (12.3)].
Under
Pharmacokinetics (12.3)
Hepatic
Impairment
In a steady
state study comparing 46 patients with mild (n=17; expansion of
some portal areas; Ishak Score 1-2), moderate (n=20; expansion
of most portal areas with occasional portal-to-portal and
portal-to-central bridging; Ishak Score 3-4), or severe (n=9;
marked bridging with occasional cirrhosis without decompensation
indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure
of hepatic impairment, the multiple dose pharmacokinetic
disposition of nevirapine and its five oxidative metabolites
were not altered. However, approximately 15% of these patients
with hepatic fibrosis had nevirapine trough concentrations above
9,000 ug/mL (2-fold the usual mean trough). Therefore, patients
with hepatic impairment should be monitored carefully for
evidence of drug induced toxicity [see Warnings and Precautions
(5.1)]. The patients studied were receiving antiretroviral
therapy containing Viramune 200 mg twice-daily for at least 6
weeks prior to pharmacokinetic sampling, with a median duration
of therapy of 3.4 years.
Pediatric
Patients
Pharmacokinetic
data for nevirapine have been derived from two sources: a 48
week pediatric trial in
South Africa
(BI Trial 1100.1368) involving 123 HIV-1 positive,
antiretroviral naïve patients aged 3 months to 16 years; and a
consolidated analysis of five Pediatric AIDS Clinical Trials
Group (PACTG) protocols comprising 495 patients aged 14 days to
19 years.
BI Trial
1100.1368 studied the safety, efficacy, and pharmacokinetics of
a weight-based and a body surface area (BSA)-based dosing
regimen of nevirapine. In the weight-based regimen, pediatric
patients up to 8 years of age received a dose of 4 mg/kg once
daily for two weeks followed by 7 mg/kg twice daily thereafter.
Patients 8 years and older were dosed 4 mg/kg once daily for two
weeks followed by 4 mg/kg twice daily thereafter. In the BSA
regimen all pediatric patients received 150 mg/m2 once daily for
two weeks followed by 150 mg/m2 twice daily thereafter [see Use
in Specific Populations (8.4) and Adverse Reactions (6.2)].
Dosing of nevirapine at 150 mg/m2 BID (after a two-week lead in
of 150 mg/m2 QD) produced geometric mean or mean trough
nevirapine concentrations between 4-6 µg/mL (as targeted from
adult data). In addition, the observed trough nevirapine
concentrations were comparable between the two dosing regimens
studied (BSA and weight-based methods).
The
consolidated analysis of Pediatric AIDS Clinical Trials Group
(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the
evaluation of pediatric patients less than 3 months of age
(n=17). The plasma nevirapine concentrations observed were
within the range observed in adults and the remainder of the
pediatric population, but were more variable between patients,
particularly in the second month of age. For dose
recommendations for pediatric patients see Dosage and
Administration (2.2).
Under
Clinical Studies (14.0)
Clinical
Studies in Pediatric Patients (14.2)
The pediatric
safety and efficacy of VIRAMUNE was examined in BI Trial
1100.1368, an open-label, randomized clinical study performed in
South Africa
in which 123 HIV-1 infected treatment naïve patients between 3
months and 16 years of age received VIRAMUNE oral solution for
48 weeks. Patients were divided into 4 age groups (3 months to
<2 years, 2 to <7 years, 7 to <12 years, and 12 to ≤16 years)
and randomized to receive one of two VIRAMUNE doses, determined
by 2 different dosing methods [body surface area (150mg/m2) and
weight-based dosing (4 or 7mg/kg)] in combination with
zidovudine and lamivudine [see Adverse Reactions (6.2),Use in
Specific Population (8.4), and Clinical Pharmacology (12.3)].
The total daily dose of VIRAMUNE did not exceed 400 mg in either
regimen. There were 66 patients in the body surface area (BSA)
dosing group and 57 patients in the weight-based (BW) dosing
group.
Baseline
demographics included: 49% male; 81% Black and 19% Caucasian; 4%
had previous exposure to ARVs. Patients had a median baseline
HIV RNA of 5.45 log10 copies/mL and a median baseline CD4 cell
count of 527 cells/mm3 (range 37-2279). One hundred and five
(85%) completed the 48 weeks period while 18 (15%) discontinued
prematurely. Of the patients who discontinued prematurely, 9
(7%) discontinued due to adverse reactions and 3 (2%)
discontinued due to virologic failure. Overall the proportion of
patients who achieved and maintained an HIV RNA <400 copies/mL
at 48 weeks was 47% (58/123). For dose recommendations for
pediatric patients see Dosage and Administration (2.2).
You can view
the complete, updated labeling using this link to
Drugs@FDA
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search
Action&SearchTerm=Viramune&SearchType=BasicSearch), clicking on
the appropriate dosage form, and following links for “Labeling
Information.”
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly
Struble
Division of Antiviral Drug Products
Food and Drug Administration |
