On March 23, 2015, FDA approved revisions to the Epivir (lamivudine) and Ziagen (abacavir sulfate) labels to each provide for once-daily dosing in pediatric patients 3 months of age and older in combination with other antiretroviral agents for the treatment of HIV-1 infection. The specific changes to each label are summarized below.
Epivir (lamivudine)
Section 2 DOSAGE AND ADMINISTRATION was updated as follows:
2.2 Pediatric Patients
The recommended oral dose of EPIVIR oral solution in HIV 1-infected pediatric patients aged 3 months and older is 4 mg per kg twice daily or 8 mg per kg once daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral agents. Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution [see Clinical Pharmacology (12.3)].
EPIVIR is also available as a scored tablet for HIV 1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing EPIVIR tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow EPIVIR tablets, the oral solution formulation should be prescribed. The recommended oral dosage of EPIVIR tablets for HIV 1-infected pediatric patients is presented in Table 1.
Table 1. Dosing Recommendations for EPIVIR Scored (150-mg) Tablets in Pediatric Patients
|
|
Once-daily Dosing Regimena |
Twice-daily Dosing Regimen Using Scored 150‑mg Tablet |
||
|
Weight (kg) |
AM Dose |
PM Dose |
Total Daily Dose |
|
|
14 to <20 |
1 tablet (150 mg) |
½ tablet (75 mg) |
½ tablet (75 mg) |
150 mg |
|
³20 to <25 |
1½ tablets (225 mg) |
½ tablet (75 mg) |
1 tablet (150 mg) |
225 mg |
|
³25 |
2 tablets (300 mg)b |
1 tablet (150 mg) |
1 tablet (150 mg) |
300 mg |
a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies (14.2)].
b Patients may alternatively take one 300-mg tablet, which is not scored.
Section 6 ADVERSE REACTIONS was updated to include results from trial COL105677 as follows:
Pediatric Subjects Once-daily vs Twice-daily Dosing (COL105677)
The safety of once-daily compared with twice-daily dosing of EPIVIR was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.
Section 12 CLINICAL PHARMACOLOGY was updated to include the pharmacokinetic data for once daily dosing.
Pediatric Patients: The pharmacokinetics of lamivudine have been studied after either single or repeat doses of EPIVIR in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution according to the recommended dosage regimen achieved approximately 25% lower plasma concentrations of lamivudine compared with HIV‑1‑infected adults. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults. The absolute bioavailability of both EPIVIR tablets and oral solution are lower in children than adults. The relative bioavailability of EPIVIR oral solution is approximately 40% lower than tablets containing lamivudine in pediatric subjects despite no difference in adults. The mechanisms for the diminished absolute bioavailability of lamivudine and relative bioavailability of lamivudine solution are unknown.
The pharmacokinetics of lamivudine dosed once daily in HIV‑1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA-15 [n = 17], PENTA 13 [n = 19], and ARROW PK [n = 35]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice- versus once-daily dosing of abacavir and lamivudine. These 3 trials demonstrated that once-daily dosing provides similar AUC0-24 to twice-daily dosing of lamivudine at the same total daily dose when comparing the dosing regimens within the same formulation (i.e., either the oral solution or the tablet formulation). The mean Cmax was approximately 80% to 90% higher with lamivudine once-daily dosing compared with twice-daily dosing.
Table 8. Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Pediatric Trials
|
|
Trial (Number of Subjects) |
|||||
|
|
ARROW PK (n = 35) |
PENTA-13 (n = 19) |
PENTA-15 (n = 17)a |
|||
|
Age Range |
3-12 years |
2-12 years |
3-36 months |
|||
|
Formulation |
Tablet |
Solution and Tabletb |
Solution |
|||
|
Parameter |
Once Daily |
Twice Daily |
Once Daily |
Twice Daily |
Once Daily |
Twice Daily |
|
Cmax (mcg/mL) |
3.17 (2.76, 3.64) |
1.80 (1.59, 2.04) |
2.09 (1.80, 2.42) |
1.11 (0.96, 1.29) |
1.87 (1.65, 2.13) |
1.05 (0.88, 1.26) |
|
AUC(0-24) (mcg·h/mL) |
13.0 |
12.0 |
9.80 |
8.88 |
8.66 |
9.48 |
a N = 16 for PENTA-15 Cmax.
b Five subjects in PENTA-13 received lamivudine tablets.
Section 14 CLINICAL STUDIES was updated with results from trial COL105677
Once-daily Dosing
ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV–1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing EPIVIR and abacavir, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks on treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of EPIVIR and abacavir, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation: at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.
The proportion of subjects with HIV-1 RNA of less than 80 copies per mL through 96 weeks is shown in Table 12. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.
Table 12. Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3)
|
Outcome |
EPIVIR plus Abacavir Twice-daily Dosing (n = 333) |
EPIVIR plus Abacavir Once-daily Dosing (n = 336) |
|
HIV-1 RNA <80 copies/mLb |
70% |
67% |
|
HIV-1 RNA ≥80 copies/mLc |
28% |
31% |
|
No virologic data |
|
|
|
Discontinued due to adverse event or death |
1% |
<1% |
|
Discontinued study for other reasonsd |
0% |
<1% |
|
Missing data during window but on study |
1% |
1% |
a Analyses were based on the last observed viral load data within the Week 96 window.
b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.
c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.
d Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).
Ziagen (abacavir sulfate)
Section 2 DOSAGE AND ADMINISTRATION was updated as follows:
2.2 Pediatric Patients
The recommended oral dose of ZIAGEN oral solution in HIV 1 infected pediatric patients aged 3 months and older is 8 mg per kg twice daily or 16 mg per kg once-daily (up to a maximum of 600 mg daily) in combination with other antiretroviral agents.
ZIAGEN is also available as a scored tablet for HIV 1 infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing ZIAGEN tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN tablets for HIV 1 infected pediatric patients is presented in Table 1.
Table 1. Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients
|
Weight (kg) |
Once-daily Dosing Regimena |
Twice-daily Dosing Regimen |
||
|
AM Dose |
PM Dose |
Total Daily Dose |
||
|
14 to <20 |
1 tablet (300 mg) |
½ tablet (150 mg) |
½ tablet (150 mg) |
300 mg |
|
³20 to <25 |
1½ tablets (450 mg) |
½ tablet (150 mg) |
1 tablet (300 mg) |
450 mg |
|
³25 |
2 tablets (600 mg) |
1 tablet (300 mg) |
1 tablet (300 mg) |
600 mg |
a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once daily dosing after 36 weeks of treatment [see Clinical Studies (14.2)].
Section 6 ADVERSE REACTIONS was updated to include results from trial COL105677 as follows:
Pediatric Subjects Once-daily vs Twice-daily Dosing (COL105677)
The safety of once-daily compared with twice-daily dosing of EPIVIR was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.
Section 12 CLINICAL PHARMACOLOGY was updated to include the pharmacokinetic data for once daily dosing. Pediatric Patients: The pharmacokinetics of abacavir have been studied after either single or repeat doses of ZIAGEN in 169 pediatric subjects. Subjects receiving abacavir oral solution according to the recommended dosage regimen achieved plasma concentrations of abacavir similar to adults. Subjects receiving abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects receiving oral solution.
The pharmacokinetics of abacavir dosed once daily in HIV 1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice- versus once-daily dosing of abacavir and lamivudine. For the oral solution as well as the tablet formulation, these 3 trials demonstrated that once-daily dosing provides comparable AUC0-24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6- to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.
Section 14 CLINICAL STUDIES was updated with results from trial COL105677
Once-daily Dosing
ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing ZIAGEN and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of ZIAGEN and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed compared with 71% of subjects in the once-daily cohort.
The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 11. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.
Table 11. Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3)
|
Outcome |
ZIAGEN plus Lamivudine Twice-daily Dosing (n = 333) |
ZIAGEN plus Lamivudine Once-daily Dosing (n = 336) |
|
HIV-1 RNA <80 copies/mLb |
70% |
67% |
|
HIV-1 RNA ≥80 copies/mLc |
28% |
31% |
|
No virologic data |
|
|
|
Discontinued due to adverse event or death |
1% |
<1% |
|
Discontinued study for other reasonsd |
0% |
<1% |
|
Missing data during window but on study |
1% |
1% |
a Analyses were based on the last observed viral load data within the Week 96 window.
b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.
c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.
d Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).
The completed and revised product label will be available soon at DAILYMED OR Drugs@FDA
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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