Lamivudine (Page 6 of 8)

14.2 Pediatric Subjects

Clinical Endpoint Trial ACTG300 was a multicenter, randomized, double-blind trial that provided for comparison of lamivudine plus RETROVIR (zidovudine) with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-white. The mean baseline CD4+ cell count was 868 cells per mm3 (mean: 1,060 cells per mm3 and range: 0 to 4,650 cells per mm3 for subjects aged less than or equal to 5 years; mean: 419 cells per mm3 and range: 0 to 1,555 cells per mm3 for subjects aged over 5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL. The median duration on trial was 10.1 months for the subjects receiving lamivudine plus RETROVIR and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 11.

Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death)

Endpoint LAMIVUDINE plus RETROVIR (n = 236) Didanosine (n = 235)
HIV-1 disease progression or death (total)Physical growth failureCentral nervous system deteriorationCDC Clinical Category CDeath 15 (6.4%)7 (3.0%)4 (1.7%)2 (0.8%)2 (0.8%) 37 (15.7%)6 (2.6%)12 (5.1%)8 (3.4%)11 (4.7%)


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 lamivudine 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 lamivudine 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 Lamivudine plus Abacavir Twice-Daily Dosing (n = 333) Lamivudine plus Abacavir Once-Daily Dosing (n = 336)
HIV-1 RNA <80 copies/mLb HIV-1 RNA ≥80 copies/mLc No virologic data Discontinued due to adverse event or death Discontinued study for other reasonsd Missing data during window but on study 70%28% 1% 0% 1% 67% 31% <1% <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).
Analyses by formulation demonstrated the proportion of subjects with HIV-1 RNA of less than 80 copies per mL at randomization and Week 96 was higher in subjects who had received tablet formulations of lamivudine and abacavir (75% [458/610] and 72% [434/601]) than in those who had received solution formulation(s) (with lamivudine solution given at weight band-based doses approximating 8 mg per kg per day) at any time (52% [29/56] and 54% [30/56]), respectively [see Warnings and Precautions (5.6)]. These differences were observed in each different age group evaluated.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamivudine tablets, USP 150 mg, are white coloured, biconvex, capsule shaped, film-coated tablets having a scoreline on one side and ‘ML 1’ debossed on the other side.

Bottle of 60 tablets NDC 33342-001-09

Lamivudine tablets, USP 300 mg, are grey coloured, biconvex, capsule shaped, film-coated tablets, debossed with ‘U27’ on one side and plain on the other side.

Bottle of 30 tablets NDC 33342-002-07

Store lamivudine tablets at 20° to 25°C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients with Hepatitis B or C Co-infection
Inform patients co-infected with HIV-1 and HBV that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.1)].

Differences in Formulations of Lamivudine Tablets
Advise patients that lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV tablets. If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in lamivudine tablets (not EPIVIR-HBV) should be used [see Warnings and Precautions (5.1)].

Lactic Acidosis/Hepatomegaly with Steatosis
Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking lamivudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.2)].

Risk of Pancreatitis
Advise parents or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.3)].

Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when lamivudine tablets are started [see Warnings and Precautions (5.4)].

Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution
Advise patients that an all-tablet regimen should be used when possible due to an increased rate of treatment failure among pediatric subjects who received lamivudine oral solution concomitantly with other antiretroviral oral solutions [see Warnings and Precautions (5.5)].

Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine tablets during pregnancy [see Use in Specific Populations(8.1)].

Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].

Missed Dosage
Instruct patients that if they miss a dose of lamivudine tablets, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].

RETROVIR is trademark owned by or licensed to the ViiV Healthcare group of companies.

EPIVIR-HBV is a trademark owned by or licensed to the GSK group of companies.

All other trademarks herein are the property of their respective owners.

Manufactured for:
Macleods Pharma USA, Inc.
Plainsboro, NJ 08536

Manufactured by:
Macleods Pharmaceuticals Ltd.
Daman (U.T.), INDIA
September 2020

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