Lamivudine (Page 6 of 7)

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)	15 (6.4%)	37 (15.7%)
Physical growth failure	7 (3.0%)	6 (2.6%)
Central nervous system deterioration	4 (1.7%)	12 (5.1%)
CDC Clinical Category C	2 (0.8%)	8 (3.4%)
Death	2 (0.8%)	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)

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).
Outcome	Lamivudine p lus Abacavir Twice-Daily Dosing (n = 333)	Lamivudine p lus 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%

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 EPIVIR 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 Scored Tablets USP, 150 mg

White to off white scored capsule shaped, film coated tablets, debossed on both tablet faces, such that, when broken in half “L” and “5” code is present on both halves of the tablet (“L” on one side and “5” on the opposite face of the tablet).

Bottle of 60 tablets (NDC 68180-602-07) with child-resistant closure.

Bottle of 100 tablets (NDC 68180-602-01) with child-resistant closure.

Lamivudine Tablets USP, 300 mg

Gray coloured capsule shaped, film coated tablets, debossed with “L” on one side and “6” on the other side.

Bottle of 30 tablets (NDC 68180-603-06) with child-resistant closure.

Recommended Storage:

Store at 25°C (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

Advise patients that lamivudine tablets contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV tablets and oral solution. 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 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 tablet is started [see WARNINGS AND PRECAUTIONS (5.4)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lamivudine 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)].

^* The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Goa — 403722

India

Revised: August 2019 ID: 260999

PATIENT INFORMATION

LAMIVUDINE (la-MIV-ue-deen)

TABLETS USP

Rx only

What is the most important information I should know about lamivudine tablets?

Lamivudine tablets can cause serious side effects, including:

• Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 (Human Immunodeficiency Virus type 1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking lamivudine tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death.
  • Do not run out of lamivudine tablets. Refill your prescription or talk to your healthcare provider before your lamivudine tablets is all gone.
  • Do not stop lamivudine tablets without first talking to your healthcare provider.
  • If you stop taking lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.

• Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with lamivudine tablets and become harder to treat (resistant).

What are lamivudine tablets?

Lamivudine tablet is a prescription medicine used together with other antiretroviral medicines to treat Human Immunodeficiency Virus (HIV-1) infection.

HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

Lamivudine tablets (used to treat HIV-1 infection) contain a higher dose of the same active ingredient (lamivudine) than is in the medicine EPIVIR-HBV tablets and oral solution (used to treat HBV). If you have both HIV-1 and HBV, you should not use EPIVIR-HBV to treat your infections.

The safety and effectiveness of lamivudine tablets have not been established in children under 3 months of age.

Who should not take lamivudine tablets?

Do not take lamivudine tablets if you are allergic to lamivudine or any of the ingredients in lamivudine tablets. See the end of this Patient Information leaflet for a complete list of ingredients in lamivudine tablets.

What should I tell my healthcare provider before taking lamivudine tablets?

Before you take lamivudine tablets, tell your healthcare provider if you:

• have or have had liver problems, including hepatitis B or C virus infection.
• have kidney problems.
• are pregnant or plan to become pregnant. Taking lamivudine tablets during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant.

Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

• are breastfeeding or plan to breastfeed. Do not breastfeed if you take lamivudine tablets.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medications interact with lamivudine tablets. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with lamivudine tablets.

Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take lamivudine tablets with other medicines.

How should I take lamivudine tablets?

• Take lamivudine tablets exactly as your healthcare provider tells you to take it.
• If you miss a dose of lamivudine tablets, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take.
• Stay under the care of a healthcare provider during treatment with lamivudine tablets.
• Lamivudine tablets may be taken with or without food.
• For children 3 months and older, your healthcare provider will prescribe a dose of lamivudine tablets based on your child’s body weight.
• Tell your healthcare provider if you or your child has trouble swallowing tablets. Lamivudine tablets also comes as a liquid (oral solution).
• Do not run out of lamivudine tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.
• If you take too much lamivudine tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of lamivudine tablets?

• Lamivudine tablets can cause serious side effects including:
• See “What is the most important information I should know about lamivudine tablets?”.
• Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take lamivudine tablets. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:
  • feel very weak or tired
  • unusual (not normal) muscle pain
  • trouble breathing
  • stomach pain with nausea and vomiting
  • feel cold, especially in your arms and legs
  • feel dizzy or light-headed
  • have a fast or irregular heartbeat
• Serious liver problems can happen in people who take lamivudine tablets. In some cases these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
  • your skin or the white part of your eyes turns yellow (jaundice)
  • dark or “tea-colored” urine
  • light-colored stools (bowel movements)
  • loss of appetite for several days or longer
  • nausea
  • pain, aching, or tenderness on the right side of your stomach area

You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese).

• Risk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with lamivudine tablets if they:
  • have taken nucleoside analogue medicines in the past
  • have a history of pancreatitis
  • have other risk factors for pancreatitis

Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving lamivudine tablets to your child if their symptoms and blood test results show that your child may have pancreatitis.

• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking lamivudine tablets.

The most common side effects of lamivudine tablets in adults include:

• headache
• nausea
• generally not feeling well
• tiredness
• nasal signs and symptoms
• diarrhea
• cough

The most common side effects of lamivudine tablets in children include fever and cough.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of lamivudine tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store lamivudine tablets?

• Store lamivudine tablets at room temperature between 68°F to 77°F (20°C to 25°C).

Keep lamivudine tablets and all medicines out of the reach of children.

General information about the safe and effective use of lamivudine tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use lamivudine tablets for a condition for which it was not prescribed. Do not give lamivudine tablets to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about lamivudine tablets that is written for health professionals.

For more information, go to www.lupinpharmaceuticals.com or call 1-800-399-2561.

What are the ingredients in lamivudine tablets?

Active ingredient: lamivudine

Inactive ingredients:

Lamivudine scored 150-mg film-coated tablets: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide.

Lamivudine 300-mg film-coated tablets: crospovidone, hypromellose, iron oxide black, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide.

This Patient Information has been approved by the U.S. Food and Drug Administration.

^* The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Goa — 403722

India

Revised: August 2019 ID#: 261051