Abacavir and Lamivudine: Package Insert and Label Information (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.

Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.

Mutagenicity

Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Impairment of Fertility

Abacavir: Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.

Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax ) in humans at the dose of 300 mg.

13.2 Animal Toxicology and/or Pharmacology

Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.

14 CLINICAL STUDIES

14.1 Adults

One abacavir and lamivudine tablet given once daily is an alternative regimen to EPIVIR tablets 300 mg once daily plus ZIAGEN tablets 2 x 300 mg once daily as a component of antiretroviral therapy.

The following trial was conducted with the individual components of abacavir and lamivudine.

Therapy-Naive Adults

CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm3 (range: 21 to 918 cells per mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per mL).

The outcomes of randomized treatment are provided in Table 4.

Table 4. Outcomes of Randomized Treatment through Week 48 (CNA30021)
*
Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).
Includes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.
Includes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other.
Outcome ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386)
Responder * 64% (71%) 65% (72%)
Virologic failure 11% (5%) 11% (5%)
Discontinued due to adverse reactions 13% 11%
Discontinued due to other reasons 11% 13%

After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm3 in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm3 in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.

14.2 Pediatric Subjects

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 abacavir 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 abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. 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.

Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as abacavir and lamivudine.

The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

Table 5. Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3)
Outcome Abacavir plus Lamivudine Twice-Daily Dosing (n = 333) Abacavir 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 Risk difference (95% CI) of response rate is -2.4% (-9% to 5%) 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).

16 HOW SUPPLIED/STORAGE AND HANDLING

Abacavir and lamivudine tablets USP is available as tablets. Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are orange coloured, capsule shaped, biconvex, film coated tablets debossed with ‘C’ on one side and plain on another sides. They are packaged as follows:

Container pack of 30 tablets NDC 69097-362-02

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 (Medication Guide).

Hypersensitivity Reactions

Inform patients:

  • that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of abacavir and lamivudine, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir and lamivudine. The complete text of the Medication Guide is reprinted at the end of this document.
  • to carry the Warning Card with them.
  • how to identify a hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].
  • that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking abacavir and lamivudine.
  • that a hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir and lamivudine is not immediately discontinued.
  • to not restart abacavir and lamivudine or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
  • that if they have a hypersensitivity reaction, they should dispose of any unused abacavir and lamivudine tablets to avoid restarting abacavir.
  • that a hypersensitivity reaction is usually reversible if it is detected promptly and abacavir and lamivudine is stopped right away.
  • that if they have interrupted abacavir and lamivudine for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
  • to not restart abacavir and lamivudine or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

Patients with Hepatitis B or C Co-infection

Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see Warnings and Precautions (5.2)].

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 abacavir and lamivudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [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 abacavir and lamivudine tablets are 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 abacavir and 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 Dose

Instruct patients that if they miss a dose of abacavir and 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)].

Availability of Medication Guide

Instruct patients to read the Medication Guide before starting abacavir and lamivudine tablets and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Disclaimer: Other brands listed are the registered trademarks of their respective owners and are not trademarks of Cipla Limited.

Manufactured by

Cipla Limited, MIDC, Patalganga

M.S. 410220, INDIA

Manufactured for

10 Independence Boulevard, Suite 300, Warren

NJ — 07059

Revised: 01/2022

MEDICATION GUIDE

Abacavir and Lamivudine tablets USP

(a bak’ a vir and la miv’ ue deen)

600mg/300mg

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

Abacavir and lamivudine tablets can cause serious side effects, including:

  • Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with abacavir and lamivudine tablets and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.

If you get a symptom from 2 or more of the following groups while taking abacavir and lamivudine tablets, call your healthcare provider right away to find out if you should stop taking abacavir and lamivudine tablets.

Symptom(s)
Group 1 Fever
Group 2 Rash
Group 3 Nausea, vomiting, diarrhea, abdominal (stomach area) pain
Group 4 Generally ill feeling, extreme tiredness, or achiness
Group 5 Shortness of breath, cough, sore throat

A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times.

If you stop abacavir and lamivudine tablets because of an allergic reaction, never take abacavir and lamivudine tablets or any other abacavir-containing medicine (TRIUMEQ, TRIZIVIR, or ZIAGEN) again.

  • If you have an allergic reaction, dispose of any unused abacavir and lamivudine tablets. Ask your pharmacist how to properly dispose of medicines.
  • If you take abacavir and lamivudine tablets or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death.
  • If you stop abacavir and lamivudine tablets for any other reason, even for a few days, and you are not allergic to abacavir and lamivudine tablets, talk with your healthcare provider before taking it again. Taking abacavir and lamivudine tablets again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.

If your healthcare provider tells you that you can take abacavir and lamivudine tablets again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.

  • Worsening of hepatitis B virus (HBV) infection. If you have HBV infection and take abacavir and lamivudine tablets, your HBV may get worse (flare-up) if you stop taking abacavir and lamivudine tablets. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.
  • Do not run out of abacavir and lamivudine tablets. Refill your prescription or talk to your healthcare provider before your abacavir and lamivudine tablets are all gone.
  • Do not stop abacavir and lamivudine tablets without first talking to your healthcare provider.
  • If you stop taking abacavir and lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking abacavir and lamivudine tablets.
  • Resistant HBV. If you have human immunodeficiency virus-1 (HIV-1) and HBV, the HBV can change (mutate) during your treatment with abacavir and lamivudine tablets and become harder to treat (resistant).
  • For more information about side effects, see “What are the possible side effects of abacavir and lamivudine tablets?”

What are abacavir and lamivudine tablets?

Abacavir and lamivudine tablets are prescription medicine used with other HIV-1 medicines to treat HIV-1 infection.

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

Abacavir and lamivudine tablet contains the prescription medicines abacavir and lamivudine.

Abacavir and lamivudine tablets should not be used in children weighing less than 55 pounds (25 kg).

Do not take abacavir and lamivudine tablets if you:

  • have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with abacavir and lamivudine tablets.
  • are allergic to abacavir, lamivudine, or any of the ingredients in abacavir and lamivudine tablets. See the end of this Medication Guide for a complete list of ingredients in abacavir and lamivudine tablets.
  • have certain liver problems.

Before you take abacavir and lamivudine tablets tell your healthcare provider about all of your medical conditions, including if you:

  • have been tested and know whether or not you have a particular gene variation called HLA-B*5701.
  • have or have had liver problems, including hepatitis B or C virus infection.
  • have kidney problems.
  • have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
  • are pregnant or plan to become pregnant.

Pregnancy Registry. There is a pregnancy registry for women who take HIV-1 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 abacavir and 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 medicines interact with abacavir and lamivudine tablets. Keep a list of your medicines to show 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 abacavir and 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 abacavir and lamivudine tablets with other medicines.

How should I take abacavir and lamivudine tablets?

  • Take Abacavir and lamivudine tablets exactly as your healthcare provider tells you to take it.
  • Do not change your dose or stop taking abacavir and lamivudine tablets without talking with your healthcare provider.
  • If you miss a dose of abacavir and lamivudine tablets, take it as soon as you remember. Do not take 2 doses at the same time or take more than. your healthcare provider tells you to take.
  • Stay under the care of a healthcare provider during treatment with abacavir and lamivudine tablets.
  • Abacavir and lamivudine tablets may be taken with or without food.
  • Tell your healthcare provider if your child has trouble swallowing abacavir and lamivudine tablets.
  • Do not run out of abacavir and 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 abacavir and lamivudine tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of abacavir and lamivudine tablets?

  • Abacavir and lamivudine tablets can cause serious side effects including:
  • See “What is the most important information I should know about abacavir and lamivudine tablets?”
    • Too much lactic acid in your blood (lactic acidosis). 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
  • Severe liver problems. In some cases, severe 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 or very overweight (obese).

  • 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 abacavir and lamivudine tablets.
  • Heart attack. Some HIV-1 medicines including abacavir and lamivudine tablets may increase your risk of heart attack

The most common side effects of abacavir and lamivudine tablets include:

  • allergic reactions
  • trouble sleeping
  • depression
  • headache or migraine
  • tiredness or weakness
  • dizziness
  • nausea
  • diarrhea

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 abacavir and lamivudine tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store abacavir and lamivudine tablets?

  • Store abacavir and lamivudine tablets at room temperature.

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

General information for safe and effective use of abacavir and lamivudine tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use abacavir and lamivudine tablets for a condition for which it was not prescribed. Do not give abacavir and 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 the information about abacavir and lamivudine tablets that is written for health professionals.

For more information go to www.ciplausa.com or call 1-866-604-3268.

What are the ingredients in abacavir and lamivudine tablets?

Active ingredients: abacavir and lamivudine

Inactive ingredients: Each film-coated abacavir and lamivudine t ablet contains the inactive ingredients microcrystalline cellulose, sodium starch glycolate, hypromellose, corn starch, colloidal silicon dioxide, magnesium stearate. The tablets are coated with a film (Opadry orange 14B53805) that is made of hyperomellose 15CP, titanium dioxide, PEG 400, FD&C Yellow No 6, polysorbate 80.

Disclaimer: Other brands listed are the registered trademarks of their respective owners and are not trademarks of Cipla Limited.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by

Cipla Limited

MIDC, Patalganga

M.S. 410220, INDIA

Manufactured for

Cipla USA, Inc.

10 Independence Boulevard, Suite 300, Warren

NJ — 07059

01/2022

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