Abacavir/Lamivudine/Zidovudine Mylan is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.

Limitations of Use

• Limited data exist on the use of Abacavir/Lamivudine/Zidovudine Mylan alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL).

Screening For HLA-B*5701 Allele Prior To Starting Abacavir/Lamivudine/Zidovudine Mylan

Screen for the HLA-B*5701 allele prior to initiating therapy with Abacavir/Lamivudine/Zidovudine Mylan.

Recommended Dosage For Adults And Pediatric Patients Weighing At Least 40 kg

The recommended dosage of Abacavir/Lamivudine/Zidovudine Mylan is one tablet taken orally twice daily with or without food.

Not Recommended Due To Lack Of Dosage Adjustment

Because Abacavir/Lamivudine/Zidovudine Mylan is a fixed-dose tablet and cannot be dose adjusted, Abacavir/Lamivudine/Zidovudine Mylan is not recommended in:

• pediatric patients who weigh less than 40 kg
• patients with creatinine clearance less than 50 mL per minute
• patients with mild hepatic impairment. Abacavir/Lamivudine/Zidovudine Mylan is contraindicated in patients with moderate or severe hepatic impairment.

Abacavir/Lamivudine/Zidovudine Mylan is contraindicated in patients:

• who have the HLA-B*5701 allele.
• with prior hypersensitivity reaction to abacavir , lamivudine, or zidovudine.
• with moderate or severe hepatic impairment.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of Abacavir/Lamivudine/Zidovudine Mylan. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:

• All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with Abacavir/Lamivudine/Zidovudine Mylan or reinitiation of therapy with Abacavir/Lamivudine/Zidovudine Mylan, unless patients have a previously documented HLA-B*5701 allele assessment.
• Abacavir/Lamivudine/Zidovudine Mylan is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.
• Before starting Abacavir/Lamivudine/Zidovudine Mylan, review medical history for prior exposure to any abacavircontaining product. NEVER restart Abacavir/Lamivudine/Zidovudine Mylan or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.
• To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue Abacavir/Lamivudine/Zidovudine Mylan immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).
• If a hypersensitivity reaction cannot be ruled out, do not restart Abacavir/Lamivudine/Zidovudine Mylan or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.
• If a hypersensitivity reaction is ruled out, patients may restart Abacavir/Lamivudine/Zidovudine Mylan. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of Abacavir/Lamivudine/Zidovudine Mylan or any other abacavir-containing product is recommended only if medical care can be readily accessed.
• A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.

Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of Abacavir/Lamivudine/Zidovudine Mylan, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Abacavir/Lamivudine/Zidovudine Mylan should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm³ or hemoglobin less than 9.5 grams per dL.

Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with Abacavir/Lamivudine/Zidovudine Mylan. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with Abacavir/Lamivudine/Zidovudine Mylan.

Lactic Acidosis And Severe Hepatomegaly With Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN^® (abacavir), EPIVIR^® (lamivudine), and RETROVIR^® (zidovudine). Treatment with Abacavir/Lamivudine/Zidovudine Mylan should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients With Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence of Lamivudine-resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV–1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).

Use With Interferon-And Ribavirin-Based Regimens

Patients receiving interferon alfa with or without ribavirin and Abacavir/Lamivudine/Zidovudine Mylan should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Discontinuation of Abacavir/Lamivudine/Zidovudine Mylan should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).

Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and Abacavir/Lamivudine/Zidovudine Mylan is not advised.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Abacavir/Lamivudine/Zidovudine Mylan. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Myocardial Infarction

In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.

As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

Therapy-Experienced Patients

In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients.

Related Products That Are Not Recommended

Abacavir/Lamivudine/Zidovudine Mylan is a fixed-dose combination of 3 nucleoside analogue reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine). Concomitant administration of Abacavir/Lamivudine/Zidovudine Mylan with other products containing abacavir, lamivudine, or zidovudine is not recommended. In addition, do not administer Abacavir/Lamivudine/Zidovudine Mylan in combination with products containing emtricitabine.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hypersensitivity Reaction

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/Lamivudine/Zidovudine Mylan, 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/Lamivudine/Zidovudine Mylan. 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.
• 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/Lamivudine/Zidovudine Mylan.
• that a hypersensitivity reaction can worsen and lead to hospitalization or death if Abacavir/Lamivudine/Zidovudine Mylan is not immediately discontinued.
• to not restart Abacavir/Lamivudine/Zidovudine Mylan 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 a hypersensitivity reaction is usually reversible if it is detected promptly and Abacavir/Lamivudine/Zidovudine Mylan is stopped right away.
• that if they have interrupted Abacavir/Lamivudine/Zidovudine Mylan 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/Lamivudine/Zidovudine Mylan or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

Related Products that are Not Recommended

Inform patients that they should not take Abacavir/Lamivudine/Zidovudine Mylan with ATRIPLA®, COMBIVIR, COMPLERA®, DUTREBIS^™, EMTRIVA®, EPIVIR, EPIVIR-HBV®, EPZICOM^® , RETROVIR, STRIBILD®, TRIUMEQ®, TRUVADA®, or ZIAGEN.

Neutropenia and Anemia

Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease.

Myopathy

Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.

Lactic Acidosis/Hepatomegaly

Inform patients that some HIV medicines, including Abacavir/Lamivudine/Zidovudine Mylan, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).

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.

Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.

Immune Reconstitution Syndrome

In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection.

Redistribution/Accumulation of Body Fat

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

Information about HIV-1 Infection

Abacavir/Lamivudine/Zidovudine Mylan is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.

Advise patients to remain under the care of a physician when using Abacavir/Lamivudine/Zidovudine Mylan. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others.

Advise patients not to re-use or share needles or other injection equipment.

Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.

Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Instruct patients to read the Medication Guide before starting Abacavir/Lamivudine/Zidovudine Mylan and to reread 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.

Nonclinical Toxicology

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.

Zidovudine: Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on day 91 and then to 300 mg per kg per day on day 279.

In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg per kg per day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.

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.

Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Impairment of Fertility

Abacavir or Lamivudine: Abacavir or lamivudine did not affect male or female fertility in rats at a dose associated with exposures approximately 8 or 130 times, respectively, higher than the exposures in humans at the doses of 600 mg and 300 mg (respectively).

Zidovudine: Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Abacavir/Lamivudine/Zidovudine Mylan in pregnant women. Reproduction studies with abacavir, lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine, and Zidovudine sections below). Abacavir/Lamivudine/Zidovudine Mylan should be used during pregnancy only if the potential benefits outweigh the risks.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Abacavir/Lamivudine/Zidovudine Mylan during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Abacavir

Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.

Lamivudine

Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.

Zidovudine

Reproduction studies with orally administered zidovudine in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an additional teratology study in rats, a dose of 3,000 mg per kg per day (very near the oral median lethal dose in rats of approximately 3,700 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less. Two rodent carcinogenicity studies were conducted.

Lactation

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed.

Pediatric Use

Abacavir/Lamivudine/Zidovudine Mylan is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations.

Therapy-Experienced Pediatric Trial

A randomized, double-blind trial, CNA3006, compared ZIAGEN plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir.

Geriatric Use

Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Abacavir/Lamivudine/Zidovudine Mylan in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients With Impaired Renal Function

Abacavir/Lamivudine/Zidovudine Mylan is not recommended for patients with creatinine clearance less than 50 mL per min because Abacavir/Lamivudine/Zidovudine Mylan is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of Abacavir/Lamivudine/Zidovudine Mylan is required for patients with renal impairment then the individual components should be used.

Patients With Impaired Hepatic Function

Abacavir/Lamivudine/Zidovudine Mylan is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of Abacavir/Lamivudine/Zidovudine Mylan, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used.

The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, Abacavir/Lamivudine/Zidovudine Mylan is contraindicated in these patients.

Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

The following adverse reactions are discussed in other sections of the labeling:

• Serious and sometimes fatal hypersensitivity reactions.
• Hematologic toxicity, including neutropenia and anemia.
• Symptomatic myopathy.
• Lactic acidosis and severe hepatomegaly with steatosis.
• Exacerbations of hepatitis B.
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C.
• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine.
• Immune reconstitution syndrome.
• Fat redistribution.
• Myocardial infarction.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Serious And Fatal Abacavir-Associated Hypersensitivity Reactions

In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of Abacavir/Lamivudine/Zidovudine Mylan. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).

Additional Adverse Reactions With Use Of Abacavir/Lamivudine/Zidovudine Mylan

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.

Table 1: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment

Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.

Laboratory Abnormalities

Laboratory abnormalities in CNA3005 are listed in Table 2.

Table 2: Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in CNA3005

Other Adverse Events

In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abacavir

Cardiovascular: Myocardial infarction.

Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use.

Abacavir, Lamivudine, And/Or Zidovudine

Body as a Whole: Redistribution/accumulation of body fat.

Cardiovascular: Cardiomyopathy.

Digestive: Stomatitis.

Endocrine and Metabolic: Gynecomastia.

Gastrointestinal: Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.

General: Vasculitis, weakness.

Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.

Hepatic: Lactic acidosis and hepatic steatosis , elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B.

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Arthralgia, myalgia, muscle weakness, rhabdomyolysis. Nervous: Dizziness, paresthesia, peripheral neuropathy, seizures.

Psychiatric: Insomnia and other sleep disorders. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

There is no known specific treatment for overdose with Abacavir/Lamivudine/Zidovudine Mylan. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Abacavir

It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine

Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Zidovudine

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3'azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.

Pharmacokinetics in Adults

In a single-dose, 3-way crossover bioavailability trial of 1 Abacavir/Lamivudine/Zidovudine Mylan tablet versus 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) administered simultaneously in healthy subjects (n = 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all 3 components. One Abacavir/Lamivudine/Zidovudine Mylan tablet was bioequivalent to 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).

Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0-12 h) was 6.02 ± 1.73 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.

Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3'-amino-3'deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.

In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.

Table 3: Pharmacokinetic Parameters^a for Abacavir, Lamivudine, and Zidovudine in Adults

Effect of Food on Absorption of Abacavir/Lamivudine/Zidovudine Mylan

Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of Abacavir/Lamivudine/Zidovudine Mylan with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24).