DRUGS & SUPPLEMENTS

Lamivudine; Zidovudine; Abacavir

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Lamivudine; Zidovudine; Abacavir uses


1 INDICATIONS AND USAGE

Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) .

Lamivudine; Zidovudine; Abacavir, a combination of abacavir, lamivudine, and zidovudine, each nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection. (1)

2 DOSAGE AND ADMINISTRATION

  • Before initiating Lamivudine; Zidovudine; Abacavir, screen for the HLA‑B*5701 allele because Lamivudine; Zidovudine; Abacavir contains abacavir.
  • Adults and pediatric patients weighing at least 40 kg: 1 tablet twice daily. (2.2)
  • Because Lamivudine; Zidovudine; Abacavir is a fixed-dose tablet and cannot be dose adjusted, Lamivudine; Zidovudine; Abacavir is not recommended in patients requiring dosage adjustment or patients with hepatic impairment. (2.3, 4)

2.1 Screening for HLA-B*5701 Allele prior to Starting Lamivudine; Zidovudine; Abacavir

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

2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

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

2.3 Not Recommended Due to Lack of Dosage Adjustment

Because Lamivudine; Zidovudine; Abacavir is a fixed-dose tablet and cannot be dose adjusted, Lamivudine; Zidovudine; Abacavir is not recommended for:

  • pediatric patients who weigh less than 40 kg .
  • patients with creatinine clearance less than 50 mL per minute .
  • patients with mild hepatic impairment. Lamivudine; Zidovudine; Abacavir is contraindicated in patients with moderate or severe hepatic impairment .
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3 DOSAGE FORMS AND STRENGTHS

Lamivudine; Zidovudine; Abacavir tablets contain 300 mg of abacavir as Lamivudine; Zidovudine; Abacavir, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green, capsule-shaped, film-coated, and imprinted with “GX LL1” on one side with no markings on the reverse side.

Tablets: 300 mg abacavir, 150 mg lamivudine, and 300 mg zidovudine. (3)

4 CONTRAINDICATIONS

Lamivudine; Zidovudine; Abacavir 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 .
  • Presence of HLA-B*5701 allele. (4)
  • Prior hypersensitivity reaction to abacavir, lamivudine, or zidovudine (4)
  • Moderate or severe hepatic impairment. (4, 8.7)

5 WARNINGS AND PRECAUTIONS

  • Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue Lamivudine; Zidovudine; Abacavir as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both.
  • Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. (5.6)
  • Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.7, 5.8)

5.1 Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of Lamivudine; Zidovudine; Abacavir. 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 Lamivudine; Zidovudine; Abacavir or reinitiation of therapy with Lamivudine; Zidovudine; Abacavir, unless patients have a previously documented HLA‑B*5701 allele assessment.
  • Lamivudine; Zidovudine; Abacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑B*5701-positive patients.
  • Before starting Lamivudine; Zidovudine; Abacavir, review medical history for prior exposure to any abacavir-containing product. NEVER restart Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir. 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 Lamivudine; Zidovudine; Abacavir 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.

5.2 Hematologic Toxicity/Bone Marrow Suppression

Zidovudine, a component of Lamivudine; Zidovudine; Abacavir, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.

5.3 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 Lamivudine; Zidovudine; Abacavir.

5.4 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®, EPIVIR® (lamivudine), and RETROVIR® (zidovudine). Treatment with Lamivudine; Zidovudine; Abacavir 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).

5.5 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).

5.6 Use with Interferon- and Ribavirin-Based Regimens

Patients receiving interferon alfa with or without ribavirin and Lamivudine; Zidovudine; Abacavir should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR and RETROVIR (zidovudine). Discontinuation of Lamivudine; Zidovudine; Abacavir 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).

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

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Lamivudine; Zidovudine; Abacavir. 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.

5.8 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, 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.

5.9 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).

5.10 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 .

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6 ADVERSE REACTIONS

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 .

The most commonly reported adverse reactions (incidence at least 10%) in clinical trials were nausea, headache, malaise and fatigue, and nausea and vomiting. (6.1) 

To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Lamivudine; Zidovudine; Abacavir . 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 Lamivudine; Zidovudine; Abacavir

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.


Adverse Reaction


ZIAGEN plus Lamivudine/Zidovudine

(n = 262)


Indinavir plus Lamivudine/Zidovudine

(n = 264)


Nausea


19%


17%


Headache


13%


9%


Malaise and fatigue


12%


12%


Nausea and vomiting


10%


10%


Hypersensitivity reaction


8%


2%


Diarrhea


7%


5%


Fever and/or chills


6%


3%


Depressive disorders


6%


4%


Musculoskeletal pain


5%


7%


Skin rashes


5%


4%


Ear/nose/throat infections


5%


4%


Viral respiratory infections


5%


5%


Anxiety


5%


3%


Renal signs/symptoms


<1%


5%


Pain (non-site-specific)


<1%


5%


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.


Laboratory Parameter


ZIAGEN plus Lamivudine/Zidovudine

(n = 262)


Indinavir plus Lamivudine/Zidovudine

(n = 264)


Elevated CPK (>4 x ULN)


18 (7%)


18 (7%)


ALT (>5.0 x ULN)


16 (6%)


16 (6%)


Neutropenia (<750/mm3)


13 (5%)


13 (5%)


Hypertriglyceridemia (>750 mg/dL)


5 (2%)


3 (1%)


Hyperamylasemia (>2.0 x ULN)


5 (2%)


1 (<1%)


Hyperglycemia (>13.9 mmol/L)


2 (<1%)


2 (<1%)


Anemia (Hgb ≤6.9 g/dL)


0 (0%)


3 (1%)


ULN = Upper limit of normal.


n = Number of patients assessed.


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.

6.2 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.

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7 DRUG INTERACTIONS

  • Methadone: An increased methadone dose may be required in a small number of patients.
  • Agents antagonistic with zidovudine: Concomitant use should be avoided (7.2).
  • Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.2))

7.1 Abacavir

Methadone

In a trial of 11 HIV-1‑infected subjects receiving methadone‑maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

7.2 Zidovudine

Agents Antagonistic with Zidovudine

Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:

  • Stavudine
  • Doxorubicin
  • Nucleoside analogues, e.g., ribavirin

Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:

  • Ganciclovir
  • Interferon alfa
  • Ribavirin
  • Other bone marrow suppressive or cytotoxic agents
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8 USE IN SPECIFIC POPULATIONS

  • Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Lamivudine; Zidovudine; Abacavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population . The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose .

Data

Human Data: Abacavir: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens.

Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery .

Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).

Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR (zidovudine) and COMBIVIR® (lamivudine and zidovudine).

Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery .

Animal Data:Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown‑rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.

Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit], respectively). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from gestation Day 6 through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.

Zidovudine: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

8.2 Lactation

Risk Summary

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. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving Lamivudine; Zidovudine; Abacavir.

8.4 Pediatric Use

Lamivudine; Zidovudine; Abacavir 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.

8.5 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 Lamivudine; Zidovudine; Abacavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy .

8.6 Patients with Impaired Renal Function

Lamivudine; Zidovudine; Abacavir is not recommended for patients with creatinine clearance less than 50 mL per min because Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir is required for patients with renal impairment then the individual components should be used .

8.7 Patients with Impaired Hepatic Function

Lamivudine; Zidovudine; Abacavir is a fixed‑dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of Lamivudine; Zidovudine; Abacavir, 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, Lamivudine; Zidovudine; Abacavir 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.

10 OVERDOSAGE

There is no known specific treatment for overdose with Lamivudine; Zidovudine; Abacavir. 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.

11 DESCRIPTION

Lamivudine; Zidovudine; Abacavir tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN), lamivudine (also known as EPIVIR or 3TC), and zidovudine (also known as RETROVIR, azidothymidine, or ZDV) with inhibitory activity against HIV-1.

Lamivudine; Zidovudine; Abacavir tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as Lamivudine; Zidovudine; Abacavir, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY® green 03B11434) that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.

Lamivudine; Zidovudine; Abacavir: The chemical name of Lamivudine; Zidovudine; Abacavir is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Lamivudine; Zidovudine; Abacavir is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2-H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula:

Lamivudine; Zidovudine; Abacavir is a white to off-white solid and soluble in water. Dosages are expressed in terms of abacavir.

Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid and is soluble in water.

Zidovudine: The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula:

Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.

Lamivudine; Zidovudine; Abacavir lamivudine C:\Users\lb814145\Desktop\PDR Corrections\ZDV.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lamivudine; Zidovudine; Abacavir is an antiretroviral agent .

12.3 Pharmacokinetics

Pharmacokinetics in Adults

In a single-dose, 3-way crossover bioavailability trial of 1 TRIZIVIR 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 Lamivudine; Zidovudine; Abacavir 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.


Parameter


Abacavir


Lamivudine


Zidovudine


Oral bioavailability (%)


86 ± 25


n = 6


86 ± 16


n = 12


64 ± 10


n = 5


Apparent volume of distribution (L/kg)


0.86 ± 0.15


n = 6


1.3 ± 0.4


n = 20


1.6 ± 0.6


n = 8


Systemic clearance (L/h/kg)


0.80 ± 0.24


n = 6


0.33 ± 0.06


n = 20


1.6 ± 0.6


n = 6


Renal clearance (L/h/kg)


0.007 ± 0.008


n = 6


0.22 ± 0.06


n = 20


0.34 ± 0.05


n = 9


Elimination half-life (h)


1.45 ± 0.32


n = 20


5 to 7b


0.5 to 3b


a Data presented as mean ± standard deviation except where noted.


b Approximate range.


Effect of Food on Absorption of Lamivudine; Zidovudine; Abacavir

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 Lamivudine; Zidovudine; Abacavir with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) .

Specific Populations

Renal Impairment:TRIZIVIR: The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated.

Hepatic Impairment:TRIZIVIR: The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated.

Pregnancy: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.

Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.

Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.

Race: Abacavir and Lamivudine: There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components.

Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interactions

The drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using Lamivudine; Zidovudine; Abacavir. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine.

Cytochrome P450 Enzymes: Abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Glucuronyl Transferase: Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV‑1‑infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

Other Interactions

Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.

Methadone: In a trial of 11 HIV‑1‑infected subjects receiving methadone‑maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV‑1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi‑drug regimen to HIV‑1/HCV co‑infected subjects .

The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.


Coadministered

Drug and Dose


Drug and Dose


n


Concentrations of Abacavir, Lamivudine, or Zidovudine


Concentration of Coadministered

Drug


AUC


Variability


Ethanol

0.7 g/kg


Abacavir single 600 mg


24


↑41%


90% CI:

35% to 48%


b


Nelfinavir

750 mg every 8 h x 7 to 10 days


Lamivudine single 150 mg


11


↑10%


95% CI:

1% to 20%




Trimethoprim 160 mg/

Sulfamethoxazole

800 mg daily x 5 days


Lamivudine single 300 mg


14


↑43%


90% CI:

32% to 55%




Atovaquone

750 mg every 12 h

with food


Zidovudine 200 mg every 8 h


14


↑31%


Range:

23% to 78%c




Clarithromycin

500 mg twice daily


Zidovudine 100 mg every 4 h x 7 days


4


↓12%


Range:

↓34% to ↑14%


Not Reported


Fluconazole

400 mg daily


Zidovudine 200 mg every 8 h


12


↑74%


95% CI:

54% to 98%


Not Reported


Methadone

30 to 90 mg daily


Zidovudine 200 mg every 4 h


9


↑43%


Range:

16% to 64%c




Nelfinavir

750 mg every 8 h x 7 to 10 days


Zidovudine single 200 mg


11


↓35%


Range:

28% to 41%




Probenecid

500 mg every 6 h x 2 days


Zidovudine 2 mg/kg every 8 h x 3 days


3


↑106%


Range:

100% to 170%c


Not Assessed


Rifampin

600 mg daily x 14 days


Zidovudine 200 mg every 8 h x 14 days


8


↓47%


90% CI:

41% to 53%


Not Assessed


Ritonavir

300 mg every 6 h x 4 days


Zidovudine 200 mg every 8 h x 4 days


9


↓25%


95% CI:

15% to 34%




Valproic acid

250 mg or 500 mg

every 8 h x 4 days


Zidovudine 100 mg every 8 h x 4 days


6


↑80%


Range:

64% to 130%c


Not Assessed


↑ = Increase; ↓ = Decrease; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.

aSee Drug Interactions (7) for additional information on drug interactions.

bThe drug-drug interaction was only evaluated in males.

cEstimated range of percent difference.

12.4 Microbiology

Mechanism of Action

Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV‑TP), an analogue of deoxyguanosine‑5′‑triphosphate (dGTP). CBV‑TP inhibits the activity of HIV‑1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC‑TP). The principal mode of action of 3TC‑TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV‑TP). The principal mode of action of ZDV‑TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity

Abacavir: The antiviral activity of abacavir against HIV‑1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV‑1IIIB and HIV‑1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV‑2 isolates (n = 4), ranged from 0.024 to 0.49 microM.

Lamivudine: The antiviral activity of lamivudine against HIV‑1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV‑2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV‑1 activity of lamivudine by 3.5‑fold in MT‑4 cells.

Zidovudine: The antiviral activity of zidovudine against HIV‑1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV‑1 from therapy‑naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV‑1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV‑2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.

Neither abacavir, lamivudine, nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), RETROVIR (zidovudine).

Resistance

HIV‑1 isolates with reduced susceptibility to abacavir, lamivudine, or zidovudine have been selected in cell culture and were also recovered from subjects treated with abacavir, lamivudine, and zidovudine, or the combinations of the individual components.

Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions, K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.

Zidovudine: Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine‑treated subjects showed thymidine analogue mutation (TAM) substitutions in HIV‑1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with a greater number of substitutions. In some subjects harboring zidovudine‑resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.

Cross‑Resistance

Cross‑resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with TAM substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

TAMs are selected by zidovudine and confer cross‑resistance to abacavir, didanosine, stavudine, and tenofovir. Cross‑resistance between lamivudine and zidovudine has not been reported.

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 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 non-metastasizing 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), non-metastasizing 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: 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.

Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

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

The following trial was conducted with the individual components of Lamivudine; Zidovudine; Abacavir .

CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV‑1-infected, therapy‑naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV‑1 RNA 10,000 to 100,000 copies per mL and plasma HIV‑1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median pretreatment CD4+ cell count was 360 cells per mm3, and median plasma HIV-1 RNA was 4.8 log10 copies per mL. Proportions of subjects with plasma HIV‑1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV‑1 MONITOR® Test) through 48 weeks of treatment are summarized in Table 5.


Outcome


ZIAGEN plus Lamivudine/Zidovudine

(n = 262)


Indinavir plus Lamivudine/Zidovudine

(n = 265)


Respondera


49%


50%


Virologic failureb


31%


28%


Discontinued due to adverse reactions


10%


12%


Discontinued due to other reasonsc


11%


10%


a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL.


b Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48.


c Includes consent withdrawn, lost to follow-up, protocol violations, those with missing data, clinical progression, and other.


Treatment response by plasma HIV-1 RNA strata is shown in Table 6.


Screening

HIV1 RNA

(copies/mL)


ZIAGEN plus Lamivudine/Zidovudine

(n = 262)


Indinavir plus Lamivudine/Zidovudine

(n = 265)


<400 copies/mL


n


<400 copies/mL


n


≥10,000 - ≤100,000


50%


166


48%


165


>100,000


48%


96


52%


100


In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir.

Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm3 was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamivudine; Zidovudine; Abacavir is available as tablets. Each tablet contains 300 mg of abacavir as Lamivudine; Zidovudine; Abacavir, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue‑green capsule-shaped, film‑coated, and imprinted with GX LL1 on one side with no markings on the reverse side. They are packaged as follows:

Bottles of 60 tablets (NDC 49702-217-18).

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

17 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 Lamivudine; Zidovudine; Abacavir, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about Lamivudine; Zidovudine; Abacavir. 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 Lamivudine; Zidovudine; Abacavir.
  • that a hypersensitivity reaction can worsen and lead to hospitalization or death if Lamivudine; Zidovudine; Abacavir is not immediately discontinued.
  • to not restart Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir to avoid restarting abacavir.
  • that a hypersensitivity reaction is usually reversible if it is detected promptly and Lamivudine; Zidovudine; Abacavir is stopped right away.
  • that if they have interrupted Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir or any other abacavir‑containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

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 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; Zidovudine; Abacavir if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity .

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 healthcare provider .

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 .

Drug Interactions

Advise patients that other medications may interact with Lamivudine; Zidovudine; Abacavir and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of Lamivudine; Zidovudine; Abacavir .

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; Zidovudine; Abacavir is started .

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 .

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Lamivudine; Zidovudine; Abacavir 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 .

Missed Dose

Instruct patients that if they miss a dose of Lamivudine; Zidovudine; Abacavir, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose .

Availability of Medication Guide

Instruct patients to read the Medication Guide before starting Lamivudine; Zidovudine; Abacavir 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.

COMBIVIR, EPIVIR, RETROVIR, Lamivudine; Zidovudine; Abacavir, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.

Other brands are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2017 the ViiV Healthcare group of companies. All rights reserved.

TRZ:10PI


MEDICATION GUIDE

Lamivudine; Zidovudine; Abacavir® (TRY-zih-veer)

(abacavir, lamivudine, and zidovudine)

tablets


What is the most important information I should know about Lamivudine; Zidovudine; Abacavir?

Lamivudine; Zidovudine; Abacavir can cause serious side effects, including:

  • Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir, call your healthcare provider right away to find out if you should stop taking Lamivudine; Zidovudine; Abacavir.
  •                                                                                      Symptom
  •           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 Lamivudine; Zidovudine; Abacavir because of an allergic reaction, never take Lamivudine; Zidovudine; Abacavir (abacavir, lamivudine and zidovudine) or any other abacavircontaining medicine (EPZICOM ®, TRIUMEQ ® , or ZIAGEN ® ) again.
  • If you have an allergic reaction, dispose of any unused Lamivudine; Zidovudine; Abacavir. Ask your pharmacist how to properly dispose of medicines.
  • If you take Lamivudine; Zidovudine; Abacavir or any other abacavir‑containing medicine again after you have had an allergic reaction, within hours you may get lifethreatening symptoms that may include very low blood pressure or death.
  • If you stop Lamivudine; Zidovudine; Abacavir for any other reason, even for a few days, and you are not allergic to Lamivudine; Zidovudine; Abacavir, talk with your healthcare provider before taking it again. Taking Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.

  • Blood problems. Zidovudine (RETROVIR®), one of the medicines in Lamivudine; Zidovudine; Abacavir, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). These blood cell problems are especially likely to happen in people with advanced human immunodeficiency virus type 1 (HIV-1) disease or AIDS. Your healthcare provider should check your blood cell counts regularly during treatment with Lamivudine; Zidovudine; Abacavir.
  • Muscle pain or weakness (myopathy) can happen during treatment with Lamivudine; Zidovudine; Abacavir. Zidovudine (RETROVIR), one of the medicines in Lamivudine; Zidovudine; Abacavir, can cause muscle pain or weakness when used for a long time.
  • Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take Lamivudine; Zidovudine; Abacavir. 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                                            -  feel cold, especially in your arms and legs

         -  unusual (not normal) muscle pain                           -  feel dizzy or light-headed

         -  trouble breathing                                                     -  have a fast or irregular heartbeat

         -  stomach pain with nausea and vomiting   

  • Serious liver problems can happen in people who take Lamivudine; Zidovudine; Abacavir. 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                  -  loss of appetite for several days or longer

             turns yellow (jaundice)                                           -  nausea

         -  dark or “tea-colored” urine                                     -  pain, aching, or tenderness on the right side

         -  light-colored stools (bowel movements)                     of your stomach area

You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time.

  • Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking Lamivudine; Zidovudine; Abacavir. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease is serious and may lead to death.
  • Do not run out of Lamivudine; Zidovudine; Abacavir. Refill your prescription or talk to your healthcare provider before your Lamivudine; Zidovudine; Abacavir is all gone.
  • Do not stop Lamivudine; Zidovudine; Abacavir without first talking to your healthcare provider.
  • If you stop taking Lamivudine; Zidovudine; Abacavir, 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; Zidovudine; Abacavir and become harder to treat (resistant).
  • Use with interferon and ribavirinbased regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines, and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking Lamivudine; Zidovudine; Abacavir and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms.

What is Lamivudine; Zidovudine; Abacavir?

Lamivudine; Zidovudine; Abacavir is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used alone or with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Lamivudine; Zidovudine; Abacavir contains 3 prescription medicines, abacavir (ZIAGEN), lamivudine (EPIVIR®) and zidovudine (RETROVIR).

Lamivudine; Zidovudine; Abacavir should not be used in children weighing less than 88 pounds (40 kg).


Who should not take Lamivudine; Zidovudine; Abacavir?

Do not take Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir.
  • are allergic to abacavir or any of the ingredients in Lamivudine; Zidovudine; Abacavir. See the end of this Medication Guide for a complete list of ingredients in Lamivudine; Zidovudine; Abacavir.
  • have liver problems.

What should I tell my healthcare provider before taking Lamivudine; Zidovudine; Abacavir?

Before you take Lamivudine; Zidovudine; Abacavir, tell your healthcare provider 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 low blood cell counts (bone marrow problem). Ask your healthcare provider if you are not sure.
  • have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
  • drink alcohol or take medicines that contain alcohol.
  • are pregnant or plan to become pregnant. 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; Zidovudine; Abacavir.
  • 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 Lamivudine; Zidovudine; Abacavir. 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 Lamivudine; Zidovudine; Abacavir.

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; Zidovudine; Abacavir with other medicines.


How should I take Lamivudine; Zidovudine; Abacavir?

  • Take Lamivudine; Zidovudine; Abacavir exactly as your healthcare provider tells you to take it.
  • If you miss a dose of Lamivudine; Zidovudine; Abacavir, 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 Lamivudine; Zidovudine; Abacavir.
  • Lamivudine; Zidovudine; Abacavir may be taken with or without food.
  • Tell your healthcare provider if you or your child has trouble swallowing Lamivudine; Zidovudine; Abacavir tablets.
  • Do not run out of TRZIVIR. 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; Zidovudine; Abacavir, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of Lamivudine; Zidovudine; Abacavir?

  • Lamivudine; Zidovudine; Abacavir can cause serious side effects including:
  • See “What is the most important information I should know about Lamivudine; Zidovudine; Abacavir?”
  • 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; Zidovudine; Abacavir.
  • Changes in body fat can happen in people who take HIV‑1 medicines. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
  • Heart attack (myocardial infarction). Some HIV-1 medicines including Lamivudine; Zidovudine; Abacavir may increase your risk of heart attack.

The most common side effects of Lamivudine; Zidovudine; Abacavir include:

         -  nausea                                                -  weakness or tiredness

         -  headache                                            -  vomiting

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; Zidovudine; Abacavir. For more information, ask your healthcare provider or pharmacist. 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 Lamivudine; Zidovudine; Abacavir?

  • Store Lamivudine; Zidovudine; Abacavir at 59°F to 86°F (15°C to 30°C).

Keep Lamivudine; Zidovudine; Abacavir and all medicines out of the reach of children.


General information for safe and effective use of Lamivudine; Zidovudine; Abacavir.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lamivudine; Zidovudine; Abacavir for a condition for which it was not prescribed. Do not give Lamivudine; Zidovudine; Abacavir 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 Lamivudine; Zidovudine; Abacavir that is written for health professionals.

For more information go to www. TRIZIVIR.com or call 1-877-844-8872.


What are the ingredients in Lamivudine; Zidovudine; Abacavir?

Active ingredients:abacavir, lamivudine, and zidovudine

Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate

Tablet film coating contains: OPADRY® green 03B11434 made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.

  •   Manufactured for:                                              by:
  •   ViiV Healthcare                                                 GlaxoSmithKline
  •   Research Triangle Park, NC 27709                   Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc, Basingstoke, UK

EPIVIR, EPZICOM, RETROVIR, TRIUMEQ, Lamivudine; Zidovudine; Abacavir, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

©2017 the ViiV Healthcare group of companies. All rights reserved.

TRZ:10MG


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


Revised: 03/2017


PRINICIPAL DISPLAY PANEL

NDC 49702-217-18

Lamivudine; Zidovudine; Abacavir®

(abacavir sulfate, lamivudine, and zidovudine)

300 mg 150 mg 300 mg

TABLETS

Each tablet contains Lamivudine; Zidovudine; Abacavir equivalent to 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine.

Store at 25oC (77oF); excursions permitted to 15o to 30oC (59o to 86oF).

Rx only

Notice to Authorized Dispenser:

Each time Lamivudine; Zidovudine; Abacavir is dispensed, give the patient a Medication Guide and Warning Card from the carton.

60 Tablets

©2017 the ViiV Healthcare group of companies

  • 10000000146020 Rev. 4/17
Lamivudine; Zidovudine; Abacavir 60 count carton

Lamivudine; Zidovudine; Abacavir pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Lamivudine; Zidovudine; Abacavir available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Lamivudine; Zidovudine; Abacavir destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Lamivudine; Zidovudine; Abacavir Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Lamivudine; Zidovudine; Abacavir pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ZIAGEN (ABACAVIR SULFATE) TABLET, FILM COATED ZIAGEN (ABACAVIR SULFATE) SOLUTION [VIIV HEALTHCARE COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ZIDOVUDINE TABLET, FILM COATED [LANNETT COMPANY, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."LAMIVUDINE TABLET, FILM COATED [APOTEX CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Lamivudine; Zidovudine; Abacavir?

Depending on the reaction of the Lamivudine; Zidovudine; Abacavir after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Lamivudine; Zidovudine; Abacavir not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Lamivudine; Zidovudine; Abacavir addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Lamivudine; Zidovudine; Abacavir, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Lamivudine; Zidovudine; Abacavir consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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