Side Effects of Trizivir (abacavir, lamivudine, zidovudine)

Trizivir (abacavir, lamivudine, zidovudine) is a combination of antiviral medications used for treating infections with the human immunodeficiency virus (HIV).

Anti-HIV drugs are often used in combination to increase HIV suppression and to reduce the chance of the HIV developing resistance to any single drug. Trizivir does not reduce the transmission of HIV among individuals, and it does not cure HIV or AIDS. 

Drug interactions of Trizivir include:

• methadone,
• sorbitol-containing medicines,
• stavudine, doxorubicin,
• nucleoside analogues (e.g., ribavirin),
• ganciclovir,
• interferon alfa,
• and other bone marrow suppressive or cytotoxic agents. 

Tell your doctor if you are pregnant or plan to become pregnant before using Trizivir; it is unknown how it would affect a fetus. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Trizivir during pregnancy. 

Use of Trizivir by nursing women has not been adequately studied. HIV-infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant that is not infected.

What are the common side effects of Trizivir?

Common side effects of Trizivir include: 

• nausea,
• diarrhea,
• vomiting,
• weight loss,
• and difficulty sleeping.

What are the serious side effects of Trizivir?

Serious side effects of Trizivir include:

• hypersensitivity reactions (symptoms include fever, rash, nausea, vomiting, diarrhea, abdominal pain, fatigue, aches, shortness of breath, cough, and sore throat),
• pancreatitis,
• liver failure,
• metabolic disturbance (lactic acidosis),
• decrease in blood cells,
• muscle pain,
• and weakness and nerve damage in the extremities (peripheral neuropathy).

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.

Lamivudine

Sorbitol

Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines.

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

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.
• Lipoatrophy.
• 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 Trizivir. These reactions have been characterized by 2 or more of the following signs or symptoms:

• fever;
• rash;
• gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain);
• constitutional symptoms (including generalized malaise, fatigue, or achiness);
• 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 Trizivir

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.