Ziagen (abacavir) Side Effects, Warnings, and Drug Interactions

Ziagen (abacavir) is a type of oral antiviral medication called a reverse transcriptase inhibitor used to treat infections with human immunodeficiency virus (HIV). Ziagen does not kill existing HIV virus, and it is not a cure for HIV.

Common side effects of Ziagen include:

• nausea,
• vomiting,
• headache,
• fatigue,
• allergic reactions,
• diarrhea,
• loss of appetite,
• difficulty sleeping,
• muscle pain,
• increased triglyceride levels,
• rash,
• anxiety,
• depression,
• and fever.

Serious side effects of Ziagen include:

• severe allergic reactions (symptoms include skin rash, fever, weakness, swelling and difficulty breathing),
• pancreatitis,
• liver failure,
• and metabolic disturbance (lactic acidosis). 

Drug interactions of Ziagen include alcohol. Use of Ziagen during pregnancy has not been adequately evaluated. It is not known whether Ziagen is excreted in breast milk. HIV infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant that is not infected.

The most common side effects are:

• nausea,
• vomiting,
• headache,
• fatigue,
• allergic reactions,
• diarrhea,
• loss of appetite,
• difficulty sleeping,
• muscle pain,
• increased triglyceride levels,
• rash,
• anxiety,
• depression, and
• fever.

The most serious side effects are:

• severe allergic reactions,
• pancreatitis,
• liver failure,
• and metabolic disturbance (lactic acidosis).

Symptoms of an allergic reaction include:

• skin rash,
• fever,
• weakness,
• swelling
• and difficulty breathing.

Abacavir must be stopped as soon an allergic reaction is suspected, and it should not be restarted after an allergic reaction.

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

• Serious and sometimes fatal hypersensitivity reactions.
• Lactic acidosis and severe hepatomegaly with steatosis.
• Immune reconstitution syndrome.
• Fat redistribution.
• Myocardial infarction.

Clinical Trials Experience In Adult Subjects

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. 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 Ziagen

Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with Ziagen 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.

Table 2: 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 (CNA30024^a) through 48 Weeks of Treatment

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with Ziagen 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 3.

Table 3: 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 Ziagen in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.

Ziagen Once Daily versus Ziagen Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with Ziagen 600 mg once daily or Ziagen 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar.

For hypersensitivity reactions, subjects receiving Ziagen once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving Ziagen twice daily. However, subjects receiving Ziagen 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received Ziagen 300 mg twice daily.

Five percent (5%) of subjects receiving Ziagen 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving Ziagen 300 mg twice daily. Two percent (2%) of subjects receiving Ziagen 600 mg once daily had severe diarrhea while none of the subjects receiving Ziagen 300 mg twice daily had this event.

Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with Ziagen 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.

Table 4: Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment

Laboratory abnormalities in CNA3005 are listed in Table 5.

Table 5: Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005

The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.

Clinical Trials Experience In Pediatric Subjects

Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing)

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with Ziagen 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m² twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m² twice daily from CNA3006 are listed in Table 6.

Table 6: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment

Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving Ziagen (CNA3006) as compared with adult subjects (CNA30024).

Other Adverse Events

In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.

Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of Ziagen was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Ziagen. 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 exposures.

Body as a Whole

Redistribution/accumulation of body fat.

Cardiovascular

Myocardial infarction.

Hepatic

Lactic acidosis and hepatic steatosis.

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.

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.