Ziagen (Abacavir Sulfate) - Side Effects and Adverse Reactions

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 practice.

Adults: 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, ≥5% Frequency) in Therapy-Naive Adults (CNA30024^*) Through 48 Weeks of Treatment

* This study used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 patients in the abacavir group and 3% of 325 patients in the zidovudine group.
† Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.
Adverse Reaction	ZIAGEN plus Lamivudine plus Efavirenz (n = 324)	Zidovudine plus Lamivudine plus Efavirenz (n = 325)
Dreams/sleep disorders	10%	10%
Drug hypersensitivity	9%	<1%â€
Headaches/migraine	7%	11%
Nausea	7%	11%
Fatigue/malaise	7%	10%
Diarrhea	7%	6%
Rashes	6%	12%
Abdominal pain/gastritis/ gastrointestinal signs and symptoms	6%	8%
Depressive disorders	6%	6%
Dizziness	6%	6%
Musculoskeletal pain	6%	5%
Bronchitis	4%	5%
Vomiting	2%	9%

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, ≥5% Frequency) in Therapy-Naive Adults (CNA3005) Through 48 Weeks of Treatment

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 patients 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, patients receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for patients receiving ZIAGEN twice daily. However, patients receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with patients who received ZIAGEN 300 mg twice daily. Five percent (5%) of patients receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of patients receiving ZIAGEN 300 mg twice daily. Two percent (2%) of patients receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the patients 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

ULN = Upper limit of normal.
n = Number of patients assessed.
Grade 3/4 Laboratory Abnormalities	ZIAGEN plus Lamivudine plus Efavirenz (n = 324)	Zidovudine plus Lamivudine plus Efavirenz (n = 325)
Elevated CPK (>4 X ULN)	8%	8%
Elevated ALT (>5 X ULN)	6%	6%
Elevated AST (>5 X ULN)	6%	5%
Hypertriglyceridemia (>750 mg/dL)	6%	5%
Hyperamylasemia (>2 X ULN)	4%	5%
Neutropenia (ANC <750/mm3)	2%	4%
Anemia (Hgb ≤6.9 gm/dL)	<1%	2%
Thrombocytopenia (Platelets <50,000/mm3)	1%	<1%
Leukopenia (WBC ≤1,500/mm3)	<1%	2%

Laboratory abnormalities in CNA3005 are listed in Table 5.

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

ULN = Upper limit of normal.
n = Number of patients assessed.
Grade 3/4 Laboratory Abnormalities	Number of Subjects by Treatment Group
	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%)

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

Pediatric Patients: Therapy-Experienced Pediatric Patients: 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/kg twice daily, lamivudine 4 mg/kg twice daily, and zidovudine 180 mg/m² twice daily compared with lamivudine 4 mg/kg twice daily and zidovudine 180 mg/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, ≥5% Frequency) in Therapy-Experienced Pediatric Patients (CNA3006) Through 16 Weeks of Treatment

Adverse Reaction	ZIAGEN plus Lamivudine plus Zidovudine (n = 102)	Lamivudine plus Zidovudine (n = 103)
Fever and/or chills	9%	7%
Nausea and vomiting	9%	2%
Skin rashes	7%	1%
Ear/nose/throat infections	5%	1%
Pneumonia	4%	5%
Headache	1%	5%

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

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of ZIAGEN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ZIAGEN.

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.