Ziagen Side Effects

Please note - some side effects for Ziagen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Ziagen - for the Consumer

Ziagen

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Ziagen:

Headache; lack of energy; mild nausea; tiredness; trouble sleeping; unusual dreams; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Ziagen:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); burning, numbness, or tingling of the skin; change in the amount of urine produced; chest pain or discomfort, numbness of an arm or leg, or sudden vision changes; ear pain; eye pain, redness, or swelling; fainting; fever or chills; general feeling of being unwell; mental or mood changes (eg, depression); mouth sores; red, swollen, blistered, or peeling skin; severe or persistent dizziness; severe or persistent nausea, vomiting, or diarrhea; shortness of breath, cough, or sore throat; stomach pain; swollen lymph nodes; symptoms of lactic acidosis (eg, fast breathing; muscle pain; unusual cold feeling in the arms or legs; sluggishness; unusual drowsiness, dizziness, or lightheadedness); symptoms of liver problems (eg, yellowing of the skin or eyes, dark urine, pale stools, loss of appetite, severe or persistent tiredness); unusual achiness or swelling.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Ziagen Solution

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Ziagen Solution:

Headache; lack of energy; mild nausea; tiredness; trouble sleeping; unusual dreams; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Ziagen Solution:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); burning, numbness, or tingling of the skin; change in the amount of urine produced; chest pain or discomfort, numbness of an arm or leg, or sudden vision changes; ear pain; eye pain, redness, or swelling; fainting; fever or chills; general feeling of being unwell; mental or mood changes (eg, depression); mouth sores; red, swollen, blistered, or peeling skin; severe or persistent dizziness; severe or persistent nausea, vomiting, or diarrhea; shortness of breath, cough, or sore throat; stomach pain; swollen lymph nodes; symptoms of lactic acidosis (eg, fast breathing; muscle pain; unusual cold feeling in the arms or legs; sluggishness; unusual drowsiness, dizziness, or lightheadedness); symptoms of liver problems (eg, yellowing of the skin or eyes, dark urine, pale stools, loss of appetite, severe or persistent tiredness); unusual achiness or swelling.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Ziagen Side Effects - for the Professional

Ziagen

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

• Serious and sometimes fatal hypersensitivity reaction. In one study, once-daily dosing of abacavir was associated with more severe hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].
• Lactic acidosis and severe hepatomegaly [see Boxed Warning, Warnings and Precautions (5.2)].
• Immune reconstitution syndrome [see Warnings and Precautions (5.3].
• Fat redistribution [see Warnings and Precautions (5.4].
• Myocardial infarction [see Warnings and Precautions (5.5)].

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 (CNA30024a) Through 48 Weeks of Treatment

a 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.
b 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%b
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.

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Side Effects by Body System - for Healthcare Professionals

General

Patients receiving once-daily abacavir had a significantly higher incidence of severe hypersensitivity reactions and severe diarrhea than patients on the twice-daily regimen.

Hypersensitivity

Hypersensitivity side effects have included serious and sometimes fatal hypersensitivity reactions. Frequently observed signs and symptoms have included, but were not limited to, fever, skin rash (maculopapular, urticarial, or variable appearance), malaise, fatigue, achiness, nausea, vomiting, diarrhea, abdominal pain, pharyngitis, dyspnea, and cough. Other symptoms of abacavir hypersensitivity have included lethargy, myolysis, edema, abnormal chest X-ray (infiltrates), paresthesia, anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, death, lymphadenopathy, mucous membrane lesions (conjunctivitis and stomatitis), elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia. Drug hypersensitivity (Grades 2 to 4; 9%) and hypersensitivity reaction (Grades 2 to 4; 8%) have been reported when abacavir was administered in combination with other antiretrovirals. There has been at least one report of abacavir hypersensitivity reaction presenting as acute fibrinous and organizing pneumonia.

In one case report a 57-year-old HIV positive male presented to medical attention with a 2-day history of fever, malaise, and diarrhea related to initiation of abacavir. Six days prior to the onset of symptoms the patient's antiretroviral therapy was switched from efavirenz and lamivudine-zidovudine to zidovudine, abacavir, and lopinavir-ritonavir after a drop in his CD4 cell count. The patient developed acute dyspnea and severe hypoxemia, hemoptysis, and diffuse bilateral pulmonary infiltrates within 72 hours of admission and abacavir was discontinued due to suspicion of a hypersensitivity reaction. Three days following discontinuation of abacavir the patient's status improved and chest films showed resolution of infiltrates.

Abacavir hypersensitivity is a clinical syndrome affecting multiple organs generally characterized by a sign or symptom in two or more of the following groups:
(1) Fever
(2) Rash
(3) Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)
(4) Constitutional (including generalized malaise, fatigue, or achiness)
(5) Respiratory (including dyspnea, cough, or pharyngitis)

A strong predictor of hypersensitivity reaction may be the presence of human leukocyte antigen subtype B*5701 (HLA-B*5701). Analyzing past studies, patients testing positive for the HLA-B*5701 allele had a greater risk (61% to about 70%) of developing hypersensitivity reactions with abacavir, while patients without the HLA-B*5701 allele had a low risk (less than 1% to 4%); therefore, screening for the HLA-B*5701 allele is recommended prior to starting abacavir treatment. Therapy with an abacavir-containing regimen is not recommended for HLA-B*5701-positive patients and should be considered only with close medical supervision under exceptional conditions where potential benefit outweighs the risk. Considerably less frequently, HLA-B*5701-negative patients may experience hypersensitivity reaction with abacavir.

Abacavir should be permanently discontinued as soon as a hypersensitivity reaction is suspected. Severe or fatal hypersensitivity reactions can also occur within hours after restarting abacavir in patients who have no identified history or unrecognized symptoms of this reaction. It should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible, to minimize the risk of a life-threatening hypersensitivity reaction.

Hepatic

Hepatic side effects have included elevated ALT (greater than 5 times ULN; 6%) and AST (greater than 5 times ULN; up to 6%) when abacavir was administered in combination with other antiretrovirals. The reported frequencies were similar to those observed during clinical trials with zidovudine and lamivudine administration. Increased gamma-glutamyltransferase was observed in the expanded access program. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretroviral agents. Lactic acidosis and hepatic steatosis have been reported during postmarketing experience.

Gastrointestinal

Gastrointestinal side effects of at least moderate intensity have included nausea (up to 19%), nausea and vomiting (10%), diarrhea (7%), abdominal pain/gastritis/gastrointestinal signs and symptoms (6%), and vomiting (2%) when abacavir was administered in combination with other antiretrovirals. Loss of appetite/anorexia has been reported. Pancreatitis was observed in the expanded access program.

Nervous system

Nervous system side effects of at least moderate intensity have included headache (13%), headaches/migraine (7%), and dizziness (6%) when abacavir was administered in combination with other antiretrovirals. Insomnia and other sleep disorders have been reported.

Other

In one case report, a 31-year-old HIV-infected male patient switched to abacavir and experienced a disulfiram-like reaction with nausea, facial flushing, and tachycardia following alcohol consumption. When the patient was rechallenged with a shot of vodka, the same reaction occurred.

In another case, a 27-year-old HIV-infected male patient switched to abacavir and noticed reduced alcohol tolerance. The patient reported that he felt as if he had ingested 1.5 bottles of wine following 3 glasses, with loss of memory until the next morning and vomiting. The patient was able to tolerate small quantities of alcohol or alcohol consumed with food.

Other side effects of at least moderate intensity have included malaise and fatigue (12%), fatigue/malaise (7%), fever and/or chills (6%), and non-site-specific pain (less than 1%) when abacavir was administered in combination with other antiretrovirals. Asthenia, reduced alcohol tolerance, and disulfiram-like reaction have been reported.

Psychiatric

Psychiatric side effects of at least moderate intensity have included dreams/sleep disorders (10%), depressive disorders (6%), and anxiety (5%) when abacavir was administered in combination with other antiretrovirals. Mania, worsening of preexisting depression, and lethargy have been reported.

Dermatologic

Dermatologic side effects of at least moderate intensity have included rashes (6%) and skin rashes (5%) when abacavir was administered in combination with other antiretrovirals. Sweet's syndrome has been reported. Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported during postmarketing experience.

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. Due to overlap of clinical signs and symptoms between abacavir hypersensitivity and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be permanently discontinued in such cases.

Metabolic

Metabolic side effects have included mild elevations of blood glucose, elevated creatine phosphokinase (greater than 4 times ULN; up to 8%), hypertriglyceridemia (greater than 750 mg/dL; up to 6%), hyperamylasemia (greater than 2 times ULN; up to 4%), and hyperglycemia (greater than 13.9 mmol/L; less than 1%). At least one case of hypoglycemia has been reported. Redistribution and/or accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients taking antiretroviral agents; however, a causal relationship has not been established. Redistribution/accumulation of body fat has been reported during postmarketing experience.

Hematologic

Hematologic side effects have included neutropenia (ANC less than 750/mm3; up to 5%), thrombocytopenia (platelets less than 50,000/mm3; 1%), anemia (Hgb 6.9 g/dL or less; less than 1%), and leukopenia (WBC 1500/mm3 or less; less than 1%) when abacavir was administered in combination with other antiretrovirals. The reported frequencies were similar to those observed during clinical trials with zidovudine and lamivudine administration. Agranulocytosis has been reported after the addition of abacavir to a multi-drug regimen. Rarely, eosinophilia has been reported.

Musculoskeletal

Musculoskeletal side effects of at least moderate intensity have included musculoskeletal pain (up to 6%).

Immunologic

Immunologic side effects of at least moderate intensity have included ear/nose/throat infections (5%) and viral respiratory infections (5%) when abacavir was administered in combination with other antiretrovirals. Immune reconstitution syndrome has been reported. Autoimmune disorders (e.g., Graves' disease, polymyositis, and Guillain-Barre syndrome) have been reported in the setting of immune reconstitution.

Respiratory

Respiratory side effects of at least moderate intensity have included bronchitis (4%) when abacavir was administered in combination with other antiretrovirals. Tachypnea, cough, and pharyngitis have also been reported.

Cardiovascular

Cardiovascular side effects have included myocardial infarction during postmarketing experience.

A study investigating the frequency of myocardial infarction (MI) in patients taking combination antiretroviral treatment showed an increased risk of MI with the use of abacavir within the previous 6 months; however, these results are not conclusive. The manufacturer reviewed its own clinical study databases and although the results of the analysis are inconclusive, they did not show an excess risk of MI. A meta-analysis conducted by the FDA showed no statistically significant difference in MI events between patients who received abacavir and those who did not.

Renal

Renal side effects of at least moderate intensity have included renal signs/symptoms (not specified) in less than 1% of patients when abacavir was administered in combination with other antiretrovirals. Acute renal failure and interstitial nephritis have been reported.

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