Trizivir Side Effects

Please note - some side effects for Trizivir 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 Trizivir - for the Consumer

Trizivir

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 Trizivir:

Decreased appetite; diarrhea; headache; joint or muscle pain; nausea; nervousness; tiredness; vomiting; weakness.

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

Severe allergic reactions (fever; rash; tiredness; achiness; nausea; diarrhea; vomiting; stomach pain; sore throat; hives; itching; difficulty breathing; cough; tightness in the chest; swelling of the mouth, face, lips, or tongue); dark urine; depression; excess hunger, thirst, or urination; fainting; fast, shallow breathing; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; mouth ulcers; numbness, tingling, or pain in the hands and feet; pale stools; red, swollen, blistered, or peeling skin; severe or persistent muscle pain, weakness, or cramping; swollen lymph nodes; unusual tiredness or weakness; yellowing of the skin or eyes.

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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Trizivir Side Effects - for the Professional

Trizivir

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

• Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.2)].
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.3)].
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.4)].
• Acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.5)].
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [Warnings and Precautions (5.6)].
• Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)].
• Immune reconstitution syndrome [see Warnings and Precautions (5.7)].
• Fat redistribution [see Warnings and Precautions (5.8)].
• Myocardial infarction [see Warnings and Precautions (5.9)].

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared with rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

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, ≥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 subjects receiving abacavir in study 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 study CNA3005 are listed in Table 2.

Table 2. Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in Study CNA3005

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%)
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.

Postmarketing Experience

In addition to adverse reactions reported from clinical studies, the following reactions have been identified during postmarketing use of abacavir, lamivudine, and/or zidovudine. 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 abacavir, lamivudine and/or zidovudine.

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 [see Warnings and Precautions (5.8)].

Cardiovascular: Cardiomyopathy.

Digestive: Stomatitis.

Endocrine and Metabolic: Gynecomastia, hyperglycemia.

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 [see Warnings and Precautions (5.4)], elevated bilirubin, elevated transaminases, posttreatment exacerbation of hepatitis B [see Warnings and Precautions (5.5)].

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Arthralgia, myalgia, muscle weakness, CPK elevation, 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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Side Effects by Body System - for Healthcare Professionals

General

The adverse effects are sometimes difficult to distinguish from the symptomatology observed during the clinical course of AIDS, as well as from the possible adverse effects of other drugs used in the treatment of HIV infection. Many of the side effects associated with nucleoside reverse transcriptase inhibitor therapy (myopathy, pancreatitis, liver failure, lactic acidosis, etc.) are attributable to their direct toxic effect on mitochondria which causes decreased mitochondrial energy-generating capacity.

Hypersensitivity

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.

Hypersensitivity side effects associated with abacavir 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), fatigue, nausea, vomiting, diarrhea, abdominal pain, pharyngitis, malaise, achiness, 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. Hypersensitivity reaction (Grades 2 to 4; 8%) has been reported when abacavir was administered with lamivudine and zidovudine. Sensitization reactions (including anaphylaxis) and urticaria have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Gastrointestinal

Gastrointestinal side effects of at least moderate intensity have included nausea (19%), nausea and vomiting (10%), and diarrhea (7%) when abacavir was administered with lamivudine and zidovudine. Abdominal cramps have been reported. Oral ulcerations and lesions have been observed with the use of lamivudine and flatulence has been reported with the use of zidovudine. Pancreatitis was observed in the expanded access program. Abdominal pain, anorexia and/or decreased appetite, pancreatitis, oral mucosal pigmentation, stomatitis, and dyspepsia have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Hepatic

Severe acute exacerbations of hepatitis, including fatalities, have been reported in patients coinfected with hepatitis B virus and HIV-1 who have discontinued antihepatitis B therapy, including lamivudine. The causal relationship to stopping lamivudine treatment is unknown.

Hepatic side effects have included elevated ALT (greater than 5 times ULN; 6%) and liver function test abnormalities when abacavir was administered with lamivudine and zidovudine. The reported frequencies were similar to those observed during clinical trials with zidovudine and lamivudine administration. One patient with preexisting hepatitis B developed acute hepatic failure two weeks after starting zidovudine therapy. 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. Hepatic decompensation, sometimes fatal, has been reported in patients coinfected with HIV-1 and hepatitis C virus who were receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Lactic acidosis and hepatic steatosis, elevated bilirubin, elevated transaminases, and posttreatment exacerbations of hepatitis B have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Nervous system

Nervous system side effects of at least moderate intensity have included headache (13%) when abacavir was administered with lamivudine and zidovudine. Generalized seizures, status epilepticus, confusion, paresthesia, somnolence, vertigo, and Wernicke's syndrome have been reported, although rarely, with the use of zidovudine. Insomnia and other sleep disorders, paresthesia, peripheral neuropathy, seizures, and dizziness have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Other

Other side effects of at least moderate intensity have included malaise and fatigue (12%), fever and/or chills (6%), and non-site-specific pain (less than 1%) when abacavir was administered with lamivudine and zidovudine. Weakness has been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Metabolic

Metabolic side effects have included elevated creatine phosphokinase (greater than 4 times ULN; 7%), hypertriglyceridemia (greater than 750 mg/dL; 2%), hyperamylasemia (greater than 2 times ULN; 2%), and hyperglycemia (greater than 13.9 mmol/L; less than 1%). 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. Although progressive subcutaneous fat wasting has been attributed to the use of protease inhibitors, nucleoside reverse transcriptase inhibitors may have an independent contribution. Hyperglycemia and redistribution/accumulation of body fat have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Progressive subcutaneous fat wasting has been observed in patients naive to protease inhibitors, however, not to the same degree as in patients on a combination regimen that includes a protease inhibitor.

Dermatologic

Dermatologic side effects of at least moderate intensity have included skin rashes (5%) when abacavir was administered with lamivudine and zidovudine. Hair loss has been associated with lamivudine therapy in a few patients. Several cases of nailbed hyperpigmentation have been associated with zidovudine. Leukocytoclastic vasculitis with eosinophilia and fever has also been reported with the use of zidovudine. Rash and Sweet's syndrome have been reported with abacavir. Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported during postmarketing experience with abacavir. Alopecia, erythema multiforme, and Stevens-Johnson syndrome have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Bluish or brownish-black discoloration of nails has developed during the first month or two of zidovudine therapy and usually disappeared within 2 months if the drug was discontinued. Discoloration has occurred as longitudinal streaks or transverse bands.

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.

Hematologic

Zidovudine has been associated with hematologic toxicity (including neutropenia and severe anemia), particularly in patients with advanced HIV-1 disease. Abacavir/lamivudine/zidovudine should be used with caution in patients with bone marrow suppression indicated by granulocyte count below 1000 cells/mm3 or hemoglobin less than 9.5 g/dL. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease treated with abacavir/lamivudine/zidovudine. Periodic blood counts are recommended for HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease.

Hematologic side effects have included neutropenia (less than 750/mm3; 5%) when abacavir was administered with lamivudine and zidovudine. 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. Hematologic toxicity (including neutropenia and severe anemia) has been reported with zidovudine. Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, thrombocytopenia, and splenomegaly have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Musculoskeletal

In one zidovudine study, myalgias and elevated creatine phosphokinase occurred in 8% of treated patients with a CD4 cell count less than 200/mm3, and in none of the patients with higher CD4 cell counts. Dosage reduction has not affected the course of myopathy, although drug discontinuation sometimes resulted in improvement of symptoms, generally within a month. Muscle biopsy has shown atrophic and sometimes necrotic fibers, ragged-red fibers, and large accumulations of mitochondrial and fibrillar sarcoplasmic inclusions.

Musculoskeletal side effects of at least moderate intensity have included musculoskeletal pain (5%) when abacavir was administered with lamivudine and zidovudine. Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine. Myalgia, arthralgia, muscle weakness, creatine phosphokinase elevation, and rhabdomyolysis have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Psychiatric

Psychiatric side effects of at least moderate intensity have included depressive disorders (6%), anxiety (5%), and worsening of preexisting depression when abacavir was administered with lamivudine and zidovudine. Other psychiatric side effects reported with the use of zidovudine have included isolated cases of mania, anxiety, and grandiosity.

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 with lamivudine and zidovudine. 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. The emergence of lamivudine-resistant hepatitis B virus (HBV) has been reported in HIV-1-infected patients who were treated with lamivudine-containing regimens in the presence of coinfection with HBV.

Cardiovascular

Cardiovascular side effects have included rare cases of reversible congestive heart failure, syncope, and vasodilation with zidovudine. Myocardial infarction has been reported during postmarketing experience with abacavir. Cardiomyopathy and vasculitis have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

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.

Respiratory

Respiratory side effects have included nasal symptoms and cough in patients treated with lamivudine and zidovudine simultaneously. Abnormal breath sounds/wheezing have been reported during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

Genitourinary

Genitourinary side effects have included gynecomastia during postmarketing experience with abacavir, lamivudine, and/or zidovudine.

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 with lamivudine and zidovudine.

Ocular

Ocular side effects have included a case of macular edema deemed definitively associated with zidovudine in a patient with a history of anterior uveitis secondary to syphilis.

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