Frequently Asked Questions

Abacavir Sulfate/Lamivudine/Zidovudine

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n: a-BAK-a-vir SUL-fate/la-MIV-ue-deen/zye-DOE-vue-deen Class: Nucleoside analog reverse transcriptase inhibitor combination

Antiviral combinations


Trade Names

Trizivir
- Tablets abacavir sulfate 300 mg/lamivudine 150 mg/zidovudine 300 mg

Pharmacology

Inhibits replication of HIV by incorporation into HIV DNA and production of incomplete, nonfunctional DNA.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Abacavir

Rapidly absorbed and extensively distributed. Oral bioavailability 86%.

Lamivudine

Rapidly absorbed and extensively distributed. Oral bioavailability 86%.

Zidovudine

Rapidly absorbed and extensively distributed. Oral bioavailability 64%.

Distribution

Abacavir

Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma proteins was independent of concentration. Vd approximately 0.86 L/kg.

Lamivudine

Binding to plasma protein is low. Vd approximately 1.3 L/kg.

Zidovudine

Binding to plasma protein is low. Vd approximately 1.6 L/kg.

Metabolism

In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP-450 enzymes.

Abacavir

The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.

Lamivudine

Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine

Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is 3'-azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV AUC is about 3-fold greater than the zidovudine AUC.

Elimination

Systemic Cl

Abacavir approximately 0.8 L/h/kg; lamivudine approximately 0.33 L/h/kg; zidovudine approximately 1.6 L/h/kg.

Renal Cl

Abacavir approximately 0.007 L/h/kg; lamivudine approximately 0.22 L/h/kg; zidovudine approximately 0.34 L/h/kg.

Elimination half-life

Abacavir approximately 1.45 h; lamivudine 5 to 7 h; zidovudine 0.5 to 3 h.

Food effects

Administration of abacavir/lamivudine/zidovudine with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions.

Indications and Usage

Use alone or in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Contraindications

Patients with hepatic impairment; patients with previously demonstrated hypersensitivity to abacavir or any component of the product; never restart any abacavir-containing product following a hypersensitivity reaction, regardless of HLA-B*570 status.

Dosage and Administration

Adults and Adolescents (at least 40 kg)

PO 1 tablet twice daily.

General Advice

  • May be used alone or in combination with other antiretrovirals.
  • Administer without regard to meals. Administer with food if GI upset occurs.
  • If a dose is missed, administer the missed dose as soon as noted and then administer the next dose at the regularly scheduled time.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Acetaminophen, nelfinavir, rifamycins (eg, rifampin), ritonavir

Zidovudine plasma concentrations may be reduced, decreasing the pharmacologic effects.

Atovaquone, fluconazole, methadone, probenecid, valproic acid

Zidovudine plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Doxorubicin, ribavirin, stavudine

Antagonistic relationship has been demonstrated between these agents and zidovudine.

Ethanol

Abacavir plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Food

When administered with a high-fat meal, the abacavir, lamivudine, and zidovudine C max may be decreased; however, Trizivir may be given with or without food.

Ganciclovir, interferon-alpha, other bone marrow suppressive or cytotoxic agents

May increase the hematologic toxicity of zidovudine.

Methadone

Abacavir may increase methadone Cl, necessitating a dosage increase in some patients.

Phenytoin

Zidovudine Cl may be decreased. Phenytoin levels may increase, decrease, or not change.

Trimethoprim/sulfamethoxazole

Serum concentrations of lamivudine may be elevated, increasing the pharmacologic and adverse reactions.

Zalcitabine

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of each other.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cardiomyopathy (postmarketing).

CNS

Headache (13%); fatigue, malaise (12%); depression (6%); anxiety (5%); dizziness, insomnia and other sleep disorders, paresthesia, peripheral neuropathy, seizures (postmarketing).

Dermatologic

Skin rash (5%); alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria (postmarketing).

EENT

Ear/nose/throat infections (5%).

Endocrine

Gynecomastia (postmarketing).

GI

Nausea (19%); nausea/vomiting (10%); diarrhea (7%); abdominal pain, anorexia, decreased appetite, dyspepsia, oral mucosal pigmentation, stomatitis (postmarketing).

Hematologic-Lymphatic

Anemia, aplastic anemia, lymphadenopathy, splenomegaly, thrombocytopenia (postmarketing).

Hepatic

Elevated bilirubin, elevated transaminases, hepatic steatosis, lactic acidosis, pancreatitis, posttreatment exacerbation of hepatitis (postmarketing).

Lab Tests

Elevated CPK (7%); increased ALT (6%); neutropenia (5%); hyperamylasemia, hypertriglyceridemia (2%).

Metabolic

Body accumulation/fat redistribution, hyperglycemia (postmarketing).

Musculoskeletal

Musculoskeletal pain (5%); arthralgia, muscle weakness, myalgia, rhabdomyolysis (postmarketing).

Respiratory

Viral respiratory infections (5%); abnormal breath sounds/wheezing (postmarketing).

Miscellaneous

Hypersensitivity (8%); fever/chills (6%); anaphylaxis, vasculitis, weakness (postmarketing).

Precautions

Warnings

Intended only for patients whose regimen would otherwise include abacavir, lamivudine, and zidovudine.

Hypersensitivity reactions

Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir. The reaction is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever; (2) rash; (3) GI, including abdominal pain, diarrhea, nausea, or vomiting; (4) constitutional, including achiness, fatigue, or generalized malaise; (5) respiratory, including cough, dyspnea, or pharyngitis. Discontinue Trizivir as soon as a hypersensitivity reaction is suspected. Permanently discontinue Trizivir if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Patients carrying the HLA-B*5710 allele are at a high risk for experiencing a hypersensitivity reaction to abacavir.

Following a hypersensitivity reaction to abacavir, never restart Trizivir or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.

Reintroduction of Trizivir or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions.

Hematologic toxicity

Zidovudine has been associated with hematologic toxicity, including neutropenia and severe anemia. Prolonged zidovudine use has been associated with symptomatic myopathy.

Lactic acidosis and severe hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of nucleoside analogues alone or in combination.

Exacerbations of hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients coinfected with hepatitis B virus (HBV) and HIV who have discontinued lamivudine. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who discontinue Trizivir and are coinfected with HIV and HBV. Initiation of anti–hepatitis B therapy may be warranted.


Monitor

Hematologic

Frequently monitor blood cell counts in patients with advanced HIV disease and in patients receiving combination therapy with Trizivir , interferon alpha, and ribavirin. Periodically monitor blood cell counts in HIV-infected patients with asymptomatic or early HIV disease.

Hepatic

Monitor patients with coinfection with HBV and HIV for posttreatment exacerbations of hepatitis B for several months after stopping treatment. Closely monitor patients receiving combination therapy with Trizivir , interferon alpha, and ribavirin; hepatic decompensation has been reported.

Hypersensitivity reaction

Monitor patient for signs/symptoms of allergic reaction to abacavir. Discontinue use if a sign or symptom in 2 or more of the following groups is noted: fever; rash; GI, including abdominal pain, diarrhea, nausea, or vomiting; constitutional, including achiness, fatigue, or generalized malaise; and respiratory, including cough, dyspnea, or pharyngitis. If hypersensitivity reaction is documented, ensure the reaction is reported to Abacavir Hypersensitivity Registry as noted in the package insert.

Lactic acidosis

Monitor patient for signs/symptoms of lactic acidosis (profound weakness or tiredness; unexpected stomach discomfort; feeling cold, dizzy, or light-headed; slow or irregular heartbeat). Withhold drug if suspected.


Pregnancy

Category C .

Lactation

HIV-infected mothers should not breast-feed their infants.

Abacavir

Undetermined.

Lamivudine and zidovudine

Excreted in breast milk.

Children

Not intended for use in children. Do not administer to adolescents who weigh less than 40 kg (88 lb) because it is a fixed-dose tablet that cannot be adjusted for this population.

Elderly

Use with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity.

Hypersensitivity

Fatal hypersensitivity reactions have been associated with abacavir use and have occurred within hours after reintroduction of abacavir in patients who have no identified history or unrecognized symptoms of hypersensitivity.

Renal Function

Because this is a fixed-dose combination, do not use for patients requiring dose adjustments (eg, CrCl less than 50 mL/min).

Hepatic Function

Contraindicated in patients with impaired hepatic function because this is a fixed-dose combination that cannot be adjusted for hepatically impaired patients.

Bone marrow suppression

Use with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm 3 or Hgb less than 9.5 g/dL.

Fat redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance have been reported. Mechanism and long-term consequences of these events is unknown.

Fixed-dose combination

Contains abacavir, lamivudine, and zidovudine in a fixed-dose tablet. Ensure patient is not receiving abacavir, lamivudine, or zidovudine in any other doseforms. Because the dose cannot be adjusted, do not administer to patients who weigh less than 40 kg or other patients who may require a dose adjustment (eg, dose-related toxicity, hepatic or renal impairment).

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

MI

Use of abacavir within the 6 months prior to combined antiretroviral therapy may increase the risk of MI.

Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine.

Posttreatment exacerbations of hepatitis

In patients treated with lamivudine for chronic HBV, there is clinical and laboratory evidence of hepatitis exacerbations after discontinuation of lamivudine.

Therapy-experienced patients

Patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who have HIV-1 isolates containing multiple mutations conferring NRTI resistance have limited response to abacavir. Thus, potential cross-resistance between abacavir and other NRTIs should be considered when selecting new regimens for therapy-experienced patients.

Overdosage

Symptoms

Confusion, dizziness, drowsiness, headache, lethargy, nausea, vomiting.

Patient Information

  • Caution patient not to take any other HIV medications that contain abacavir, lamivudine, or zidovudine.
  • Advise patient to review Medication Guide before starting therapy and to read and check for new information each time the medication is refilled.
  • Advise patient to review, and carry with them at all times, the Warning Card summarizing the symptoms of abacavir hypersensitivity reaction.
  • Advise patient that this drug may be used alone or in combination with other HIV medications. Instruct patient taking other HIV medications to continue to take them as prescribed by health care provider.
  • Instruct patient to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Instruct patient to take 1 tablet twice daily without regard to meals but to take with food if stomach upset occurs.
  • Instruct patient to discontinue use and notify health care provider immediately if 2 or more of the following symptoms occur: (1) fever; (2) rash; (3) diarrhea, nausea, stomach area pain, or vomiting; (4) achiness, extreme tiredness, or generalized body discomfort; (5) cough, shortness of breath, or sore throat.
  • Caution patient not to restart this medication or any other abacavir-containing medication if they experience a hypersensitivity reaction to this medication. Explain to patient that restarting abacavir or an abacavir-containing product could cause a more serious, and possibly fatal, reaction.
  • Caution patient that if therapy is interrupted for a few days for reasons other than a hypersensitivity reaction (eg, interruption in drug supply) and is then restarted, there is a risk of experiencing a serious or fatal hypersensitivity reaction. Advise patient to talk with health care provider before restarting the medication on their own. Advise patient that if health care provider tells them they can take the medication again, to start taking it when they are around medical help or people who can call a health care provider if necessary.
  • Caution patient that medication can cause a rare but serious condition called lactic acidosis with liver enlargement, and that profound weakness or tiredness; unexpected stomach discomfort; feeling cold, dizzy, or light-headed; or slow or irregular heartbeat may be symptoms of this condition. Instruct patient to immediately inform health care provider if these symptoms develop.
  • Caution patient who has concurrent infection with HBV that their hepatitis may worsen if therapy is stopped and that their liver function should be followed closely for several months after stopping the medication. Advise patient that they may need to begin taking anti-HBV medications.
  • Advise patient that medication may cause changes in body fat distribution (eg, increased amount of fat in upper back and neck, breasts, and around the back, chest, and stomach area; loss of fat from arms, legs, and face) and that the cause and long-term health effects of these changes are not known at this time. Advise patient to report changes in body fat distribution to health care provider.
  • Advise patient that long-term use can cause muscle weakness and to report this to health care provider immediately if noted or suspected.
  • Inform patient that drug does not completely eliminate HIV virus and does not reduce the risk of transmitting HIV to others through sexual contact or blood contamination. Instruct patient that appropriate precautions must still be followed.
  • Advise patient that drug is not a cure for HIV infection and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections, and that they should remain under a health care provider's care.
  • Instruct mother not to breast-feed her infant because of the risk of transmitting the HIV virus to the infant and the potential for serious adverse reactions from medication transmitted to her infant through breast milk.

Copyright © 2009 Wolters Kluwer Health.

Not all side effects for abacavir / lamivudine / zidovudine may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to abacavir / lamivudine / zidovudine: oral tablet

In addition to its needed effects, some unwanted effects may be caused by abacavir / lamivudine / zidovudine. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking abacavir / lamivudine / zidovudine:

More common
  • Chills
Less common
  • Abdominal or stomach pain
  • cough
  • diarrhea
  • fever
  • headache
  • muscle weakness
  • nausea
  • numbness or tingling of the face, feet, or hands
  • pain in the joints
  • pain in the muscles
  • pale skin
  • shortness of breath
  • skin rash
  • sore throat
  • swelling of the feet or lower legs
  • swelling of the feet or lower legs
  • unusual feeling of discomfort or illness
  • unusual tiredness or weakness
  • vomiting
  • yellow eyes or skin
Rare
  • Black, tarry stools
  • blood in the urine or stools
  • pinpoint red spots on the skin
  • unusual bleeding or bruising

Some of the side effects that can occur with abacavir / lamivudine / zidovudine may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Bone pain
  • loss of appetite
  • sleeplessness
  • trouble sleeping

For Healthcare Professionals

Applies to abacavir / lamivudine / zidovudine: oral tablet

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

Dermatologic

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.[Ref]

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.[Ref]

Hematologic

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

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.[Ref]

References

1. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). NIH. National Institutes of Health "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: URL: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf." ([2011 Oct 14]):

2. "Product Information. Combivir (lamivudine-zidovudine)" Glaxo Wellcome, Research Triangle PK, NC.

3. Brinkman K, terHofstede HJM, Burger DM, Smeitinkt JAM, Koopmans PP "Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway." AIDS 12 (1998): 1735-44

4. Toerner JG, Cvetkovich T "Kawasaki-like Syndrome: Abacavir Hypersensitivity?" Clin Infect Dis 34 (2002): 131-2

5. "Product Information. Trizivir (abacavir / lamivudine / zidovudine)" Glaxo Wellcome, Research Triangle Pk, NC.

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