Abacavir Sulfate

Name: Abacavir Sulfate

Interactions for Abacavir Sulfate

Abacavir not metabolized by CYP isoenzymes1 and does not inhibit CYP3A4, 2C9, or 2D6.1 Interactions with drugs metabolized by these CYP isoenzymes unlikely.1

The following drug interactions are based on studies using abacavir.1 Drug interaction studies not performed using abacavir/lamivudine, abacavir/dolutegravir/lamivudine, or abacavir/lamivudine/zidovudine.228 229 240 When fixed combinations used, consider interactions associated with each drug in the fixed combination.228 229 240

Specific Drugs

Drug

Interaction

Comments

Alcohol

Increased abacavir AUC and half-life; no effect on alcohol concentrations1

Although common metabolic pathways are involved, clinically important interaction not expected1

Atazanavir

No in vitro evidence of antagonistic antiretroviral effects203

Darunavir

Pharmacokinetic interactions not expected204

No in vitro evidence of antagonistic antiretroviral effects203

Delavirdine

Pharmacokinetic interactions unlikely45 46

Didanosine

No in vitro evidence of antagonistic antiretroviral effects1

Dolutegravir

No in vitro evidence of antagonistic antiretroviral effects236

Efavirenz

Pharmacokinetic interactions unlikely45 46

In vitro evidence of additive antiretroviral effects 213

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Clinically important interactions with abacavir not expected177

Elvitegravir

Elvitegravir, ritonavir-boosted elvitegravir, or cobicistat-boosted elvitegravir: No clinically important interactions with abacavir242

No in vitro evidence of antagonistic antiretroviral effects242

Emtricitabine

No in vitro evidence of antagonistic antiretroviral effects 1

Etravirine

No in vitro evidence of antagonistic antiretroviral effects214

Fosamprenavir

Pharmacokinetic interaction unlikely205

In vitro evidence of synergistic antiretroviral effects205

Lamivudine

No clinically important pharmacokinetic interactions1 63 229

No in vitro evidence of antagonistic antiretroviral effects1

Ledipasvir and sofosbuvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Clinically important interactions with abacavir not expected181

Lopinavir and ritonavir

Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Possible decreased abacavir concentrations207

Clinical importance unknown207

Maraviroc

No in vitro evidence of antagonistic antiretroviral effects224

Methadone

Increased clearance of methadone;1 no effect on abacavir pharmacokinetics1

Experts state dosage adjustments not necessary;200 manufacturer of abacavir states an increase in methadone dosage may be required in a small number of patients1

Nelfinavir

In vitro evidence of synergistic antiretroviral effects208

Nevirapine

Pharmacokinetic interactions unlikely45 46

No in vitro evidence of antagonistic antiretroviral effects1

Raltegravir

In vitro evidence of additive or synergistic antiretroviral effects225

Ribavirin

No in vitro effect on antiretroviral activity of abacavir against HIV-11

Rilpivirine

Pharmacokinetic interaction not expected226

No in vitro evidence of antagonistic antiretroviral effects226

Simeprevir

Clinically important interaction with abacavir not expected187

Stavudine

No in vitro evidence of antagonistic antiretroviral effects1

Tenofovir

Pharmacokinetic interactions unlikely221

No in vitro evidence of antagonistic antiretroviral effects1

Tipranavir

Ritonavir-boosted tipranavir: Decreased abacavir AUC200 211

In vitro evidence of additive antiretroviral effects211

Appropriate dosages for concomitant use with respect to safety and efficacy not established200 211

Zidovudine

No clinically important pharmacokinetic interactions1 63 229

No in vitro evidence of antagonistic antiretroviral effects1

Actions and Spectrum

  • Abacavir is a carbocyclic NRTI.1 2 3 4 46

  • Pharmacologically related to, but structurally different from, other NRTIs (e.g., didanosine, emtricitabine, lamivudine, stavudine, zidovudine); also differs pharmacologically and structurally from other currently available antiretrovirals.1 200

  • A prodrug that is inactive until converted intracellularly to carbovir triphosphate.1 2 3 4

  • Active in vitro against HIV-1 and HIV-2.1 2 Has some in vitro activity against HBV and cytomegalovirus (CMV), but is inactive against other human viruses tested, including herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus, and influenza virus type A.2

  • Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1

  • HIV-1 with reduced susceptibility to abacavir have been produced in vitro1 2 4 6 and have emerged during therapy with the drug.1 2 6 16 60 61

  • Abacavir-resistant HIV may be cross-resistant to some other NRTIs (e.g., didanosine, emtricitabine, lamivudine, stavudine, tenofovir).1 4 6 16 49 HIV isolates highly resistant to multiple NRTIs also have reduced susceptibility to abacavir.6 16

Advice to Patients

  • Medication guide and warning card must be provided to the patient each time abacavir or fixed combination containing abacavir is dispensed.1 228 229 240 Medication guide and warning card include information on symptoms of abacavir hypersensitivity reactions.1 228 229 240

  • Importance of patient reading the medication guide and warning card prior to initiating therapy and each time prescription is refilled;1 228 229 240 importance of carrying the warning card.1 228 229 240

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 228 229 240 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 228 229 240

  • Importance of using abacavir in conjunction with other antiretroviralsnot for monotherapy.1 228 229 240 Abacavir/lamivudine used in conjunction with other antiretrovirals;228 abacavir/dolutegravir/lamivudine used alone as a complete treatment regimen or in conjunction with other antiretrovirals;240 abacavir/lamivudine/zidovudine used alone as a complete treatment regimen or in conjunction with other antiretrovirals.229

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 228 229 240

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.226

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

  • Possibility of potentially fatal hypersensitivity reactions to abacavir.1 228 229 240 Discontinue the drug and consult clinicians immediately if signs or symptoms of hypersensitivity, including fever, rash, GI symptoms (nausea, vomiting, diarrhea, abdominal pain), constitutional symptoms (generalized fatigue, malaise, achiness), or respiratory symptoms (sore throat, shortness of breath, cough) occur while receiving abacavir or abacavir-containing preparation.1 228 229 240

  • Do not restart abacavir or abacavir-containing preparation after a hypersensitivity reaction since more severe symptoms may recur within hours and may include life-threatening hypotension and death.1 228 229 240

  • Advise patients that if abacavir therapy is interrupted for reasons other than hypersensitivity (e.g., interruption in drug supply), it should not be reinitiated without consulting clinicians since a severe or fatal hypersensitivity reaction can occur when the drug is reintroduced.1 228 229 240 Reinitiate the drug under such circumstances only if medical care is readily available.1 228 229 240

  • If taking abacavir (Ziagen), importance of not taking another abacavir-containing preparation.1 If taking abacavir/lamivudine (Epzicom), importance of not taking another abacavir- or lamivudine-containing preparation.228 If taking abacavir/dolutegravir/lamivudine (Triumeq), importance of not taking another abacavir- or lamivudine- containing preparation.240 If taking abacavir/lamivudine/zidovudine (Trizivir), importance of not taking another abacavir-, lamivudine-, or zidovudine-containing preparation.229

  • Advise patients that lactic acidosis and severe hepatomegaly have been reported.1 228 229 240

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 228 229 240

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1 228 229 240

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 228 229 240 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 228 229 240 (See Cautions.)

What is the most important information i should know about abacavir (ziagen)?

Stop using abacavir and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.

Once you have had an allergic reaction to abacavir, you must never use it again.

Read the Warning Card that comes with this medication, and carry it with you at all times so you will know the symptoms of allergic reaction to watch for.

Some people develop lactic acidosis while taking abacavir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

Abacavir can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking abacavir: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Do not allow this medicine to run out completely before you get your prescription refilled. It is important that you not stop taking abacavir once you have started. If you miss several doses in a row, you may have a dangerous or even fatal allergic reaction once you start taking abacavir again. If you stop taking abacavir for any reason, talk to your doctor before you start taking the medication again.

What should i discuss with my healthcare provider before taking abacavir (ziagen)?

Do not take this medication if you have ever had an allergic reaction to any medicine that contains abacavir, including Ziagen, Epzicom, or Trizivir. Once you have had an allergic reaction to abacavir, you must never use it again.

Some people develop a life-threatening condition called lactic acidosis while taking abacavir. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.

Abacavir can also cause severe or life-threatening effects on your liver. You should not take abacavir if you have moderate or severe liver disease.

Do not take abacavir with any other medication that contains abacavir, such as Epzicom or Trizivir.

To make sure you can safely take abacavir, tell your doctor if you have any of these other conditions:

  • heart disease, high blood pressure;
  • liver disease;
  • a risk factor for heart disease such as smoking, diabetes, or high cholesterol; or
  • if you have used an HIV medication in the past, such as didanosine (Videx), emtricitabine (Atripla, Complera, Emtriva, Truvada), lamivudine (Combivir, Epivir, Epzicom, Trizivir), stavudine (Zerit), tenofovir (Viread), zalcitabine (Hivid), or zidovudine (Retrovir).

You may need a blood test before you start taking abacavir for the first time, or if you are restarting the medication after stopping for reasons not related to an allergic reaction.

FDA pregnancy category C. It is not known whether abacavir will harm an unborn baby. HIV can be passed to your baby if you are not properly treated during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of abacavir on the baby.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

What should i avoid while taking abacavir (ziagen)?

Avoid drinking alcohol. It may increase your risk of liver damage.

Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Side effects

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

  • Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
  • Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
  • Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS].
  • Fat redistribution [see WARNINGS AND PRECAUTIONS].
  • Myocardial infarction [see WARNINGS AND PRECAUTIONS].

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 [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) 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 (CNA30024a) through 48 Weeks of Treatment

Adverse Reaction ZIAGEN plus Lamivudine plus Efavirenz
(n = 324)
Zidovudine plusLamivudine 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%
a This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.
b Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.

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

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 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

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%
ULN = Upper limit of normal.
n = Number of subjects assessed.

Laboratory abnormalities in CNA3005 are listed in Table 5.

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

Grade 3/4 Laboratory Abnormalities 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/mm ) 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 subjects assessed.

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

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 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 [see WARNINGS AND PRECAUTIONS].

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 [see ADVERSE REACTIONS].

Read the entire FDA prescribing information for Ziagen (Abacavir Sulfate)

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