Ziagen (Abacavir Sulfate)
Abacavir is a nucleoside analogue reverse transcriptase inhibitor. It is a selective antiviral agent against HIV-1 and HIV-2, including HIV-1 isolates that are resistant to zidovudine, lamivudine, zalcitabine, didanosine or nevirapine. In vitro studies have demonstrated that its mechanism of action in relation to HIV is inhibition of the HIV reverse transcriptase enzyme, an event which results in chain termination and interruption of the viral replication cycle. Abacavir shows synergy in vitro in combination with nevirapine or zidovudine. It has been shown to be additive in combination with didanosine, zalcitabine, lamivudine and stavudine.
Abacavir is rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir in adults is about 83%. Following oral administration, the mean time (t max) to maximal serum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour for the solution formulation. There are no differences observed between the AUC for the tablet or solution. At therapeutic dosages (300 mg twice daily), the steady state C max of abacavir tablets is approximately 3µg/mL, and the AUC over a dosing interval of 12 hours is approximately 6µg.h/mL. The C max value for the oral solution is slightly higher than for the tablet.
Food delayed absorption and decreased C max but did not affect overall plasma concentrations (AUC). Therefore, abacavir can be taken with or without food.
Abacavir Is A Nucleoside Analogue Reverse Transcriptase Inhibitor. It Is A Selective Antiviral Agent Against HIV-1 And HIV-2, Including HIV-1 Isolates That Are Resistant To Zidovudine, Lamivudine, Zalcitabine, Didanosine Or Nevirapine. In Vitro Studies Have Demonstrated That Its Mechanism Of Action In Relation To HIV Is Inhibition Of The HIV Reverse Transcriptase Enzyme, An Event Which Results In Chain Termination And Interruption Of The Viral Replication Cycle. Abacavir Shows Synergy In Vitro In Combination With Nevirapine Or Zidovudine. It Has Been Shown To Be Additive In Combination With Didanosine, Zalcitabine, Lamivudine And Stavudine.
Abacavir Is Rapidly And Well Absorbed Following Oral Administration. The Absolute Bioavailability Of Oral Abacavir In Adults Is About 83%. Following Oral Administration, The Mean Time (t Max) To Maximal Serum Concentrations Of Abacavir Is About 1.5 Hours For The Tablet Formulation And About 1.0 Hour For The Solution Formulation. There Are No Differences Observed Between The AUC For The Tablet Or Solution. At Therapeutic Dosages (300 Mg Twice Daily), The Steady State C Max Of Abacavir Tablets Is Approximately 3µg/mL, And The AUC Over A Dosing Interval Of 12 Hours Is Approximately 6µg.h/mL. The C Max Value For The Oral Solution Is Slightly Higher Than For The Tablet.
Food Delayed Absorption And Decreased C Max But Did Not Affect Overall Plasma Concentrations (AUC). Therefore, Abacavir Can Be Taken With Or Without Food.
In patients with previously demonstrated hypersensitivity to any of the components of the products.
Hypersensitivity Reactions: Fatal hypersensitivity reactions have been associated with therapy with abacavir. Patients developing signs or symptoms of hypersensitivity (which include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain, and respiratory symptoms such as pharyngitis, dyspnea or cough) must stop taking abacavir and contact their doctor immediately. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute onset respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis or flu-like illness) are possible. Abacavir must never be restarted following a hypersensitivity reaction, as more severe symptoms will recur within hours and may include life-threatening hypotension and death. To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). Abacavir should not be re-started even if a recurrence of symptoms occurs following rechallenge with alternative medication(s).
Severe or fatal hypersensitivity reactions can occur within hours after abacavir reintroduction in patients who have no identified history or unrecognized symptoms of hypersensitivity during their initial period of use of abacavir.
If therapy with abacavir has been discontinued and restarting therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. Patients who have stopped abacavir due to possible adverse reactions or illness should be advised to contact their doctor before restarting. If a hypersensitivity reaction cannot be ruled out, abacavir should not be restarted.
In ongoing clinical trials, hypersensitivity reactions have been reported in approximately 4% (range 0 to 7.3%) of adult and pediatric patients receiving abacavir. Symptoms can occur at any time during therapy, however, they usually appear within the first 6 weeks (median time is 11 days) of treatment with abacavir (see Precautions, Information to Be Provided to the Patient and Adverse Effects).
A warning card with information for the patient about this hypersensitivity reaction is included in the abacavir pack (see Adverse Effects).
The Canadian Ziagen Support Line: To facilitate the diagnosis of hypersensitivity reactions with abacavir, the Canadian Ziagen Support Line has been established. This service is made available through the toxicology and poison control service at the Children's Hospital of Eastern Ontario. 1-800-868-8898 is a bilingual, 24-hour toll-free line, staffed by qualified nurses specially trained in abacavir safety issues.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering abacavir to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with abacavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Other Warnings: A patient with a diagnosis of AIDS dementia and a history of seizure disorder experienced a seizure 3 days after stopping abacavir therapy. In the absence of an autopsy, a definitive diagnosis could not be adequately made, and a possible relationship to abacavir therefore could not be ruled out.
General: Abacavir should always be used in combination with other antiretroviral agents. When antiretroviral regimens are changed due to loss of virologic response, abacavir should not be added as a single agent.
Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. At systemic exposures approximately 9 times higher than that in humans at the therapeutic dose, abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay.
Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.
Long-term carcinogenicity studies of abacavir in animals are in progress.
Therapy-experienced Patients: In clinical trials, patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients.
In heavily pre-treated NRTI patients, the reduction in viral load with abacavir was very low. The degree of viral load reduction as part of a new combination regimen will depend on the nature and duration of prior therapy which may have selected for HIV-1 variants with cross-resistance to abacavir.
Information to Be Provided to the Patient: Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir, which may result in death. Patients developing signs or symptoms of hypersensitivity (which include fever, skin rash, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain, and respiratory symptoms such as sore throat, shortness of breath or cough) should discontinue treatment with abacavir and seek medical evaluation immediately. Abacavir should not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death. In order to avoid restarting abacavir, patients who have experienced a hypersensitivity reaction should be asked to return the remaining abacavir tablets or oral solution to the pharmacy. Patients who have stopped therapy with abacavir for any reason, and particularly due to side effects or illness should be advised to contact their physician before restarting therapy. It is important that a physician determine that the reason for stopping therapy was not related to a hypersensitivity reaction. Patients should be reminded that a hypersensitivity reaction can occur at any time.
The Patient Information leaflet provides written information for the patient, and should be dispensed with each new prescription and refill. A Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction should be provided to the patient by the pharmacist with each prescription. Patients should be instructed to carry this card with them.
Patients should be advised that the long-term effects of abacavir are unknown at this time.
Abacavir tablets and oral solution are for oral ingestion only.
Patients should be advised of the importance of taking abacavir exactly as it is prescribed.
Patients receiving abacavir or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
Patients should be advised that current antiretroviral therapy, including abacavir, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.
Abacavir oral solution contains sorbitol, which may cause abdominal pain and diarrhea. Sorbitol is metabolized to fructose and is therefore unsuitable for patients who have hereditary fructose intolerance.
Geriatrics: Clinical studies of abacavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Children: The clinical studies in pediatric patients to date have not clearly established the safety and efficacy of abacavir in this population. In this population, hypersensitivity reactions may be particularly difficult to identify.
Pregnancy: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Developmental toxicity (depressed fetal body weight and reduced crown-rump length) and increased incidences of fetal anasarca and skeletal malformations were observed when rats were treated with abacavir at doses of 1000 mg/kg during organogenesis. This dose produced 35 times the human exposure, based on AUC. In a fertility study, evidence of toxicity to the developing embryo and fetuses (increased resorptions, decreased fetal body weights) occurred only at 500 mg/kg/day. The offspring of female rats treated with abacavir at 500 mg/kg (beginning at embryo implantation and ending at weaning) showed increased incidence of stillbirth and lower body weights throughout life. In the rabbit, there was no evidence of drug-related developmental toxicity and no increases in fetal malformations at doses up to 700 mg/kg (8.5 times the human exposure at the recommended dose, based on AUC).
There are no adequate and well-controlled studies in pregnant women. Abacavir should be used during pregnancy only if the potential benefits outweigh the risk.
To monitor maternal-fetal outcomes of pregnant women exposed to abacavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department (1-800-668-6051).
Lactation: It is recommend that HIV infected women do not breast-feed their infants under any circumstances, in order to avoid transmission of HIV. It is therefore recommended that mothers do not breast-feed their babies while receiving treatment with abacavir.
Abacavir and its metabolites are secreted into the milk of lactating rats. It is expected that these will also be secreted into human milk, although this has not been confirmed. There are no data available on the safety of abacavir when administered to babies less than 3months old.
Impaired Renal Function: The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Other drugs that are eliminated by acyl glucuronide formation are known to accumulate in patients with renal impairment, therefore it is possible the 5'-glucuronide and 5'-carboxylic acid metabolites of abacavir might accumulate in patients with impaired renal function. The clinical significance of this is not known.
Drug Interactions : Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for drug interactions involving abacavir is low. Abacavir shows low potential to inhibit metabolism mediated by the cytochrome P450 3A4 enzyme. It has also been shown in vitro not to interact with drugs that are metabolized by CYP3A4, CYP2C9 or CYP2D6 enzymes. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for drug interactions with antiretroviral protease inhibitors and other drugs metabolized by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
The metabolism of abacavir is altered by concomitant ethanol, resulting in an increase in AUC of abacavir of about 41%. The clinical significance of this is unknown. Abacavir has no effect on the metabolism of ethanol.
Retinoid compounds such as isotretinoin are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.
Hypersensitivity Reactions: There have been 17reported deaths related to abacavir hypersensitivity reactions. In addition, there have been 6deaths where the relationship is less clear. There are further deaths where a contribution of possible hypersensitivity reaction cannot be definitively ruled out.
Therapy with abacavir must not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death. Patients developing signs or symptoms of hypersensitivity should discontinue treatment as soon as a hypersensitivity reaction is first suspected, and must seek medical evaluation immediately. To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). Abacavir should not be restarted even if a recurrence of symptoms occurs following rechallenge with alternative medication(s).
Severe or fatal hypersensitivity reactions can occur within hours after abacavir reintroduction in patients who have no identified history or unrecognized symptoms of hypersensitivity during their initial period of use of abacavir (see Warnings and Precautions, Information to Be Provided to the Patient).
If therapy with abacavir has been discontinued and restarting therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. Patients who have stopped abacavir due to possible adverse reactions or illness should be advised to contact their doctor before restarting.
In clinical studies, approximately 4% of patients receiving abacavir developed a hypersensitivity reaction. This reaction is characterized by the appearance of symptoms indicating multi-organ body system involvement. Symptoms can occur at any time during therapy however they usually appear within the first 6weeks (median time to onset 11 days) of initiation of treatment with abacavir.
Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever.
The signs and symptoms of this hypersensitivity reaction are listed below. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.
Skin: rash (usually maculopapular or urticarial).
Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, mouth ulceration.
Respiratory: dyspnea, sore throat, cough.
Miscellaneous: fever, fatigue, malaise, edema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis.
Neurological/Psychiatry: headache, paraesthesia.
Hematological: lymphopenia.
Liver/pancreas: elevated liver function tests, hepatic failure.
Musculoskeletal: myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase.
Urology: elevated creatinine, renal failure.
Some patients who experienced a hypersensitivity reaction were initially thought to have acute onset or worsening respiratory disease. The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute onset respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis or flu-like illness) are possible.
Symptoms worsen with continued therapy, and usually resolve upon discontinuation of abacavir. Risk factors that may predict the occurrence or severity of hypersensitivity to abacavir have not been identified.
Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours.
Adults: Clinical adverse events with a ³5% frequency during therapy with abacavir 300 mg twice daily and lamivudine 150 mg twice daily and zidovudine 300 mg twice daily compared with lamivudine 150mg twice daily and zidovudine 300 mg twice daily from CNAA/B3003 are listed in Table I. This table also displays the events rated as severe (grade 3 or 4) by the physician.
Laboratory abnormalities occurred infrequently and were similar in type and frequency in the 2 treatment groups (neutropenia, elevated liver enzymes, and elevated triglycerides).
Clinical adverse events with a >5% frequency during therapy with abacavir 300 mg twice daily and lamivudine 150 mg twice daily and zidovudine 300 mg twice daily compared with lamivudine 150 mg twice daily, zidovudine 300 mg twice daily and indinavir 800 mg three times daily from CNAA/B3005 are listed in Table II. Table II also displays the events rated as severe (grade 3 or 4) by the physician.
Children: Clinical adverse events with a ³5% frequency during therapy with abacavir 8 mg/kg twice daily and lamivudine 4 mg/kg twice daily and zidovudine 180mg/m 2 twice daily compared with lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m 2 twice daily from CNAA3006 are listed in Table III. This table also displays the events rated as severe (grade 3 or 4) by the treating physician.
Laboratory abnormalities occurred infrequently and were similar in type and frequency in the 2 treatment groups (neutropenia, anemia, thrombocytopenia, elevated liver enzymes, elevated amylase/lipase, increased bilirubin, increased creatinine).Additional adverse reactions (grades 2, 3, and 4) occurring in less than 5% of patients receiving abacavir in controlled studies, and considered at least possibly related to treatment are listed below:
Body as a Whole: hypersensitivity, chest pain, edema and swelling, pain.
Digestive: constipation, decreased appetite, oral ulceration.
Pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain.
Hemic/Lymphatic: leukopenia.
Musculoskeletal: muscle pain.
Nervous System: neuropathy.
A patient with a diagnosis of AIDS dementia and a history of seizure disorder experienced a seizure 3 days after stopping abacavir therapy. In the absence of an autopsy, a definitive diagnosis could not be adequately made, and a possible relationship to abacavir therefore could not be ruled out.
Skin: pruritus, sweating.
Symptoms and Treatment: There is no known antidote for abacavir. Single doses up to 1200 mg and daily doses up to 1800 mg of abacavir have been administered to patients in clinical studies. No unexpected adverse reactions were reported. The effects of higher doses are not known. If overdosage occurs, the patient should be monitored for evidence of toxicity (see Adverse Effects), and standard supportive treatment applied as necessary. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis. Although no data are available, administration of activated charcoal may be used to aid in removal of unabsorbed drug.
A Patient Information Leaflet and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.
Abacavir can be taken with or without food.
Adults: The recommended dose is 300 mg (1tablet or 15 mL of oral solution) twice daily.
The Canadian Ziagen Support Line: To facilitate the diagnosis of hypersensitivity reactions with abacavir, the Canadian Ziagen Support Line has been established. This service is made available through the toxicology and poison control service at the Children's Hospital of Eastern Ontario. 1-800-868-8898 is a bilingual, 24-hour toll-free line, staffed by qualified nurses specially trained in abacavir safety issues.
Renal Impairment: There are no pharmacokinetic data available in renally impaired patients; no dosing recommendations can be made.
Hepatic Impairment: There are no pharmacokinetic data available in hepatically impaired patients; no dosing recommendations can be made.
Information for the Patient: See Blue Section--Information for the Patient “Ziagen”.
Oral Solution: Each mL of clear to opalescent, yellowish, strawberry-banana flavored liquid, contains: abacavir sulfate equivalent to abacavir 20 mg. Nonmedicinal ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), hydrochloric acid, methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium citrate (dihydrate), sodium hydroxide and sorbitol solution. Bottles of 240 mL. Store between 15 and 25°C.
Tablets: Each yellow, biconvex, capsule-shaped, film-coated tablet, imprinted with “GX 623” on one side with no marking on the reverse side, contains: abacavir sulfate equivalent to abacavir 300 mg. Nonmedicinal ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate 80, sodium starch glycolate, titanium dioxide, triacetin and yellow iron oxide. Bottles of 60. Store between 15 and 30°C.
