Abacavir sulfate The chemical name of abacavir sulfate is [4R-(2-Amino-6-cyclopropylamino-purin-9-yl)- cyclopent-2-en-1S-yl]-methanol sulfate (2:1), and has the following structural formula:
HN
N
N
H2N
N
N
. H2SO4 The molecular formula of abacavir sulfate is (C14H18N6O)2.H2SO4 and it has a relative molecular mass of 670.76.
188062-50-2
Abacavir sulfate is a white to off-white crystalline powder with a solubility of approximately 77 mg/mL in water at 25C. ZIAGEN is supplied in tablets containing 300mg of abacavir sulfate. ZIAGEN tablets also contain microcrystalline cellulose, sodium starch glycollate, magnesium stearate, colloidal anhydrous silica, glycerol triacetate, hypromellose, titanium dioxide, polysorbate 80 and iron oxide yellow (E172). ZIAGEN is supplied in oral solution containing 20 mg/mL of abacavir sulfate. ZIAGEN oral solution also contains sorbitol (34%), saccharin sodium, sodium citrate, anhydrous citric acid, methyl hydroxybenzoate, propyl hydroxybenzoate, propylene glycol, artificial strawberry and banana flavour and purified water.
Abacavir is a nucleoside analogue reverse transcriptase inhibitor. It is a selective antiretroviral agent against HIV-1 and HIV-2, including HIV-1 isolates with reduced susceptibility to zidovudine, lamivudine, zalcitabine, didanosine or nevirapine. Abacavir is metabolised intracellularly to the active moiety, carbovir 5'-triphosphate (TP). 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 and zidovudine. It has been shown to be additive in combination with didanosine, zalcitabine, lamivudine and stavudine. In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the sampling time, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. The steady state pharmacokinetic properties of abacavir 600 mg once daily was compared to abacavir 300 mg twice daily in a crossover study in 27 HIV-infected patients. Intracellular carbovir triphosphate exposures in peripheral blood mononuclear cells were higher for abacavir 600 mg once daily with respect to AUC24,ss(32 %, higher), Cmax 24,ss (99% higher) and trough values (18% higher), compared to the 300 mg twice daily regimen. These data support the use of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021- See Clinical experience). Genetic analysis of isolates from patients failing an abacavir-containing regimen demonstrated that reverse transcriptase amino acid residue 184 was consistently the most frequent position for NRTI resistance-associated mutations (M184V or M184I). The second most frequent mutation was L74V. Mutations Y115F and K65R were uncommon. In a study of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), there was a low overall incidence of virologic failure at 48 weeks in both the once and twice daily treatment groups (10% and 8% respectively). Additionally for technical reasons genotyping was restricted to samples with plasma HIV-1 RNA >500 copies/ml. This resulted in a small sample size. Therefore no firm conclusions could be drawn regarding differences in treatment emergent mutations between the two treatment groups. Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 8/20). L74V, Y115F and K65R were the other RT mutations observed in the study. Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a >2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared to 41% (7/17) of the failure isolates in the twice-daily abacavir group had a >2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range 0.79 to >116) and 1.1 (range 0.68 to >116) in the once-daily and twice-daily abacavir arms, respectively.
Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. Viruses containing abacavir and lamivudine resistance-associated mutations, namely, M184V, L74V, Y115F and K65R, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in vitro and in patients. The M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and
zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine and the K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the L74V plus the M184V/I mutation, viruses with K65R with or without the M184V/I mutation, and viruses with thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.
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 to maximal serum concentrations (tmax) 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 a dosage of 300 mg twice daily, the mean steady state Cmax of abacavir from tablet administration was 3.00 ug/ml, and the mean AUC over a dosing interval of 12 hours was 6.02 ug.h/ml (daily AUC of approximately 12.0 ug.h/ml). The Cmax value for the oral solution is slightly higher than the tablet. After a 600 mg abacavir tablet dose, the mean abacavir Cmax was approximately 4.26 ug/ml and the mean AUC was 11.95 ug.h/ml. Food delayed absorption of abacavir and decreased the Cmax but did not affect overall plasma concentrations (AUC). The clinical significance is not known. Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic characteristics of the active ingredients and the in vitro dissolution behaviour of abacavir tablets in water, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Following intravenous administration, the apparent volume of distribution was about 0.8 L/kg, indicating that abacavir penetrates freely into body tissues. Studies in HIV infected patients have shown good penetration of abacavir into the cerebrospinal fluid (CSF), with a CSF to plasma AUC ratio of between 30 to 44%. In a Phase I pharmacokinetic study, the penetration of abacavir into the CSF was investigated following administration of abacavir 300 mg twice a day. The mean concentration of abacavir achieved in the CSF 1.5 hours post dose was 0.14 ug/mL. In a further pharmacokinetic study using 600 mg abacavir twice a day, the CSF concentration of abacavir increased over time, from approximately 0.13 ug/mL at 0.5 to 1 hour after dosing, to approximately 0.74 ug/mL after 3 to 4 hours. While peak concentrations may not have been attained by 4 hours, the observed values are 9 fold greater than the IC50 of abacavir of 0.08 ug/mL or 0.26uM.
In vitro
studies indicate that at therapeutic concentration plasma protein binding capacity of abacavir is low to moderate (~49%). This indicates a low likelihood for drug interactions through plasma protein binding displacement.
Abacavir is primarily metabolised by the liver with less than 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. These metabolites are excrected in the urine.
The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant drug accumulation. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine; the remainder is eliminated in the faeces.
Hepatically impaired:
Abacavir is metabolised primarily by the liver. There are no results of studies on the effect of hepatic impairment on the pharmacokinetics of abacavir available currently. The pharmacokinetics have not been studied in patients with moderate or severe hepatic impairment, therefore ZIAGEN is contra-indicated in these patients. (see also CONTRAINDICATIONS & DOSAGE AND ADMINISTRATION SECTIONS).
Renally impaired:
Abacavir is primarily metabolised by the liver with less than 2% excreted in the urine as the unchanged drug. As there are no pharmacokinetic data available in renally impaired patients dosing recommendations can not be made at this time.
Children:
Abacavir is rapidly and well absorbed from an oral solution administered to children. The overall pharmacokinetic parameters in children are comparable to adults, with slightly greater variability in plasma concentrations. The recommended dose for children from three months and weighing less than 30 kg is 8 mg/kg twice daily. In a clinical pharmacokinetic study, this dose resulted in mean AUC and mean Cmax higher than those observed in studies of adults taking 300 mg twice a day.
Elderly
: The pharmacokinetics of abacavir have not been studied in patients over 65 years of age. When treating elderly patients consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, and concomitant disease or other drug therapy.
Description of Clinical Studies: Therapy-Naive Adults: CNAAB3003 is an ongoing, multicenter, double-blind, placebo-controlled study in which 173 HIV-infected, therapy-naive adults were randomised to receive either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and zidovudine (300 mg twice daily) or lamivudine (150 mg twice daily) and zidovudine (300 mg twice daily). The duration of double-blind treatment was 16 weeks. Study participants were: male (76%), Caucasian (54%), African-American (28%), and Hispanic (16%). The median age was 34 years, the median pretreatment CD4 cell count was 450 cells/mm3, and median plasma HIV-1 RNA was 4.5 log10 copies/mL. Proportions of patients with plasma HIV-1 RNA 400 copies/mL (using Roche Amplicor HIV-1 MONITOR Test) through 16 weeks of treatment are summarised in Figure 1.
After 24 weeks of therapy, the median CD4 increases from baseline were 87 cells/mm3 in the group receiving ZIAGEN and 86 cells/mm3 in the placebo group. Therapy-Experienced Paediatric Patients: CNAA3006 is an ongoing, randomised, double-blind study comparing ZIAGEN 8 mg/kg twice daily and lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m2 twice daily versus lamivudine 4 mg/kg twice daily and zidovudine 180 mg/m2 twice daily. Two hundred and five paediatric patients were enrolled: female (56%), Caucasian (17%), African-American (50%), Hispanic (30%), median age of 5.4 years, baseline CD4 cell percent >15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log10 copies/mL. Eighty percent and 55% of patients had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. Proportions of patients with plasma HIV-1 RNA levels 10,000 and 400 copies/mL, respectively, through 24 weeks of treatment are summarised in Figure 2.
After 24 weeks of therapy, the median CD4 change from baseline was an increase of 47 cells/mm3 in the group receiving ZIAGEN and a decrease of 10 cells/mm3 in the control group. Abacavir penetrates the cerebrospinal fluid (CSF) (see Pharmacokinetics), and has been shown to reduce HIV-1 RNA levels in the CSF. However, in a double-blind randomised clinical study of abacavir sulfate 600 mg twice a day added to background therapy in AIDS dementia, no significant difference compared with placebo was shown for neuropsychological performance (the primary endpoint).
A once daily regimen of abacavir was investigated in a multicentre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naive adults. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. Patients were stratified at baseline based on plasma HIV-1 RNA 100,000 copies/ml or >100,000 copies/ml. The duration of double-blind treatment was at least 48 weeks. The results are summarised in the table below:
| Populations | ABC once/day + 3TC + EFV (N = 384 ) | ABC twice/day + 3TC + EFV (N = 386 ) | Point Estimate | 95% CI * |
| Stratified | -1.7 | -8.4, 4.9 | ||
| Sub-group by baseline RNA | ||||
| 100,000 copies/ml | 141/217 (65%) | 145/217 (67%) | -1.8 | -10.8, 7.1 |
| >100,000 copies/ml | 112/167 (67%) | 116/169 (69%) | -1.6 | -11.6, 8.4 |
| Total population | 253/384 (66%) | 261/386 (68%) | ||
* Confidence interval
The abacavir once daily group was demonstrated to be non-inferior when compared to the twice daily group in the overall and base-line viral load sub-groups. The incidence of adverse events reported was similar in the two treatment groups.
ZIAGEN (abacavir) is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and children (see CLINICAL TRIALS). This indication is based on surrogate endpoints in studies up to 48 weeks in duration.
ZIAGEN is contra-indicated in patients with known hypersensitivity to abacavir or to any ingredient of the preparation. ZIAGEN is contra-indicated in patients with moderate or severe hepatic impairment.
In clinical studies approximately 5% of subjects given abacavir developed a hypersensitivity reaction, which in rare cases has proved fatal. Over 28,000 patients received ZIAGEN in clinical trials up to 30 June 2000. In this period there were 7 cases in which the fatal outcome may have been due to hypersensitivity.
Description
The hypersensitivity reaction is characterised by the appearance of symptoms indicating multi-organ involvement. The majority of patients have fever and/or rash as part of the syndrome. Other symptoms occurring in more than 10% of patients with the hypersensitivity reaction were: fatigue, malaise, headache, myalgia, gastrointestinal symptoms such as, nausea, vomiting, diarrhoea, or abdominal pain and respiratory signs and symptoms which include dyspnoea, sore throat, cough and abnormal chest X-ray findings (predominantly infiltrates, which can be localised). The symptoms of this hypersensitivity reaction can occur at any time during treatment with ZIAGEN, but usually occur within the first 6 weeks of therapy. The symptoms worsen with continued therapy and can be life threatening. These symptoms usually resolve upon discontinuation of ZIAGEN. Other frequently observed signs or symptoms of the hypersensitivity reaction may include pruritus, chills and musculoskeletal symptoms (rarely myolysis, arthralgia). (see ADVERSE EFFECTS).
Risk Factors
In a prospective, randomised, controlled clinical trial, 3.4% of subjects with a negative HLA- B *5701 status receiving abacavir developed a hypersensitivity reaction. Studies have shown that carriage of the HLA-B *5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. In the prospective study CNA106030 (PREDICT-1), use of pre-therapy screening for the HLA-B *5701 allele and subsequently avoiding abacavir in patients with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66 of 847) to 3.4% (27 of 803) (p<0.0001) and the incidence of hypersensitivity reactions confirmed by skin patch testing from 2.7% (23 of 842) to 0.0% (0 of 802) (p<0.0001). Based on this study, it is estimated that 48% to 61% of patients with the HLA-B *5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B *5701 allele. Clinicians should consider screening for carriage of the HLA-B *5701 allele in any HIV-infected patient without prior exposure to abacavir. Screening is recommended prior to re-intiation of abacavir in patients of unknown HLA-B *5701 status who have previously tolerated abacavir (see "Special considerations following an interruption of ZIAGEN therapy"). Use of abacavir in patients known to carry the HLA-B *5701 allele is not recommended and should be considered only under exceptional circumstances where potential benefit outweighs the risk and with close medical supervision. In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B *5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
Clinical
Management
To avoid a delay in diagnosis of hypersensitivity and to minimise the risk of a life-threatening hypersensitivity reaction, ZIAGEN,
must be discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). ZIAGEN should not be re-started even if a recurrence of symptoms occurs following rechallenge with alternative medications.
Special considerations following an interruption of ZIAGEN therapy
Regardless of a patient's HLA-B *5701 status, if therapy with ZIAGEN 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 ZIAGEN due to possible adverse reactions or illness should be advised to contact their doctor before restarting.
There have been infrequent reports of hypersensitivity reactions with a rapid onset, including life threatening reactions, following reintroduction of ZIAGEN in patients who had only one of the key symptoms of a hypersensitivity reaction (ie rash, fever, gastrointestinal, respiratory or constitutional symptoms such as fatigue or malaise). When patients who have discontinued ZIAGEN present with an indeterminate diagnosis of hypersensitivity (single symptom), the doctor should:
Assess the probability that hypersensitivity preceded the interruption
Assess the risk:benefit of reinitiating ZIAGEN
Select a medical setting in which medical care can be accessed readily, if a decision is made to reintroduce ZIAGEN.
On very rare occasions hypersensitivity reactions have been reported in patients who have re-started therapy, and who had no apparent preceding symptoms of a hypersensitivity reaction. Some of these cases were poorly documented. The clinical significance of these reports is unclear. If a decision is made to re-start ZIAGEN, this must be done only if medical care can be accessed readily by the patient or others. Screening for carriage of the HLA-B *5701 allele is recommended prior to re-initiation of abacavir in patients of unknown HLA-B *5701 status who have previously tolerated abacavir. Re-initiation of abacavir in such patients who test positive for the HLA-B *5701 allele is not recommended and should be considered only under exceptional circumstances where potential benefit outweighs the risk and with close medical supervision.
Essential patient information
Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life threatening reaction or death and that the risk of a hypersensitivity reaction is increased if they are HLA-B *5701 positive. Patients must also be informed that HLA-B *5701 negative patients can also experience abacavir hypersensitivity reaction. Therefore, ANY patient who develops signs or symptoms consistent with a possible hypersensitivity reaction to abacavir MUST CONTACT their doctor IMMEDIATELY. In order to avoid restarting ZIAGEN, patients who have experienced a hypersensitivity reaction should be asked to return the remaining ZIAGEN tablets or oral solution to the pharmacy.
Patients who have stopped ZIAGEN for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting. Each patient should be reminded to read the Package Leaflet included in the ZIAGEN pack. They should also be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir, in the treatment of HIV infection. A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea). Caution should be exercised when administering ZIAGEN to any patient, and particularly to those with known risk factors for liver disease. Treatment with ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy (see ADVERSE EFFECTS). Whilst all members of the PI and NRTI classes of medicinal products have been associated with one or more of these specific adverse events, linked to a general syndrome commonly referred to as lipodystrophy, data indicate that there are differences in the risk between individual members of the respective therapeutic classes. In addition, the lipodystrophy syndrome has a multi-factorial aetiology; with for example HIV disease status, older age and duration of antiretroviral treatment all playing important, possibly synergistic roles. The long-term consequences of these events are currently unknown. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.
Opportunistic Infections
: Patients receiving ZIAGEN 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 HIV associated diseases.
Transmission:
Patients should be advised that current antiretroviral therapies, including ZIAGEN, have not been proven to prevent the risk of HIV transmission to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post- natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
In a large prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, a total of 33,347 HIV- infected patients were followed for 157,912 person-years. The use of abacavir within the previous six months was correlated with a significantly increased risk of myocardial infarction (relative risk: 1.94, 95% CI: 1.48 - 2.55). In a pooled analysis of GSK sponsored clinical trials no excess risk of myocardial infarction was observed with abacavir use. There is no known biological mechanism to explain a potential increase. In totality the available data from observational cohorts and from controlled clinical trials are inconclusive in regard to the relationship between abacavir treatment and the risk of myocardial infarction. As a precaution the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking). As part of a triple-drug regimen, ZIAGEN is generally recommended for use with antiretroviral agents from different pharmacological classes and not solely with other nucleoside/nucleotide reverse transcriptase inhibitors. This is based on results from randomised, double-blind, controlled studies in which the proportion of subjects with early virological failure was higher in the triple nucleoside groups than in groups who received regimens involving two nucleosides in combination with an agent from a different pharmacological class. However, consideration needs to be given to a number of factors, including compliance, safety, toxicity and preservation of future treatment options, which also remain important when selecting an appropriate antiretroviral combination for a patient.
In clinical trials patients with prolonged prior 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 with prolonged prior NRTI exposure, or who have HIV-1 isolates containing multiple mutations conferring resistance to NRTIs (see Pharmacodynamics, Cross resistance).
ZIAGEN Oral Solution contains sorbitol which is metabolised to fructose and is therefore unsuitable for patients who have hereditary fructose intolerance. Sorbitol may cause abdominal pain and diarrhoea.
Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver, urinary bladder, lymph nodes and the subcutis of female rats. Nonmalignant tumours occurred in the liver of mice and rats, Harderian gland of female mice, and thyroid gland of rats. In rats, there were also increased incidences of urothelial hyperplasia and urinary bladder tumours, associated with increased urinary calculi. The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. These dose levels were equivalent to 24 to 33 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg. This is equivalent to six times the expected human systemic exposure.
Abacavir was inactive in in vitro tests for gene mutation in bacteria but it showed clastrogenic activity against human lymphocytes in vitro and in an in vivo mouse micronucleus test. 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. Abacavir was not mutagenic in bacterial mutagenicity assays.
Abacavir had no adverse effects on the mating performance of fertility of male and female rats at oral doses of up to 427 mg/kg per day, a dose expected to produce exposures approximately 30 fold higher than that in humans at the therapeutic dose based on AUC. Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
Category B3. Studies in pregnant rats showed that abacavir is transferred to the foetus through the placenta. Developmental toxicity (depressed foetal body weight and reduced crown-rump length) and increased incidences of foetal anasarca and skeletal malformations were observed when rats were treated with abacavir at doses of 648 mg/kg during organogenesis (approximately 35 times the human exposure at the recommended dose, based on AUC). In a fertility study, evidence of toxicity to the developing embryo and foetuses (increased resorptions, decreased foetal body weights) occurred only at 427 mg/kg per day. The offspring of female rats treated with abacavir at 427 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 foetal malformations at doses up to 453 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. ZIAGEN should be used during pregnancy only if the potential benefit to the mother outweighs the possible risk to the foetus. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Abacavir and its metabolites are secreted into the milk of lactating rats. Although not confirmed, it is expected that abacavir and its metabolites will also be secreted into human milk. There is no data available on the safety of abacavir when administered to babies less than three months old. Some health experts 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 ZIAGEN.
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 no 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 metabolised by CYP 3A4, 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 metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
Ethanol
: The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. Given the safety profile of abacavir these findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.
Methadone: In a pharmacokinetic study, coadministration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax, but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean methadone systemic clearance by 22%. This change is not considered clinically relevant for the majority of patients, however occasionally methadone re-titration may be required.
Retinoids:
Retinoid compounds such as isotretinoin, are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.
y
No currently available data suggest ZIAGEN affects the ability to drive or operate machinery.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV- disease and/or long-term exposure to combination antiretroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Clinical Trial Information:
The adverse events reported during ZIAGEN therapy in HIV disease were similar in adults and children. For many of these events, it is unclear whether the reported adverse events are related to ZIAGEN, or to the wide range of drugs used in the management of HIV disease or as a result of the disease process. The following adverse events occurring in more than 10% of patients treated with ZIAGEN are likely to be drug related; nausea, vomiting, lethargy and fatigue. Other commonly reported adverse events were fever, headache, diarrhoea, and anorexia. In general, adverse events have been transient and not treatment limiting. The majority were mild or moderate in severity. Table 1 lists the most common adverse events, occurring at an incidence of 5% or more, reported in controlled pivotal clinical trials in adults and paediatrics, irrespective of the investigator's assessment of possible relationship to the study drug:
| Table 1 - Summary of Most Common Adverse Events Reported in 5% of Subjects CNAAB3003 and CNAA3006 | ||||
| CNAAB3003 + (ABC 300 mg BID dose) | CNAA3006 ++++ (ABC 8 mg/Kg dose) | |||
| Adverse event | ABC/3TC/ ZDV N=83 | 3TC/ZDV N=81 | ABC/3TC/ZDV N=102 | 3TC/ZDV N=103 |
| N (%) | N (%) | N (%) | N (%) | |
| Number of Subjects reporting any adverse event | 76 (92) | 70 (86) | 88 (86) | 89 (86) |
| Nausea | 39 (47) | 33 (41) | 5 (5) | 2 (2) |
| Headache | 26 (31) | 16 (20) | 16 (16) | 12 (12) |
| Nausea & Vomiting | 13 (16) | 9 (11) | 39 (38) | 19 (18) |
| Malaise & fatigue | 28 (34) | 20 (25) | 5 (5) | 1 (1) |
| Diarrhoea | 10 (12) | 9 (11) | 16 (16) | 15 (15) |
| Cough | 6 (7) | 5 (6) | 24 (24) | 12 (12) |
| CNAAB3003 + (ABC 300 mg BID dose) | CNAA3006 ++++ (ABC 8 mg/Kg dose) | |||
| Adverse event | ABC/3TC/ ZDV N=83 | 3TC/ZDV N=81 | ABC/3TC/ZDV N=102 | 3TC/ZDV N=103 |
| N (%) | N (%) | N (%) | N (%) | |
| Ear, nose & throat infection | 3 (4) | 8 (10) | 19 (19) | 17 (17) |
| Temperature regulation disturbance | 4 (5) | 6 (7) | 19 (19) | 12 (12) |
| Feeding problems | 9 (11) | 8 (10) | 9 (9) | 2 (2) |
| Skin rashes | 4 (5) | 4 (5) | 11 (11) | 8 (8) |
| Nasal signs & symptoms | 4 (5) | 7 (9) | 11 (11) | 8 (8) |
| Sleep disorders | 6 (7) | 4 (5) | 1 (1) | 0 |
| Viral ear, nose & throat infection | 6 (7) | 5 (6) | 9 (9) | 5 (5) |
| Abdominal discomfort & pain | 3 (4) | 6 (7) | 5 (5) | 7 (7) |
| Decreased white cells | 4 (5) | 3 (4) | 4 (4) | 5 (5) |
| Neuropathy | 1 (1) | 3 (4) | 2 (2) | 1 (1) |
| Musculoskeletal pain | 6 (7) | 4 (5) | 3 (3) | 4 (4) |
ABC = Abacavir; 3TC = lamivudine; ZDV =zidovudine + Dose of 3TC 150 mg bd and ZDV 300 mg bd ++++ Dose of 3TC 4 mg/kg bd and ZDV 180 mg/m2 bd In controlled clinical studies laboratory abnormalities related to ZIAGEN treatment were uncommon, with no differences in incidence observed between ZIAGEN treated patients and the control arms.
Table 2 Most Common (Greater than or equal to 5% Incidence) Grade 2 to 4 Adverse Events (Safety Population - CNA30021)
| Adverse Event 1 | ABC OAD N=384 n (%) | ABC BID N=386 n (%) |
| Subjects with ANY Grade 2 to 4 AE | 267 (70%) | 276 (72%) |
| Drug hypersensitivity | 35 (9%) | 27 (7%) |
| Insomnia | 26 (7%) | 36 (9%) |
| Depression | 25 (7%) | 26 (7%) |
| Diarrhea 4 | 21 (5%) | 25 (6%) |
| Nausea | 21 (5%) | 25 (6%) |
| Headache | 21 (5%) | 21 (5%) |
| Rash 4 | 21 (5%) | 19 (5%) |
| Fatigue | 20 (5%) | 29 (8%) |
| Dizziness | 19 (5%) | 19 (5%) |
| Pyrexia | 19 (5%) | 13 (3%) |
| Abnormal dreams | 15 (4%) | 19 (5%) |
| Anxiety | 12 (3%) | 20 (5%) |
Table 3 Grade 3 to 4 Treatment Emergent Laboratory Abnormalities (Safety Population - CNA30021)
| Grade 3 and 4 Laboratory Abnormalities | ABC OAD N=384 N(%) | ABC BID N=386 N(%) | ||||
| Clinical Chemistry | Gr 3 | Gr 4 | Gr 3-4 | Gr 3 | Gr 4 | Gr 3-4 |
| Elevated ALT | 14 (4%) | 9 (2%) | 23 (6%) | 18 (5%) | 6 (2%) | 24 (6%) |
| Elevated AST | 10 (3%) | 13 (3%) | 23 (6%) | 9 (2%) | 5 (1%) | 14 (4%) |
| Alkaline phosphatase | 1 (<1%) | 0 | 1 (<1%) | 0 | 1 (<1%) | 1 (<1%) |
| Amylase | 13 (3%) | 2 (<1%) | 15 (4%) | 12 (3%) | 0 | 12 (3%) |
| Bilirubin | 0 | 2 (<1%) | 2 (<1%) | 1 (<1%) | 1 (<1%) | 2 (<1%) |
| Creatine kinase | 13 (3%) | 31 (8%) | 44 (12%) | 13 (3%) | 22 (6%) | 35 (9%) |
| Creatinine | 0 | 0 | 0 | 0 | 1 (<1%) | 1 (<1%) |
| Glucose | 4 (1%) | 1 (<1%) | 5 (1%) | 5 (1%) | 0 | 5 (1%) |
| Sodium | 2 (<1%) | 0 | 2 (<1%) | 1 (<1%) | 0 | 1 (<1%) |
| Triglycerides | 13 (3%) | 5 (1%) | 18 (5%) | 13 (3%) | 8 (2%) | 21 (6%) |
| Hematology | ||||||
| Hemoglobin | 0 | 1 (<1%) | 1 (<1%) | 0 | 0 | 0 |
| Neutrophils absolute | 6 (2%) | 3 (<1%) | 9 (2%) | 4 (1%) | 1 (<1%) | 5 (1%) |
| Platelets | 2 (<1%) | 0 | 2 (<1%) | 2 (<1%) | 0 | 2 (<1%) |
| WBC | 0 | 0 | 0 | 1 (<1%) | 0 | 1 (<1%) |
Other Information:
Many of the adverse events listed below (nausea, vomiting, diarrhoea, fever, fatigue, rash) occur commonly as part of abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If ZIAGEN has been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart ZIAGEN, this should be done only under direct medical supervision (see Special considerations following an interruption of ZIAGEN therapy).
The following adverse events may be related to ZIAGEN. The majority of these have not been treatment limiting.
*Metabolism and nutrition disorders
* Common:anorexia, hyperlactataemia Rare:lactic acidosis (see Special Warnings and Precautions for Use) Redistribution/accumulation of body fat (see Special warnings and special precautions for use). The incidence of this event is dependent on multiple factors including the particular antiretroviral drug combination.
*Nervous system disorders
* Common:headache
*Gastrointestinal disorders
* Common:nausea, vomiting, diarrhoea * Rare:pancreatitis has been reported, but a causal relationship to ZIAGEN treatment is uncertain.
*Skin and subcutaneous tissue disorders
* Common:rash (without systemic symptoms) * Very rare:erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
*General disorders and administration site disorders
* Common:fever, lethargy, fatigue. In controlled clinical studies laboratory abnormalities related to ZIAGEN treatment were uncommon, with no differences in incidence observed between ZIAGEN treated patients and the control arms.
Hypersensitivity: (see also PRECAUTIONS)
Clinical trial data In clinical studies approximately 5% of subjects given abacavir developed a hypersensitivity reaction, which in rare cases has proved fatal. Over 28,000 patients received ZIAGEN in clinical trials up to 30 June 2000. In this period there were seven cases in which the fatal outcome may have been due to hypersensitivity. Screening for the HLA-B *5701 status, in a prospective, randomised, controlled clinical trial showed that 3.4% of subjects with a negative HLA-B *5701 status receiving abacavir developed a hypersensitivity reaction. Following detailed analyses of the first 406/636 patients, the HSR is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Table 4 lists the symptoms occurring in more than 10% of the first 406 patients with the hypersensitivity reaction (HSR).
| Table 4 - Symptoms reported in 10% or more of hypersensitivity cases * | |
| Symptom in HSR | % of HSR cases with symptom# |
| Fever | 83% |
| Rash | 68% |
| Nausea | 38% |
| Vomiting | 25% |
| Malaise | 19% |
| Fatigue | 15% |
| Diarrhoea | 18% |
| Pruritus | 17% |
| Headache | 17% |
| Myalgia | 13% |
| Chills | 12% |
| Mouth and throat involvement | 11% |
* Approximately 5% of HSR are reported from all patients in clinical studies # Incidence of symptoms recorded for HSR as of 30/09/98. Symptoms of HSR can occur at any time while being treated with ZIAGEN but usually appear within the first six weeks of initiation of treatment with ZIAGEN (median time to onset was 11 days). The majority of 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. Further hypersensitivity reactions reported in at least 10% of patients were abdominal pain, and elevated liver function tests. Other signs and symptoms may include rarely myolysis, arthralgia, oedema, dyspnoea, sore throat, cough, headache, paraesthesia, reports of adult respiratory distress syndrome and respiratory failure. Physical findings may include lymphadenopathy and, occasionally mucous membrane lesions (conjunctivitis and mouth ulceration) and hypotension. Laboratory abnormalities that may accompany abacavir hypersensitivity include elevated liver function tests, creatine phosphokinase, creatinine or lymphopenia. Renal failure and hepatic failure and anaphylaxis have been reported in association with this hypersensitivity reaction. Some patients with hypersensitivity reactions were initially thought to have respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis or reactions to other medications. This delay in diagnosis of hypersensitivity has resulted in ZIAGEN being continued or re-introduced, leading to more hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases. If a hypersensitivity reaction cannot be ruled out, ZIAGEN or any other medicinal product containing abacavir (e.g. KIVEXA, TRIZIVIR) should not be restarted. The symptoms related to this hypersensitivity reaction worsen with continued therapy, and usually resolve upon discontinuation of ZIAGEN. Risk factors that may predict the occurrence or severity of hypersensitivity to abacavir have not been identified. Restarting ZIAGEN following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction may be more severe than on initial presentation, and may include life-threatening hypotension and death. Regardless of their HLA-B *5701 status, patients who develop this hypersensitivity reaction must discontinue ZIAGEN and must never be rechallenged with ZIAGEN or any other medicinal product containing abacavir (e.g. TRIZIVIR, KIVEXA). (see PRECAUTIONS.) There have been infrequent reports of hypersensitivity reactions with a rapid onset, including life threatening reactions, following reintroduction of ZIAGEN, in patients who had only one of the key symptoms of a hypersensitivity reaction (ie rash, fever, gastrointestinal, respiratory or constitutional symptoms such as fatigue or malaise). On very rare occasions hypersensitivity reactions have been reported in patients who have re- started therapy, and who had no apparent preceding symptoms of a hypersensitivity reaction. Some of these cases were poorly documented. The clinical significance of these reports is unclear.
Post-marketing data:
World-wide patient exposure to marketed ZIAGEN is approximately 353,000 patient years up to 31 December 2003. The HSR reporting rate in these patients is approximately 2.5 per 1000 patient years of exposure. A total of 17 patients may have died due to HSR following exposure to marketed ZIAGEN in this period.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing. For patients who are unable to swallow tablets, the tablet(s) may be crushed and 100% of the crushed tablet could be added to a small amount of semi-solid fold or liquid, all of which should be consumed immediately. Alternatively, abacavir is available as an oral solution. More accurate dosing can be achieved with the oral solution of abacavir.
Adults and adolescents weighing at least 30 kg: The recommended dose of ZIAGEN is 600 mg daily. This may be administered as either 300mg (one tablet) twice daily or 600mg (two tablets) once daily.
Children >= three months and weighing less than 30 kg:
A dosing regimen according to weight bands is recommended for ZIAGEN scored tablets. This dosing regimen for paediatric patients weighing 14 - 30 kg is based primarily on pharmacokinetic modelling. Clinicians should be aware that variability in drug exposures is possible and patients should be monitored accordingly.
Children weighing 14 to 21 kg: one-half of a scored abacavir tablet twice daily. Children weighing > 21 kg to < 30 kg: one-half of a scored abacavir tablet taken in the morning and one whole tablet taken in the evening. Children weighing at least 30 kg: the adult dosage of 300 mg twice daily or 600 mg once daily should be taken.
Children Weighing <14kg: ZIAGEN scored tablets should not be used for children weighing less than 14 kg, since doses can not be appropriately adjusted for the weight of the child. For these patients and for patients, who are unable to swallow tablets, oral solutions should be used."
Adults and adolescents over 12 years:
The recommended dose of ZIAGEN is 300 mg (15 mL of solution) twice daily.
Children three months to 12 years: The recommended dosage is 8 mg/kg twice daily up to a maximum of 600 mg (30 mL of oral solution) daily.
*Children less than three months:
There are no data available on the use of ZIAGEN in this age group.
Food reduces the Cmax and extends the Tmax of abacavir but the amount of drug absorbed is not reduced. The clinical significance of this is not known (See Pharmacokinetics).
Renal impairment: Only about 2% of abacavir is excreted unchanged in the urine. As there are no pharmacokinetic data available in renally impaired patients no dosing recommendations can be made at this time.
Hepatic impairment:
Abacavir is metabolised primarily by the liver. Significant changes are only likely to be seen in patients with decompensated chronic liver disease, but in the absence of data, no dosage recommendations can be made. ZIAGEN is contra-indicated in patients with moderate or severe hepatic impairment, as the pharmacokinetics have not been studied in these patient groups. (SEE CONTRAINDICATIONS).
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 haemodialysis. Contact the Poisons Information Centre on 13 11 26 for advice on management of overdose.
ZIAGEN tablets are supplied in polyvinyl chloride/foil blister packs containing 60 tablets. The unscored film-coated tablets are yellow, biconvex, capsule shaped and engraved with "GX 623" on one side Each tablet contains 300 mg abacavir base as the sulfate salt. The scored film-coated tablets are yellow, biconvex, capsule shaped and engraved with "GX 623" on both sides. Each tablet contains 300 mg abacavir base as the sulfate salt. Store below 30oC.
ZIAGEN Oral Solution is supplied in high density polyethylene (HDPE) bottles containing 240 mL of oral solution. A 10 mL oral dosing syringe and an adapter are also included in the pack for accurate measurement of the prescribed dose. The oral solution should be discarded two months after first opening. The oral solution is a clear to slightly opalescent yellowish aqueous solution with strawberry/banana flavouring. Each 1mL of solution contains 20 mg abacavir base as the sulfate salt. Store below 30oC.
ViiV Healthcare Pty Ltd Level 4, 436 Johnston Street Abbotsford, Victoria, 3067 Australia
S4
09 June 1999
27 August 2012
ZIAGEN(r), KIVEXA(r) and TRIZIVIR(r) are registered trade marks of the ViiV healthcare group of companies. Version 5.0