Ziagen

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Ziagen 300 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 300 mg of abacavir (as sulfate).  
 
For the full list of excipients see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablets) 
 
The scored tablets are yellow, biconvex, capsule shaped and are engraved with ‘GX 623’ on both 
sides.  
 
The tablet can be divided into equal halves. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ziagen is indicated in antiretroviral combination therapy for the treatment of Human 
Immunodeficiency Virus (HIV) infection in adults,  adolescents and children (see sections 4.4 and 
5.1). 
 
The demonstration of the benefit of Ziagen is mainly based on results of studies performed with a 
twice daily regimen, in treatment-naïve adult patients on combination therapy (see section 5.1).  
 
Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be 
performed in any HIV-infected patient, irrespective of racial origin(see section 4.4). Abacavir should 
not be used in patients known to carry the HLA-B*5701 allele 
 
 
4.2 Posology and method of administration 
 
Ziagen should be prescribed by physicians experienced in the management of HIV infection.  
 
Ziagen can be taken with or without food. 
 
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without 
crushing. 
 
Ziagen is also available as an oral solution for use in children over three months of age and weighing 
less than 14 kg and for those patients for whom the tablets are inappropriate. 
 
Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added 
to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see 
section 5.2). 
 
Adults, adolescents and children (weighing at least 25 kg): 
  



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The recommended dose of Ziagen is 600 mg daily. This may be administered as either 300 mg (one 
tablet) twice daily or 600 mg (two tablets) once daily (see sections 4.4 and 5.1).  
 
Children (weighing less than 25 kg): 
 
Dosing according to weight bands is recommended for Ziagen tablets.  
 
Children weighing ≥ 20 kg to < 25 kg: The recommended dose is 450 mg daily. This may be 
administered as either one 150 mg (one half of a tablet) taken in the morning and 300 mg (one whole 
tablet) taken in the evening, or 450 mg (one and a half tablets) taken once daily. 
 
Children weighing 14 to < 20 kg: The recommended dose is 300 mg daily. This may be administered 
as either 150 mg (one half of a tablet) twice daily or 300 mg (one whole tablet) once daily. 
 
Children less than three months of age: The clinical experience in children aged less than three 
months is limited and are insufficient to propose specific dosage recommendations (see section 5.2). 
 
Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take 
the recommended once daily dose (as described above) approximately 12 hours after the last twice 
daily dose, and then continue to take the recommended once daily dose (as described above) 
approximately every 24 hours. When changing back to a twice daily regimen, patients should take the 
recommended twice daily dose approximately 24 hours after the last once daily dose. 
 
Special populations 
 
Renal impairment 
 No dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen is 
not recommended for patients with end-stage renal disease (see section 5.2). 
 
Hepatic impairment  
 Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made in 
patients with mild hepatic impairment (Child-Pugh score 5-6). In patients with moderate or severe 
hepatic impairment, no clinical data are available, therefore the use of abacavir is not recommended 
unless judged necessary. If abacavir is used in patients with mild  hepatic impairment, then close 
monitoring is required, including  monitoring of abacavir plasma levels if feasible (see sections 4.4 
and  5.2).  
 
Elderly  
No pharmacokinetic data are currently available in patients over 65 years of age. 
 
4.3 Contraindications 
 
 
Hypersensitivity to abacavir or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8. 
 
 
 
4.4 Special warnings and  precautions for use 
 

Hypersensitivity reactions (see also section 4.8) 
 
Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) characterised 
by fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been 
observed with abacavir, some of which have been life-threatening, and in rare cases fatal, when not 
managed appropriately. 



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The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele. 
However, abacavir HSRs have been reported at a lower frequency in patients who do not carry this 
allele.   
 

Therefore the following should be adhered to: 

• HLA-B*5701 status must always be documented prior to initiating therapy. 

• Ziagen should never be initiated in patients with a positive HLA-B*5701 status, nor in 
patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous 
abacavir-containing regimen. (e.g. Kivexa, Trizivir, Triumeq)  

• Ziagen must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an 
HSR is suspected. Delay in stopping treatment with Ziagen after the onset of hypersensitivity 
may result in a life-threatening reaction.  

• After stopping treatment with Ziagen for reasons of a suspected HSR, Ziagen or any other 
medicinal product containing abacavir (e.g. Kivexa, Trizivir, Triumeq) must never be re-
initiated.  

• Restarting abacavir containing products following a suspected abacavir HSR can result in a 
prompt return of symptoms within hours. This recurrence is usually more severe than on 
initial presentation, and may include life-threatening hypotension and death. 

• In order to avoid restarting abacavir, patients who have experienced a suspected HSR should 
be instructed to dispose of their remaining Ziagen tablets  

 
Clinical description of abacavir HSR 
 
Abacavir HSR has been well characterised through clinical studies and during post marketing follow-
up. Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation 
of treatment with abacavir, although these reactions may occur at any time during therapy. 
 
Almost all HSR to abacavir include fever and/or rash . Other signs and symptoms that have been 
observed as part of abacavir HSR are described in detail in section 4.8 (Description of selected 
adverse reactions), including respiratory and gastrointestinal symptoms. Importantly, such symptoms 
may lead to misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), or 
gastroenteritis. 
 
The symptoms related to HSR worsen with continued therapy and can be life-threatening. These 
symptoms usually resolve upon discontinuation of abacavir. 
 
Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have also 
experienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8 
Description of selected adverse reactions).  Restarting abacavir in such patients must be done in a 
setting where medical assistance is readily available. 
 
 
 
 

 
 
Mitochondrial dysfunction following exposure in utero  
 
 



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Nucleoside and nucleotide  analogues  may impact mitochondrial function to a variable degree, which 
is most pronounced with stavudine, didanosine and zidovudine. There have been reports of 
mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside 
analogues ; these have predominantly concerned treatment with regimens containing zidovudine.The 
main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic 
disorders (hyperlactatemia, hyperlipasemia). These events have  often been  transitory. Late onset 
neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). 
Whether such  neurological disorders are transient or permanent is currently unknown. These findings 
should be considered for any child exposed in utero to  nucleotide and nucleotide  analogues, who 
presents with severe clinical findings of unknown etiology, particularly neurologic findings.  These 
findings do not affect current national recommendations to use antiretroviral therapy in pregnant 
women to prevent vertical transmission of HIV. 
 
Weight and metabolic parameters 

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. 

 
Pancreatitis 
 
Pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain. 
 
Triple nucleoside therapy 
 
In patients with high viral load (>100,000 copies/ml) the choice of a triple combination with abacavir, 
lamivudine and zidovudine needs special consideration (see section 5.1). 
 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily 
regimen. 
 
Liver disease 
 
The safety and efficacy of Ziagen has not been established in patients with significant underlying liver 
disorders. Ziagen is  not recommended  in patients with  moderate or severe hepatic impairment (see 
sections 4.2 and 5.2 ).  
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy, and should be 
monitored according to standard practice. If there is evidence of worsening liver disease in such 
patients, interruption or discontinuation of treatment must be considered. 
 
 
Patients co-infected with chronic hepatitis B or C virus 
 
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an 
increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral 
therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal 
products. 
 
 
Renal disease 
 
Ziagen should not be administered to patients with end-stage renal disease (see section 5.2). 



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Immune Reactivation Syndrome 
 
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens 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 CART. 
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, 
and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment 
instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) 
have also been reported to occur in the setting of immune reactivation; however, the reported time to 
onset is more variable and these events can occur many months after initiation of treatment. 
 
Osteonecrosis 
 
Although the aetiology 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 CART. 
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
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 these associated HIV diseases. 
 
Transmission 
 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines.  

Myocardial Infarction 

Observational studies have shown an association between myocardial infarction and the use of 
abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials 
showed limited numbers of myocardial infarction and could not exclude a small increase in risk.  
Overall the available data from observational cohorts and from randomised trials show some 
inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and 
the risk of myocardial infarction.  To date, there is no established biological mechanism to explain a 
potential increase in risk.  When prescribing Ziagen, action should be taken to try to minimize all 
modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the 
potential for P450 mediated interactions with other medicinal products involving abacavir is low.  
P450 does not play a major role in the metabolism of abacavir, and abacavir does not inhibit 
metabolism mediated by CYP 3A4.  Abacavir has also been shown in vitro not to inhibit CYP 3A4, 
CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism  
has not been observed in clinical studies. Therefore, there is little potential for interactions with 
antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies 
have shown that there are no clinically significant interactions between abacavir, zidovudine, and 
lamivudine. 
 



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Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on 
UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.  
 
Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC 
of abacavir of about 41%.  These findings are not considered clinically significant. Abacavir has no 
effect on the metabolism of ethanol.  
 
Methadone: in a pharmacokinetic study, co-administration 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%. The induction of drug 
metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and 
abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as 
occasionally methadone re-titration may be required.  
 
Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is 
possible but has not been studied. 
 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
both animal data as well as clinical experience in pregnant women should be taken into account. 
Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see 
section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical 
relevance in human of these data is unknown. Placental transfer of abacavir and/or its related 
metabolites has been shown to occur in human.  
 
In pregnant women, more than 800 outcomes after first trimester exposure and more than 1000 
outcomes after second and third trimester exposure indicate no malformative and foetal/neonatal effect 
of abacavir. The malformative risk is unlikely in humans based on those data. 
 
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 (see section 4.4). 
  
Breast-feeding 
 
Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into 
human milk. There are no data available on the safety of abacavir when administered to babies less 
than three months old. It is recommended that HIV infected women do not breast-feed their infants 
under any circumstances in order to avoid transmission of HIV.  
 
Fertility 
 
Studies in animals showed that abacavir had no effect on fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on ability to drive and use machines have been performed. 
 
4.8 Undesirable effects  
 



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For many adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide range 
of medicinal products used in the management of HIV infection or as a result of the disease process. 
Many of the adverse reactions listed  below occur commonly (nausea, vomiting, diarrhoea, fever, 
lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these 
symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). 
Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis 
have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal 
products containing abacavir should be permanently discontinued. 
 
 
Many of the adverse reactions have not been treatment limiting.  The following convention has been 
used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 
to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000). 
 
Metabolism and nutrition disorders 
Common: anorexia 
Very rare: lactic acidosis 
 
Nervous system disorders 
Common: headache 
 
Gastrointestinal disorders 
Common: nausea, vomiting, diarrhoea  
Rare: pancreatitis  
 
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 conditions 
Common: fever, lethargy, fatigue  
 

Description of Selected Adverse Reactions 

Abacavir hypersensitivity reactions 
The signs and symptoms of this HSR are listed below. These have been identified either from clinical 
studies or post marketing surveillance. Those reported in at least 10% of patients with a 
hypersensitivity reaction are in bold text. 
 
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. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as 
lethargy and malaise.  
 
Skin Rash (usually maculopapular or urticarial) 

 
Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration 

 
Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome, 

respiratory failure 
 

Miscellaneous Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, 
conjunctivitis, anaphylaxis 
 

Neurological/Psychiatry Headache, paraesthesia 
 



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Haematological Lymphopenia 
 

Liver/pancreas Elevated liver function tests, hepatitis, hepatic failure 
 

Musculoskeletal Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase 
 

Urology Elevated creatinine, renal failure 
 

 
 
Symptoms related to this HSR worsen with continued therapy and can be life- threatening and in rare 
instance, have been fatal. 
 
Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. 
This recurrence of the HSR is usually more severe than on initial presentation, and may include life-
threatening hypotension and death. Similar reactions have also occurred infrequently after restarting 
abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to 
stopping abacavir; and on very rare occasions have also been seen in patients who have restarted 
therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir 
tolerant). 
 
Metabolic parameters                                                                                                                       
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4) 

Immune reactivation syndrome  
In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported to occur in the setting of immune reactivation; however, the reported time to onset 
is more variable and these events can occur many months after initiation of treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see 
section 4.4). 
 
Changes in laboratory chemistries  
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. 
 
Paediatric population 
 
1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial 
(COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section 
5.1). No additional safety issues have been identified in paediatric subjects receiving either once or 
twice daily dosing compared to adults. 
 
Reporting of suspected adverse reactions  
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9  Overdose 
 
Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to 
patients in clinical studies. No additional adverse reactions to those reported for normal doses were 
reported.  The effects of higher doses are not known. If overdose occurs the patient should be 
monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as 
necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis. 
 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code: J05AF06 

 
Mechanism of action 
 
Abacavir is a NRTI. It is a potent selective inhibitor of HIV-1 and HIV-2.  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.  The antiviral 
activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse 
transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir  or 
zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease 
inhibitor (PI) amprenavir. 

 
Resistance 
 
In vitro resistance 
 
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific 
genotypic changes in the reverse transcriptase (RT) codon region (codons M184V, K65R, L74V and 
Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations 
for a clinically relevant increase in EC50 over wild-type virus.  
 
In vivo resistance (Therapy naïve patients)   
 
Isolates from most patients experiencing virological failure with a regimen containing abacavir in 
pivotal clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or 
M184I selection (45%).  The overall selection frequency for M184V or M184I was high (54%), and 
less common was the selection of L74V (5%), K65R (1%) and Y115F (1%).  The inclusion of 
zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in the 
presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%). 
 



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Therapy Abacavir + Combivir1  

Abacavir + 
lamivudine + 

NNRTI 

Abacavir + 
lamivudine + 

PI (or 
PI/ritonavir) 

Total 

Number of 
Subjects 282 1094 909 2285 

Number of 
Virological 

Failures 
43 90  158 291 

Number of 
On-Therapy  
Genotypes 

40 (100%) 51 (100%)2 141 (100%) 232 (100%) 

K65R 0 1 (2%) 2 (1%) 3 (1%) 

L74V 0 9 (18%) 3 (2%) 12 (5%) 
Y115F 0 2 (4%) 0 2 (1%) 

M184V/I 34 (85%) 22 (43%) 70 (50%) 126 (54%) 
TAMs3 3 (8%) 2 (4%) 4 (3%) 9 (4%) 

1.Combivir is a fixed dose combination of lamivudine and zidovudine 
2.Includes three non-virological failures and four unconfirmed virological failures. 
3. Number of subjects with ≥1 Thymidine Analogue Mutations (TAMs). 
 
 
TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis of 
six clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine 
(0/127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine 
(22/86, 26%).  
 
In vivo resistance (Therapy experienced patients) 
 
Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates 
of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to 
other nucleoside inhibitors. In a meta-analysis of five clinical trials where abacavir was added to 
intensify therapy, of 166 subjects, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had 
M41L, 30 (18%) had K70R and 25 (15%) had D67N.  K65R was absent and L74V and Y115F were 
uncommon (≤3%).  Logistic regression modelling of the predictive value for genotype (adjusted for 
baseline plasma HIV-1 RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral 
therapies), showed that the presence of 3 or more NRTI resistance-associated mutations was 
associated with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 
(p≤0.012).  In addition, the 69 insertion complex or the Q151M mutation, usually found in 
combination with A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir. 
 



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Baseline 
Reverse 

Transcriptase 
Mutation 

Week 4 
(n = 166) 

n 
Median 

Change vRNA 
(log10 c/ml) 

Percent with 
<400 copies/ml 

vRNA 
None 15 -0.96 40% 

M184V alone  75 -0.74 64% 
Any one NRTI 

mutation 82 -0.72 65% 

Any two NRTI-
associated 
mutations  

22 -0.82 32% 

Any three 
NRTI-

associated 
mutations 

19 -0.30 5% 

Four or more 
NRTI-

associated 
mutations 

28 -0.07 11% 

 
Phenotypic resistance and cross-resistance 
 
Phenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation, 
or M184V with multiple TAMs. Phenotypic cross-resistance to other NRTIs with M184V or M184I 
mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviral 
activities against such HIV-1 variants. The presence of M184V with K65R does give rise to cross-
resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives rise 
to cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F 
gives rise to cross-resistance between abacavir and lamivudine. Appropriate use of abacavir can be 
guided using currently recommended resistance algorithms. 
 
Cross-resistance between abacavir and antiretrovirals from other classes (e.g. PIs or NNRTIs) is 
unlikely.  
 
 
 
 
Clinical efficacy and safety 
 
The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adult 
treatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination with 
zidovudine and lamivudine. 
 
Twice daily (300 mg) administration:  
 
• Therapy naïve adults 
 
In adults treated with abacavir in combination with lamivudine and zidovudine the proportion of 
patients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treat 
analysis at 48 weeks) with corresponding rise in CD4 cells. 
 
One randomised, double blind, placebo controlled clinical study in adults has compared the 
combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and 
zidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinued 
randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence 
between the treatment regimens at week 48. Although a similar antiviral effect was observed between 



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the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable 
viral load (≤400 copies/ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT), 
86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir 
combination, particularly in the subset of patients with high viral load (>100,000 copies/ml at baseline; 
ITT, 46% versus 55%; AT, 84% versus 93% for abacavir and indinavir respectively).  
 
In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral 
therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 
300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg 
once daily. The duration of double-blind treatment was at least 48 weeks.  In the intent-to-treat (ITT) 
population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine 
group, achieved a virologic response of plasma HIV-1 RNA ≤50 copies/ml by Week 48 (point 
estimate for treatment difference: 0.8, 95% CI -6.3, 7.9). In the as treated (AT) analysis the difference 
between both treatment arms was more noticeable (88% of patients in the abacavir group, compared to 
95% of patients in the zidovudine group (point estimate for treatment difference: -6.8, 95% CI -
11.8; -1.7).  However, both analyses were compatible with a conclusion of non-inferiority between 
both treatment arms. 
 
ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147 
antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine 
(3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median 
follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be 
virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml) 
with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and 13% on the 4 
drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the 
proportion of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the 
ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety 
Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of 
patients with virologic failure. The remaining arms were continued in a blinded fashion. After a 
median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the 
ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant 
difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study, 
addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy. 
 
 
 
 
 
 

  ZDV/3TC/ABC ZDV/3TC/EFV ZDV/3TC/ABC/EFV 
Virologic failure (HIV 
RNA >200 copies/ml) 

32 weeks 26% 16% 13% 
144 weeks - 26% 25% 

Virologic success (48 
weeks HIV RNA < 50 
copies/ml) 

 63% 80% 86% 

 
• Therapy experienced adults 
 
In adults moderately exposed to antiretroviral therapy the addition of abacavir to combination 
antiretroviral therapy provided modest benefits in reducing viral load (median change 
0.44 log10 copies/ml at 16 weeks).  
 
In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit 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. 
 
 



14 

Once daily (600 mg) administration: 
 
• Therapy naïve adults 
 
The once daily regimen of abacavir is supported by a 48 weeks multi-centre, double-blind, controlled 
study (CNA30021) of 770 HIV-infected, therapy-naïve adults. These were primarily asymptomatic 
HIV infected patients - Centre for Disease Control and Prevention (CDC) stage A. They were 
randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, in combination with 
efavirenz and lamivudine given once daily. Similar clinical success (point estimate for treatment 
difference -1.7, 95% CI -8.4, 4.9) was observed for both regimens. From these results, it can be 
concluded with 95% confidence that the true difference is no greater than 8.4% in favour of the twice 
daily regimen. This potential difference is sufficiently small to draw an overall conclusion of non-
inferiority of abacavir once daily over abacavir twice daily.   
 
There was a low, similar overall incidence of virologic failure (viral load >50 copies/ml) in both the 
once and twice daily treatment groups (10% and 8% respectively). In the small sample size for 
genotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once 
daily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limited 
data derived from this study.  Long term data with abacavir used as a once daily regimen (beyond 48 
weeks) are currently limited. 
 
• Therapy experienced adults 
 
In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised  and 
received treatment with either the fixed-dose combination of abacavir/lamivudine (FDC) once daily or 
abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir 
and a PI or an NNRTI for 48 weeks. Results indicate that the FDC group was non-inferior to the 
abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area 
under the curve minus baseline (AAUCMB, -1.65 log10 copies/ml versus -1.83 log10 copies/ml 
respectively, 95% CI -0.13, 0.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%) 
and < 400 copies/ml (54% versus 57%) were also similar in each group (ITT population). However, as 
there were only moderately experienced patients included in this study with an imbalance in baseline 
viral load between the arms, these results should be interpreted with caution.  
 
In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing 
abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were 
randomised to continue this regimen or switch to abacavir/lamivudine FDC plus a PI or NNRTI for 48 
weeks.                                                                                                                                                         
 
Results indicate that the FDC group was associated with a similar virologic outcome (non-inferior) 
compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-1 RNA 
< 50 copies/ml (90% and 85% respectively, 95% CI  -2.7, 13.5).  
 
Additional information: 
 
The safety and efficacy of Ziagen in a number of different multidrug combination regimens is still not 
completely assessed (particularly in combination with NNRTIs). 
 
 Abacavir penetrates the cerebrospinal fluid (CSF) (see section 5.2), and has been shown to reduce 
HIV-1 RNA levels in the CSF.  However, no effects on neuropsychological performance were seen 
when it was administered to patients with AIDS dementia complex. 
 
Paediatric population: 
 
A randomised comparison of a regimen including once daily vs twice daily dosing of abacavir and 
lamivudine was undertaken within a randomised, multicentre, controlled study of HIV-infected, 
paediatric patients. 1206 paediatric patients aged 3 months to 17 years enrolled in the ARROW Trial 



15 

(COL105677) and were dosed according to the weight - band dosing recommendations in the World 
Health Organisation treatment guidelines (Antiretroviral therapy of HIV infection in infants and 
children, 2006). After 36 weeks on a regimen including twice daily abacavir and lamivudine, 669 
eligible subjects were randomised to either continue twice daily dosing or switch to once daily 
abacavir and lamivudine for at least 96 weeks. Of note, from this study clinical data were not available 
for children under one year old.   The results are summarised in the table below: 
 
Virological Response Based on Plasma HIV-1 RNA less than 80 copies/ml at Week 48 and Week 
96 in the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW 
(Observed Analysis) 
 

 Twice Daily 
N (%) 

Once Daily 
N (%) 

Week 0 (After ≥36 Weeks on Treatment) 
Plasma HIV-1 RNA <80 c/ml 250/331 (76) 237/335 (71) 
Risk difference (once daily-

twice daily) 
-4.8% (95% CI -11.5% to +1.9%), p=0.16 

Week 48 
Plasma HIV-1 RNA <80 c/ml 242/331 (73) 236/330 (72) 
Risk difference (once daily-

twice daily) 
-1.6% (95% CI -8.4% to +5.2%), p=0.65 

Week 96 
Plasma HIV-1 RNA <80 c/ml 234/326 (72) 230/331 (69) 
Risk difference (once daily-

twice daily) 
-2.3% (95% CI -9.3% to +4.7%), p=0.52 

 
 
The abacavir + lamivudine once daily dosing group was demonstrated to be non-inferior to the twice 
daily group according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of 
<80 c/ml at Week 48 as well as at Week 96 (secondary endpoint) and all other thresholds tested 
(<200c/ml, <400c/ml, <1000c/ml), which all fell well within this non-inferiority margin. Subgroup 
analyses testing for heterogeneity of once vs twice daily demonstrated no significant effect of sex, age, 
or viral load at randomisation. Conclusions supported non-inferiority regardless of analysis method. 
 
In a separate study comparing the unblinded NRTI combinations (with or without blinded nelfinavir) 
in children, a greater proportion treated with abacavir and lamivudine (71%) or abacavir and 
zidovudine (60%) had HIV-1 RNA ≤400 copies/ml at 48 weeks, compared with those treated with 
lamivudine and zidovudine (47%)[ p=0.09, intention to treat analysis]. Similarly, greater proportions 
of children treated with the abacavir containing combinations had HIV-1 RNA ≤50 copies/ml at 48 
weeks (53%, 42% and 28% respectively, p=0.07). 
 
In a pharmacokinetic study (PENTA 15), four virologically controlled subjects less than 12 months of 
age switched from abacavir plus lamivudine oral solution twice daily to a once daily regimen. Three 
subjects had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48. 
No safety concerns were observed in these subjects. 
 
5.2 Pharmacokinetic properties 
 
Absorption  
 
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 (tmax) to maximal 
serum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour for 
the solution formulation.  
 



16 

At therapeutic dosages a dosage of 300 mg twice daily, the mean (CV) steady state Cmax and Cmin of 
abacavir are approximately 3.00 µg/ml (30%) and 0.01 µg/ml (99%), respectively. The mean (CV) 
AUC over a dosing interval of 12 hours was 6.02 µg.h/ml (29%), equivalent to a daily AUC of 
approximately 12.0 µg.h/ml.  The Cmax value for the oral solution is slightly higher than the tablet.  
After a 600 mg abacavir tablet dose, the mean (CV) abacavir Cmax was approximately 4.26 µg/ml 
(28%) and the mean (CV) AUC∞ was 11.95 µg.h/ml (21%). 
 
Food delayed absorption and decreased Cmax but did not affect overall plasma concentrations (AUC). 
Therefore Ziagen can be taken with or without food.  
 
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 data, 
assuming that the patient crushes and transfers 100% of the tablet and ingests immediately. 
 
Distribution 
 
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 CSF, with a CSF to 
plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold 
greater than the IC50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twice 
daily.  
 
Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to 
human plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactions 
with other medicinal products through plasma protein binding displacement. 
 
Biotransformation 
 
Abacavir is primarily metabolised by the liver with approximately 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. The metabolites are excreted in the urine. 
 
Elimination 
 
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 accumulation of abacavir.  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. 
 
Intracellular pharmacokinetics 
 
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg 
dose taken prior to the 24 hour sampling period, 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.  In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP 
exposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32 %, Cmax24,ss + 99 % 
and Ctrough + 18 %) compared to the 300 mg twice daily regimen.  Overall, these data support the use 
of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy 
and safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021- 
See section 5.1 Clinical experience). 
 
Special patient populations  



17 

 
Hepatic impairment 
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in 
patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose ; the 
median (range) AUC value was 24.1 (10.4 to 54.8) ug.h/ml. The results showed that there was a mean 
(90%CI)  increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the 
elimination half-life.  No definitive  recommendation on dosage reduction is possible in patients with 
mild hepatic impairment due to the substantial variability of abacavir exposure. 
Abacavir is not recommended in patients with moderate or severe hepatic impairment. 
 
 
Renal impairment 
 
Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged 
in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to 
patients with normal renal function. Therefore no dosage reduction is required in patients with renal 
impairment. Based on limited experience Ziagen should be avoided in patients with end-stage renal 
disease. 
 
Paediatric population 
 
According to clinical trials performed in children abacavir is rapidly and well absorbed from oral 
solution and tablet formulations administered to children. Plasma abacavir exposure has been shown to 
be the same for both formulations when administered at the same dose. Children receiving abacavir 
oral solution according to the recommended dosage regimen achieve plasma abacavir exposure similar 
to adults.  Children receiving abacavir oral tablets according to the recommended dosage regimen 
achieve higher plasma abacavir exposure than children receiving oral solution because higher mg/kg 
doses are administered with the tablet formulation.  
 
There are insufficient safety data to recommend the use of Ziagen in infants less than three months 
old. The limited data available indicate that an oral solution dose of 2 mg/kg in neonates less than 30 
days old provides similar or greater AUCs, compared to the 8 mg/kg oral solution dose administered 
to older children. 
 
Pharmacokinetic data were derived from 3 pharmacokinetic studies (PENTA 13, PENTA 15 and 
ARROW PK substudy) enrolling children under 12 years of age. The data are displayed in the table 
below: 

 

Summary of Stead-State Plasma Abacavir AUC (0-24) (µg.h/ml) and Statistical Comparisons for 
Once and Twice-Daily Oral Administration Across Studies 

 
Study 

 
Age Group 

Abacavir  
16 mg/kg Once-

Daily Dosing 
Geometric Mean 

(95% Cl) 

Abacavir  
8 mg/kg Twice-

Daily Dosing 
Geometric Mean 

(95% Cl) 

Once-Versus 
Twice-Daily 
Comparison 

GLS Mean Ratio 
(90% Cl) 

ARROW PK 
Substudy 

Part 1 

3 to 12 years 
(N=36) 

15.3 
(13.3-17.5) 

15.6 
(13.7-17.8) 

0.98 
(0.89, 1.08) 

PENTA 13 2 to 12 years 
(N=14) 

13.4 
(11.8-15.2) 

9.91 
(8.3-11.9) 

1.35 
(1.19-1.54) 

PENTA 15 3 to 36 months 
(N=18) 

11.6 
(9.89-13.5) 

10.9 
(8.9-13.2) 

1.07 
(0.92-1.23) 

 



18 

In PENTA 15 study, the geometric mean plasma abacavir AUC(0-24) (95% CI) of the four subjects 
under 12 months of age who switch from a twice daily to a once daily regimen (see section 5.1) are 15.9 
(8.86, 28.5) µg.h/ml in the once-daily dosing and 12.7 (6.52, 24.6) µg.h/ml in the twice-daily dosing. 

Elderly 
 
The pharmacokinetics of abacavir has not been studied in patients over 65 years of age. 
 
5.3 Preclinical safety data 
 
Abacavir was not mutagenic in bacterial tests but showed activity in vitro in the human lymphocyte 
chromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus test. This is 
consistent with the known activity of other nucleoside analogues. These results indicate that abacavir 
has a weak potential to cause chromosomal damage both in vitro and in vivo at high test 
concentrations. 
 
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 rats in the thyroid gland of males and 
the liver, urinary bladder, lymph nodes and the subcutis of females.  
 
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. The exception was the preputial gland tumour which occurred at a dose of 
110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 
and 7 times the human systemic exposure during therapy. While the carcinogenic potential in humans 
is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential 
clinical benefit. 
 
In pre-clinical toxicology studies, abacavir treatment was shown to increase liver weights in rats and 
monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that 
abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the 
metabolism of other medicinal products hepatically metabolised has not been observed in man. 
 
 
 
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. 
 
In reproductive toxicity studies, embryo and foetal toxicity have been observed in rats but not in 
rabbits.  These findings included decreased foetal body weight, foetal oedema, and an increase in 
skeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can be 
drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.  
 
A fertility study in the rat has shown that abacavir had no effect on male or female fertility. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1  List of excipients 
 
Tablet Core 
Microcrystalline cellulose 
Sodium starch glycollate 
Magnesium stearate 
Colloidal anhydrous silica 
 



19 

 
Tablet Coating 
Triacetin 
Methylhydroxypropylcellulose 
Titanium dioxide 
Polysorbate 80 
Iron oxide yellow 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf-life 
 
3 years 
 
6.4 Special precautions for storage 
 
Do not store above 30°C  
 
6.5 Nature and contents of container 
 
Child-resistant foil blister packs (polyvinyl chloride/aluminium/paper) containing 60 tablets. 
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/112/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 8 July 1999 
 
Date of latest renewal: 21 March 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  

http://www.ema.europa.eu/
http://www.ema.europa.eu/


20 

1.  NAME OF THE MEDICINAL PRODUCT 
 
Ziagen 20 mg/ml oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of oral solution contains 20 mg of abacavir (as sulfate). 
 
Excipients with known effect: 
 
Sorbitol (E420) 340 mg/ml 
Methyl parahydroxybenzoate (E218) 1.5 mg/ml 
Propyl parahydroxybenzoate (E216) 0.18 mg/ml 
 
For the full list of excipients see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral solution 
 
The oral solution is clear to slightly opalescent yellowish, aqueous solution which may turn into a 
brown colour over time 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ziagen is indicated in antiretroviral combination therapy for the treatment of Human 
Immunodeficiency Virus (HIV) infection in adults, adolescents and children (see sections 4.4 and 
5.1).  
 
The demonstration of the benefit of Ziagen is mainly based on results of studies performed in 
treatment-naïve adult patients on combination therapy with a twice daily regimen (see section 5.1). 
 
Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be 
performed in any HIV-infected patient, irrespective of racial origin(see section 4.4).  Abacavir should 
not be used in patients known to carry the HLA-B*5701 allele. 
 
4.2 Posology and method of administration 
 
Ziagen should be prescribed by physicians experienced in the management of HIV infection.  
 
Ziagen can be taken with or without food.  
 
Ziagen is also available as a tablet formulation.  
 
 
Adults, adolescents and children (weighing at least 25 kg): 
 
The recommended dose of Ziagen is 600 mg daily (30 ml). This may be administered as either 300 mg 
(15 ml) twice daily or 600 mg (30 ml) once daily (see sections 4.4 and 5.1). 
 
 
 



21 

 
 
 
Children (weighing less than 25 kg): 
 
Children from one year of age: The recommended dose is 8 mg/kg twice daily or 16 mg/kg once daily, 
up to a maximum total daily dose of 600 mg (30 ml). 

 
Children from three months to one year of age: The recommended dose is 8 mg/kg twice daily. If a 
twice daily regimen is not feasible, a once daily regimen (16 mg/kg/day) could be considered. It should 
be taken into account that data for the once daily regimen are very limited in this population (see sections 
5.1 and 5.2). 

 
Children less than three months of age: the experience in children aged less than three months is 
limited (see section 5.2). 
 
Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take 
the recomended once daily dose (as described above) approximately 12 hours after the last twice daily 
dose, and then continue to take the recomended once daily dose (as described above) approximately 
every 24 hours. When changing back to a twice daily regimen, patients should take the recommended 
twice daily dose approximately 24 hours after the last once daily dose. 
 
Special populations 
 
Renal impairment 
No dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen is 
not recommended for patients with end-stage renal disease (see section 5.2). 
 
Hepatic impairment  
Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made in 
patients with mild hepatic impairment (Child-Pugh score 5-6). In patients with moderate or severe  
hepatic impairment, no clinical data are available, therefore the use of abacavir is not recommended 
unless judged necessary. If abacavir is used in patients with mild  hepatic impairment, then close 
monitoring is required,  including  monitoring of abacavir plasma levels if feasible (see sections 4.4 
and 5.2).  
 
Elderly  
No pharmacokinetic data are currently available in patients over 65 years of age. 
 
4.3  Contraindications 
 
Hypersensitivity to abacavir or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8. 
 
 
 
4.4  Special warnings and  precautions for use 
 

Hypersensitivity reactions (see also section 4.8): 
 
Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) characterised by 
fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed 
with abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed 
appropriately. 
 



22 

The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele. 
However, abacavir HSRs have been reported at a lower frequency in patients who do not carry this 
allele.   

Therefore the following should be adhered to: 

• HLA-B*5701 status must always be documented prior to initiating therapy. 

• Ziagen should never be initiated in patients with a positive HLA-B*5701 status, nor in patients 
with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-
containing regimen. (e.g. Kivexa, Trizivir, Triumeq)  

• Ziagen must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an 
HSR is suspected. Delay in stopping treatment with Ziagen after the onset of hypersensitivity 
may result in a life-threatening reaction.  

• After stopping treatment with Ziagen for reasons of a suspected HSR, Ziagen or any other 
medicinal product containing abacavir (e.g. Kivexa, Trizivir, Triumeq) must never be re-
initiated.  

• Restarting abacavir containing products following a suspected abacavir HSR can result in a 
prompt return of symptoms within hours. This recurrence is usually more severe than on initial 
presentation, and may include life-threatening hypotension and death. 

• In order to avoid restarting abacavir, patients who have experienced a suspected HSR should be 
instructed to dispose of their remaining Ziagen tablets  

 
• Clinical description of abacavir HSR 

 
Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up. 
Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of 
treatment with abacavir, although these reactions may occur at any time during therapy. 
 
Almost all HSR to abacavir include fever and/or rash. Other signs and symptoms that have been 
observed as part of abacavir HSR are described in detail in section 4.8 (Description of selected adverse 
reactions), including respiratory and gastrointestinal symptoms. Importantly, such symptoms may lead 
to misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), or 
gastroenteritis . 
 
The symptoms related to HSR worsen with continued therapy and can be life-threatening. These 
symptoms usually resolve upon discontinuation of abacavir.   
 
Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have also 
experienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8 
Description of selected adverse reactions).  Restarting abacavir in such patients must be done in a 
setting where medical assistance is readily available. 
 

 
 
Mitochondrial dysfunction following exposure in utero  
 
 
Nucleoside  and nucleotide analogues  may impact mitochondrial function to a variable degree, which 
is most pronounced with stavudine, didanosine and zidovudine. There have been reports of 
mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside 
analogues ; these have predominantly concerned treatment with regimens containing zidovudine.The 
main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic 



23 

disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset 
neurological disorders have been reported rarely  (hypertonia, convulsion, abnormal behaviour). 
Whether such neurological disorders are transient or permanent is currently unknown. These findings 
should be considered for any child exposed in utero to nucleotide and nucleotide analogues, who 
presents with severe clinical findings of unknown etiology, particularly neurologic findings.  These 
findings do not affect current national recommendations to use antiretroviral therapy in pregnant 
women to prevent vertical transmission of HIV. 
 
 
Weight and metabolic parameters 

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. 

 
Pancreatitis 
 
Pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain. 
 
Triple nucleoside therapy 
 
In patients with high viral load (>100,000 copies/ml) the choice of a triple combination with abacavir, 
lamivudine and zidovudine needs special consideration (see section 5.1). 
 
There have been reports of a high rate of virological failure and of emergence of resistance at an early 
stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily 
regimen. 
 
Liver disease 
 
The safety and efficacy of Ziagen has not been established in patients with significant underlying liver 
disorders. Ziagen is not recommended in patients with  moderate or  severe hepatic impairment (see 
sections 4.2 and 5.2).  
 
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy, and should be 
monitored according to standard practice. If there is evidence of worsening liver disease in such 
patients, interruption or discontinuation of treatment must be considered. 
 
 
Patients co-infected with chronic hepatitis B or C virus 
 
 
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an 
increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral 
therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal 
products. 
 
 
Renal disease 
 
Ziagen should not be administered to patients with end-stage renal disease (see section 5.2). 
 
Excipients 



24 

 
Ziagen oral solution contains 340 mg/ml of sorbitol. When taken according to the dosage 
recommendations each 15 ml dose contains approximately 5 g of sorbitol. Patients with rare hereditary 
problems of fructose intolerance should not take this medicine. Sorbitol can have a mild laxative 
effect. The calorific value of sorbitol is 2.6 kcal/g. 
 
Ziagen oral solution also contains methyl parahydroxybenzoate and propyl parahydroxybenzoate 
which may cause allergic reactions (possibly delayed). 
 
Immune Reactivation Syndrome 
 
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens 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 CART. 
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, 
and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment 
instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) 
have also been reported to occur in the setting of immune reactivation; however, the reported time to 
onset is more variable and these events can occur many months after initiation of treatment. 
 
Osteonecrosis 
 
Although the aetiology 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 CART. 
Patients should be advised to seek medical advice if they experience joint aches and pain, joint 
stiffness or difficulty in movement. 
 
 
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 these associated HIV diseases. 
 
Transmission 
 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines.  

Myocardial Infarction 

Observational studies have shown an association between myocardial infarction and the use of 
abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials 
showed limited numbers of myocardial infarction and could not exclude a small increase in risk.  
Overall the available data from observational cohorts and from randomised trials show some 
inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and 
the risk of myocardial infarction.  To date, there is no established biological mechanism to explain a 
potential increase in risk.  When prescribing Ziagen, action should be taken to try to minimize all 
modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the 
potential for P450 mediated interactions with other medicinal products involving abacavir is low.  



25 

P450 does not play a major role in the metabolism of abacavir, and abacavir does not inhibit 
metabolism mediated by CYP 3A4.  Abacavir has also been shown in vitro not to inhibit CYP 3A4, 
CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism 
has not been observed in clinical studies. Therefore, there is little potential for interactions with 
antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies 
have shown that there are no clinically significant interactions between abacavir, zidovudine, and 
lamivudine. 
 
Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on 
UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.  
 
Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC 
of abacavir of about 41%.  These findings are not considered clinically significant. Abacavir has no 
effect on the metabolism of ethanol.  
 
Methadone: in a pharmacokinetic study, co-administration 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%. The induction of drug 
metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and 
abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as 
occasionally methadone re-titration may be required.  
 
Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is 
possible but has not been studied. 
 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
both animal data as well as clinical experience in pregnant women should be taken into account. 
 
Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see 
section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical 
relevance in human of these data is unknown. Placental transfer of abacavir and/or its related 
metabolites has been shown to occur in human.  
 
In pregnant women, more than 800 outcomes after first trimester exposure and more than 1000 
outcomes after second and third trimester exposure indicate no malformative and foetal /neonatal 
effect of abacavir. The malformative risk is unlikely in humans based on those data. 
 
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 (see section 4.4). 
 
Breast-feeding 
  
Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into 
human milk. There are no data available on the safety of abacavir when administered to babies less 
than three months old. It is recommended that HIV infected women do not breast-feed their infants 
under any circumstances in order to avoid transmission of HIV. 
 
Fertility 



26 

 
Studies in animals showed that abacavir had no effect on fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on ability to drive and use machines have been performed. 
 
4.8 Undesirable effects 
 
For many adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide 
range of medicinal products used in the management of HIV infection or as a result of the disease 
process.  
Many of the adverse reactions listed  below occur commonly (nausea, vomiting, diarrhoea, fever, 
lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these 
symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). 
Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis 
have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal 
products containing abacavir should be permanently discontinued. 
 
Many of the adverse reactions have not been treatment limiting.  The following convention has been 
used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 
to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000). 
 
Metabolism and nutrition disorders 
Common: anorexia 
Very rare: lactic acidosis 
 
 
Nervous system disorders 
Common: headache 
 
Gastrointestinal disorders 
Common: nausea, vomiting, diarrhoea  
Rare: pancreatitis  
 
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 conditions 
Common: fever, lethargy, fatigue 
 
Description of Selected Adverse Reactions 

Abacavir hypersensitivity reactions 
The signs and symptoms of this HSR are listed below. These have been identified either from clinical 
studies or post marketing surveillance. Those reported in at least 10% of patients with a 
hypersensitivity reaction are in bold text. 
 
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. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as 
lethargy and malaise.  
 
 
Skin Rash (usually maculopapular or urticarial) 

 



27 

Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration 
 

Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome, 
respiratory failure 
 

Miscellaneous Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, 
conjunctivitis, anaphylaxis 
 

Neurological/Psychiatry Headache, paraesthesia 
 

Haematological Lymphopenia 
 

Liver/pancreas Elevated liver function tests, hepatitis, hepatic failure 
 

Musculoskeletal Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase 
 

Urology Elevated creatinine, renal failure 
 

 
 
 
 
 
Symptoms related to this HSR worsen with continued therapy and can be life- threatening and in rare 
instance, have been fatal. 
 
Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. 
This recurrence of the HSR is usually more severe than on initial presentation, and may include life-
threatening hypotension and death. Similar reactions have also occurred infrequently after restarting 
abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to 
stopping abacavir; and on very rare occasions have also been seen in patients who have restarted 
therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir 
tolerant). 
 
Metabolic parameters                                                                                                                           
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4) 

 
Immune reactivation syndrome  
In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported to occur in the setting of immune reactivation; however, the reported time to onset 
is more variable and these events can occur many months after initiation of treatment (see section 4.4). 
 
Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see 
section 4.4). 
 
Changes in laboratory chemistries 
 
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. 
 
Paediatric population 



28 

 
1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial 
(COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section 
5.1). No additional safety issues have been identified in paediatric subjects receiving either once or 
twice daily dosing compared to adults. 
 
Reporting of suspected adverse reactions  
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
 
 
4.9  Overdose 
 
Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to 
patients in clinical studies. No additional adverse reactions to those reported for normal doses were 
reported.  The effects of higher doses are not known. If overdose occurs the patient should be 
monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as 
necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code: J05AF06 

 
Mechanism of action 
 
Abacavir is a NRTI. It is a potent selective inhibitor of HIV-1 and HIV-2.  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.  The antiviral 
activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse 
transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir  or 
zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease 
inhibitor (PI) amprenavir. 

 
Resistance 
 
In vitro resistance 
 
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific 
genotypic changes in the reverse transcriptase (RT) codon region (codons M184V, K65R, L74V and 
Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations 
for a clinically relevant increase in EC50 over wild-type virus.  
 
In vivo resistance (Therapy naïve patients)   
 
Isolates from most patients experiencing virological failure with a regimen containing abacavir in 
pivotal clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or 
M184I selection (45%).  The overall selection frequency for M184V or M184I was high (54%), and 
less common was the selection of L74V (5%), K65R (1%) and Y115F (1%).  The inclusion of 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


29 

zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in the 
presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%). 
 

Therapy Abacavir + Combivir1  

Abacavir + 
lamivudine + 

NNRTI 

Abacavir + 
lamivudine + 

PI (or 
PI/ritonavir) 

Total 

Number of 
Subjects 282 1094 909 2285 

Number of 
Virological 

Failures 
43 90  158 291 

Number of 
On-Therapy  
Genotypes 

40 (100%) 51 (100%)2 141 (100%) 232 (100%) 

K65R 0 1 (2%) 2 (1%) 3 (1%) 

L74V 0 9 (18%) 3 (2%) 12 (5%) 
Y115F 0 2 (4%) 0 2 (1%) 

M184V/I 34 (85%) 22 (43%) 70 (50%) 126 (54%) 
TAMs3 3 (8%) 2 (4%) 4 (3%) 9 (4%) 

1.Combivir is a fixed dose combination of lamivudine and zidovudine 
2.Includes three non-virological failures and four unconfirmed virological failures. 
3. Number of subjects with ≥1 Thymidine Analogue Mutations (TAMs). 
 
TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis of 
six clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine 
(0/127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine 
(22/86, 26%).   
 
In vivo resistance (Therapy experienced patients) 
 
Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates 
of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to 
other nucleoside inhibitors. In a meta-analysis of five clinical trials where abacavir was added to 
intensify therapy, of 166 subjects, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had 
M41L, 30 (18%) had K70R and 25 (15%) had D67N.  K65R was absent and L74V and Y115F were 
uncommon (≤3%).  Logistic regression modelling of the predictive value for genotype (adjusted for 
baseline plasma HIV-1 RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral 
therapies), showed that the presence of 3 or more NRTI resistance-associated mutations was 
associated with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 
(p≤0.012).  In addition, the 69 insertion complex or the Q151M mutation, usually found in 
combination with A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir. 
 



30 

Baseline Reverse 
Transcriptase Mutation 

Week 4 
(n = 166) 

n 
Median 

Change vRNA 
(log10 c/ml) 

Percent with 
<400 copies/ml 

vRNA 
None 15 -0.96 40% 

M184V alone  75 -0.74 64% 
Any one NRTI mutation 82 -0.72 65% 

Any two NRTI-associated 
mutations  22 -0.82 32% 

Any three NRTI-associated 
mutations 19 -0.30 5% 

Four or more NRTI-
associated mutations 28 -0.07 11% 

 
Phenotypic resistance and cross-resistance 
 
Phenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation, 
or M184V with multiple TAMs. Phenotypic cross-resistance to other NRTIs with M184V or M184I 
mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviral 
activities against such HIV-1 variants. The presence of M184V with K65R does give rise to cross-
resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives rise 
to cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F 
gives rise to cross-resistance between abacavir and lamivudine. Appropriate use of abacavir can be 
guided using currently recommended resistance algorithms. 
 
Cross-resistance between abacavir and antiretrovirals from other classes (e.g. PIs or NNRTIs) is 
unlikely. 
 
Clinical efficacy and safety 
 
The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adult 
treatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination with 
zidovudine and lamivudine. 
 
Twice daily (300 mg) administration: 
 
• Therapy naïve adults 
 
In adults treated with abacavir in combination with lamivudine and zidovudine the proportion of 
patients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treat 
analysis at 48 weeks) with corresponding rise in CD4 cells. 
 
One randomised, double blind, placebo controlled clinical study in adults has compared the 
combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and 
zidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinued 
randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence 
between the treatment regimens at week 48. Although a similar antiviral effect was observed between 
the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable 
viral load (≤400 copies/ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT), 
86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir 
combination, particularly in the subset of patients with high viral load (>100,000 copies/ml at baseline; 
ITT, 46% versus 55%; AT, 84% versus 93% for abacavir and indinavir respectively). 
 
In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral 
therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 
300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg 



31 

once daily. The duration of double-blind treatment was at least 48 weeks. In the intent-to-treat (ITT) 
population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine 
group, achieved a virologic response of plasma HIV-1 RNA ≤50 copies/ml by Week 48 (point 
estimate for treatment difference: 0.8, 95% CI -6.3, 7.9). In the as treated (AT) analysis the difference 
between both treatment arms was more noticeable (88% of patients in the abacavir group, compared to 
95% of patients in the zidovudine group (point estimate for treatment difference: -6.8, 95% CI -
11.8; -1.7). However, both analyses were compatible with a conclusion of non-inferiority between 
both treatment arms. 
 
ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147 
antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine 
(3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median 
follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be 
virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml) 
with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and 13% on the 4 
drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the 
proportion of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the 
ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety 
Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of 
patients with virologic failure. The remaining arms were continued in a blinded fashion. After a 
median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the 
ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant 
difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study, 
addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy. 
 

  ZDV/3TC/ABC ZDV/3TC/EFV ZDV/3TC/ABC/EFV 
Virologic failure (HIV 
RNA >200 copies/ml) 
 

32 weeks 26% 16% 13% 
144 weeks - 26% 25% 

Virologic success (48 
weeks HIV RNA < 50 
copies/ml) 

 63% 80% 86% 

 
• Therapy experienced adults 
 
In adults moderately exposed to antiretroviral therapy the addition of abacavir to combination 
antiretroviral therapy provided modest benefits in reducing viral load (median change 
0.44 log10 copies/ml at 16 weeks).  
 
In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit 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. 
 
Once daily (600 mg) administration: 
 
• Therapy naïve adults 
 
The once daily regimen of abacavir is supported by a 48 weeks multi-centre, double-blind, controlled 
study (CNA30021) of 770 HIV-infected, therapy-naïve adults. These were primarily asymptomatic 
HIV infected patients - Centre for Disease Control and Prevention (CDC) stage A. They were 
randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, in combination with 
efavirenz and lamivudine given once daily. Similar clinical success (point estimate for treatment 
difference -1.7, 95% CI -8.4, 4.9) was observed for both regimens. From these results, it can be 
concluded with 95% confidence that the true difference is no greater than 8.4% in favour of the twice 
daily regimen. This potential difference is sufficiently small to draw an overall conclusion of non-
inferiority of abacavir once daily over abacavir twice daily. 
 



32 

There was a low, similar overall incidence of virologic failure (viral load >50 copies/ml) in both the 
once and twice daily treatment groups (10% and 8% respectively). In the small sample size for 
genotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once 
daily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limited 
data derived from this study.  Long term data with abacavir used as a once daily regimen (beyond 48 
weeks) are currently limited. 
 
• Therapy experienced adults 
 
In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised  and 
received treatment with either the fixed-dose combination of abacavir/lamivudine (FDC) once daily or 
abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir 
and a PI or an NNRTI for 48 weeks. Results indicate that the FDC group was non-inferior to the 
abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area 
under the curve minus baseline (AAUCMB, -1.65 log10 copies/ml versus -1.83 log10 copies/ml 
respectively, 95% CI -0.13, 0.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%) 
and < 400 copies/ml (54% versus 57%) were also similar in each group (ITT population). However, as 
there were only moderately experienced patients included in this study with an imbalance in baseline 
viral load between the arms, these results should be interpreted with caution.  
 
In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing 
abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were 
randomised to continue this regimen or switch to abacavir/lamivudine FDC plus a PI or NNRTI for 48 
weeks.  Results indicate that the FDC group was associated with a similar virologic outcome (non-
inferior) compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-
1 RNA < 50 copies/ml (90% and 85% respectively, 95% CI  -2.7, 13.5).  
 
Additional information: 
 
The safety and efficacy of Ziagen in a number of different multidrug combination regimens is still not 
completely assessed (particularly in combination with NNRTIs). 
 
Abacavir penetrates the cerebrospinal fluid (CSF) (see section 5.2), and has been shown to reduce 
HIV-1 RNA levels in the CSF.  However, no effects on neuropsychological performance were seen 
when it was administered to patients with AIDS dementia complex.  
 
Paediatric population: 
 
A randomised comparison of a regimen including once daily vs twice daily dosing of abacavir and 
lamivudine was undertaken within a randomised, multicentre, controlled study of HIV-infected, 
paediatric patients. 1206 paediatric patients aged 3 months to 17 years enrolled in the ARROW Trial 
(COL105677) and were dosed according to the weight - band dosing recommendations in the World 
Health Organisation treatment guidelines (Antiretroviral therapy of HIV infection in infants and 
children, 2006). After 36 weeks on a regimen including twice daily abacavir and lamivudine, 669 
eligible subjects were randomised to either continue twice daily dosing or switch to once daily 
abacavir and lamivudine for at least 96 weeks. Of note, from this study clinical data were not available 
for children under one year old.   The results are summarised in the table below: 
 
Virological Response Based on Plasma HIV-1 RNA less than 80 copies/ml at Week 48 and Week 
96 in the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW 
(Observed Analysis) 
 

 Twice Daily 
N (%) 

Once Daily 
N (%) 

Week 0 (After ≥36 Weeks on Treatment) 
Plasma HIV-1 RNA 

<80 c/ml 
250/331 (76) 237/335 (71) 



33 

Risk difference (once 
daily-twice daily) 

-4.8% (95% CI -11.5% to +1.9%), p=0.16 

Week 48 
Plasma HIV-1 RNA 

<80 c/ml 
242/331 (73) 236/330 (72) 

Risk difference (once 
daily-twice daily) 

-1.6% (95% CI -8.4% to +5.2%), p=0.65 

Week 96 
Plasma HIV-1 RNA 

<80 c/ml 
234/326 (72) 230/331 (69) 

Risk difference (once 
daily-twice daily) 

-2.3% (95% CI -9.3% to +4.7%), p=0.52 

 
 
The abacavir + lamivudine once daily dosing group was demonstrated to be non-inferior to the twice 
daily group according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of 
<80 c/mlat Week 48 as well as at Week 96 (secondary endpoint) and all other thresholds tested 
(<200c/ml, <400c/ml, <1000c/ml), which all fell well within this non-inferiority margin. Subgroup 
analyses testing for heterogeneity of once vs twice daily demonstrated no significant effect of sex, age, 
or viral load at randomisation. Conclusions supported non-inferiority regardless of analysis method. 
 
In a separate study comparing the unblinded NRTI combinations (with or without blinded nelfinavir) 
in children, a greater proportion treated with abacavir and lamivudine (71%) or abacavir and 
zidovudine (60%) had HIV-1 RNA ≤400 copies/ml at 48 weeks, compared with those treated with 
lamivudine and zidovudine (47%)[ p=0.09, intention to treat analysis]. Similarly, greater proportions 
of children treated with the abacavir containing combinations had HIV-1 RNA ≤50 copies/ml at 48 
weeks (53%, 42% and 28% respectively, p=0.07). 
 
In a pharmacokinetic study (PENTA 15), four virologically controlled subjects less than 12 months of 
age switched from abacavir plus lamivudine oral solution twice daily to a once daily regimen. Three 
subjects had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48. No 
safety concerns were observed in these subjects. 

 
 
5.2 Pharmacokinetic properties 
 
Absorption  
 
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 (tmax) 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 
a dosage of 300 mg twice daily, the mean (CV) steady state Cmax and Cmin of abacavir are 
approximately 3.00 µg/ml (30%) and 0.01 µg/ml(99%), respectively. The mean (CV) AUC over a 
dosing interval of 12 hours was 6.02 µg.h/ml (29%), equivalent to a daily AUC of approximately 
12.0 µg.h/ml.  The Cmax value for the oral solution is slightly higher than the tablet.  After a 600 mg 
abacavir tablet dose, the mean (CV) abacavir Cmax was approximately 4.26 µg/ml (28%) and the mean 
(CV) AUC∞ was 11.95 µg.h/ml (21%).  
 
Food delayed absorption and decreased Cmax but did not affect overall plasma concentrations (AUC). 
Therefore Ziagen can be taken with or without food.  
 
Distribution 



34 

 
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 CSF, with a CSF to 
plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold 
greater than the IC50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twice 
daily.  
 
Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to 
human plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactions 
with other medicinal products through plasma protein binding displacement. 
 
 
 
Biotransformation  
 
Abacavir is primarily metabolised by the liver with approximately 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. The metabolites are excreted in the urine. 
 
Elimination 
 
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 accumulation of abacavir.  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. 
 
Intracellular pharmacokinetics 
 
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg 
dose taken prior to the 24 hour sampling period, 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.  In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP 
exposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32 %, Cmax24,ss + 99 % 
and Ctrough + 18 %) compared to the 300 mg twice daily regimen.  Overall, these data support the use 
of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy 
and safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021- 
See section 5.1 Clinical experience). 
 
Special patient populations 
 
Hepatic impairment 
 
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in 
patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose; the 
median (range)  AUC values was 24.1 (10.4 to 54.8) ug.h/ml.  The results showed that there was a 
mean (90%CI)   increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in 
the elimination half-life.  No definitive recommendation on dosage reduction is possible in patients 
with mild hepatic impairment due to the substantial variability of abacavir exposure.  
Abacavir is not recommended in patients with moderate or severe hepatic impairment. 
 
Renal impairment 
 



35 

Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged 
in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to 
patients with normal renal function.  Therefore no dosage reduction is required in patients with renal 
impairment. Based on limited experience Ziagen should be avoided in patients with end-stage renal 
disease. 
 
Paediatric population  
According to clinical trials performed in children abacavir is rapidly and well absorbed from oral 
solution and tablet formulations administered to children. Plasma abacavir exposure has been shown to 
be the same for both formulations when administered at the same dose. Children receiving abacavir 
oral solution according to the recommended dosage regimen achieve plasma abacavir exposure similar 
to adults.  Children receiving abacavir oral tablets according to the recommended dosage regimen 
achieve higher plasma abacavir exposure than children receiving oral solution because higher mg/kg 
doses are administered with the tablet formulation.  
 
There are insufficient safety data to recommend the use of Ziagen in infants less than three months 
old. The limited data available indicate that an oral solution dose of 2 mg/kg in neonates less than 30 
days old provides similar or greater AUCs, compared to the 8 mg/kg oral solution dose administered 
to older children. 
 
Pharmacokinetic data were derived from 3 pharmacokinetic studies (PENTA 13, PENTA 15 and 
ARROW PK substudy) enrolling children under 12 years of age. The data are displayed in the table 
below: 

Summary of Stead-State Plasma Abacavir AUC (0-24) (µg.h/ml) and Statistical Comparisons for 
Once and Twice-Daily Oral Administration Across Studies 

 
Study 

 
Age Group 

Abacavir  
16 mg/kg Once-

Daily Dosing 
Geometric Mean 

(95% Cl) 

Abacavir  
8 mg/kg Twice-

Daily Dosing 
Geometric Mean 

(95% Cl) 

Once-Versus 
Twice-Daily 
Comparison 

GLS Mean Ratio 
(90% Cl) 

ARROW PK 
Substudy 

Part 1 

3 to 12 years 
(N=36) 

15.3 
(13.3-17.5) 

15.6 
(13.7-17.8) 

0.98 
(0.89, 1.08) 

PENTA 13 2 to 12 years 
(N=14) 

13.4 
(11.8-15.2) 

9.91 
(8.3-11.9) 

1.35 
(1.19-1.54) 

PENTA 15 3 to 36 months 
(N=18) 

11.6 
(9.89-13.5) 

10.9 
(8.9-13.2) 

1.07 
(0.92-1.23) 

 
In PENTA 15 study, the geometric mean plasma abacavir AUC(0-24) (95% CI) of the four subjects 
under 12 months of age who switch from a twice daily to a once daily regimen (see section 5.1) are 15.9 
(8.86, 28.5) µg.h/ml in the once-daily dosing and 12.7 (6.52, 24.6) µg.h/ml in the twice-daily dosing. 

 
Elderly 
 
The pharmacokinetics of abacavir has not been studied in patients over 65 years of age. 
 
5.3 Preclinical safety data 
 
Abacavir was not mutagenic in bacterial tests but showed activity in vitro in the human lymphocyte 
chromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus test. This is 
consistent with the known activity of other nucleoside analogues. These results indicate that abacavir 



36 

has a weak potential to cause chromosomal damage both in vitro and in vivo at high test 
concentrations.  
 
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 rats in the thyroid gland of males and 
the liver, urinary bladder, lymph nodes and the subcutis of females.  
 
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. The exception was the preputial gland tumour which occurred at a dose of 
110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 
and 7 times the human systemic exposure during therapy. While the carcinogenic potential in humans 
is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential 
clinical benefit. 
 
In pre-clinical toxicology studies, abacavir treatment was shown to increase liver weights in rats and 
monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that 
abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the 
metabolism of other medicinal products hepatically metabolised has not been observed in man. 
 
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. 
 
In reproductive toxicity studies, embryo and foetal toxicity have been observed in rats but not in 
rabbits.  These findings included decreased foetal body weight, foetal oedema, and an increase in 
skeletal variations/malformations, early intra-uterine deaths and still births.  No conclusion can be 
drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity. 
 
A fertility study in the rat has shown that abacavir had no effect on male or female fertility.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sorbitol 70% (E420) 
Saccharin sodium 
Sodium citrate 
Citric acid anhydrous 
Methyl parahydroxybenzoate (E218) 
Propyl parahydroxybenzoate (E216) 
Propylene glycol (E1520) 
Maltodextrin 
Lactic acid 
Glyceryl triacetate 
Artificial strawberry and banana flavours 
Purified water  
Sodium hydroxide and/or hydrochloric acid for pH adjustment. 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf-life 
 
2 years 



37 

 
After first opening the container: 2 months  
 
6.4 Special precautions for storage 
 
Do not store above 30°C.  
 
6.5 Nature and contents of container 
 
Ziagen oral solution is supplied in high density polyethylene bottles with child-resistant closures, 
containing 240 ml of oral solution. 
 
The pack also includes a polyethylene syringe-adapter and a 10 ml oral dosing syringe comprised of a 
polypropylene barrel (with ml graduations) and a polyethylene plunger. 
 
 
 
6.6 Special precautions for disposal 
 
A plastic adapter and oral dosing syringe are provided for accurate measurement of the prescribed 
dose of oral solution. The adapter is placed in the neck of the bottle and the syringe attached to this. 
The bottle is inverted and the correct volume withdrawn.  
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/112/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 8 July 1999 
 
Date of latest renewal: 21 March 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 
  

http://www.emea.europa.eu/
http://www.emea.europa.eu/


38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFCTIVE 

USE OF THE MEDICINAL PRODUCT 
 
 



39 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Film-coated Tablets 
 
Glaxo Operations UK Ltd  
(trading as Glaxo Wellcome Operations)  
Priory Street  
Ware  
Herts SG12 0DJ  
United Kingdom 
 
or 
 
GlaxoSmithKline Pharmaceuticals S.A. 
ul. Grunwaldzka 189  
60-322 Poznan  
Poland 
 
Oral Solution 
 
Glaxo Operations UK Ltd 
(trading as GlaxoWellcome Operations) 
Harmire Road 
Barnard Castle 
Co. Durham DL12 8DT 
United Kingdom 
 
or 
 
ViiV Healthcare Trading Services UK Limited  
12 Riverwalk,  
Citywest Business Campus  
Dublin 24, 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I Summary of Product 
Characteristics, 4.2). 
 
 
C.     OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING    
           AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
D.      CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND   



40 

           EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.  
 
An updated RMP should be submitted:  
 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 
If the date of the submission of a PSUR and the update of a RMP coincide, they can be submitted at 
the same time. 
 
  



41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

 
  



42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 



43 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON - TABLETS 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ziagen 300 mg film-coated tablets 
Abacavir 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 300 mg abacavir (as sulfate). 
 
 

3. LIST OF EXCIPIENTS 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated, scored tablets 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use  
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Detach enclosed Alert Card, it contains important safety information 
 
WARNING! In case of any symptoms suggesting hypersensitivity reactions, contact your doctor 
IMMEDIATELY. 
 
“Pull here” (with Alert card attached) 
 
 

8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 



44 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/112/001  
 
 

13. BATCH NUMBER 
 
Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
ziagen 300mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA  
 
PC: 
SN: 
NN 



45 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS  
 
TABLET BLISTER FOIL TEXT 
 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ziagen 300 mg tablets. 
 
Abacavir 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
 
 

3. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



46 

ALERT CARD TEXT 
 
 
SIDE 1 

 
IMPORTANT  -  ALERT CARD 

ZIAGEN (abacavir) tablets 
Carry this card with you at all times 

 
Since Ziagen contains abacavir some patients taking Ziagen may develop a hypersensitivity reaction 
(serious allergic reaction) which can be life-threatening if treatment with Ziagen is continued. 
CONTACT YOUR DOCTOR  
IMMEDIATELY for advice on whether you should stop taking Ziagen if: 
1) you get a skin rash OR 
2) you get one or more symptoms from at least TWO of the following groups 

- fever 
- shortness of breath, sore throat or cough 
- nausea or vomiting or diarrhoea or abdominal pain 
- severe tiredness or achiness or generally feeling ill 

If you have discontinued Ziagen due to this reaction, YOU MUST NEVER TAKE Ziagen or any 
other abacavir containing medicine (e.g. Kivexa, Trizivir or Triumeq) again, as within hours you may 
experience a life-threatening lowering of your blood pressure or death.       
                                                                                                              ( see reverse of card) 
 
 
SIDE 2 
 
You should immediately contact your doctor if you think you are having a hypersensitivity reaction to 
Ziagen.  Write your doctor’s details below:  
 
 
Doctor:  .......................………………  Tel: ...................…………………………………………….. 
 
 
If your doctor is not available, you must urgently seek alternative medical advice (e.g. the 
emergency unit of the nearest hospital). 
 
 
For general Ziagen information enquiries, contact GlaxoSmithKline….Tel …………… (local 
company name and telephone number will be inserted here). 
 
 



47 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON - ORAL SOLUTION 
 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ziagen 20 mg/ml oral solution 
Abacavir 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of oral solution contains 20 mg of abacavir (as sulfate) 
 
 

3. LIST OF EXCIPIENTS 
 
Contains amongst others: sorbitol (340 mg/ml, E420), methyl parahydroxybenzoate (E218) and propyl 
parahydroxybenzoate (E216). See leaflet for further information. 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
240 ml oral solution 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Detach enclosed Alert Card, it contains important safety information 
 
WARNING! In case of any symptoms suggesting hypersensitivity reactions, contact your doctor 
IMMEDIATELY. 
 
“Pull here” (with Alert card attached) 
 
  
 

8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 



48 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
Discard two months after first opening 
 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/112/002  
 
 

13. BATCH NUMBER 
 
Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 

15. INSTRUCTIONS ON USE 
 
 

16.     INFORMATION IN BRAILLE 
 
ziagen 20mg/ml 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA  
 
PC: 
SN: 
NN  

10.     SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS      
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



49 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL - ORAL SOLUTION 
 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Ziagen 20 mg/ml oral solution 
Abacavir 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of oral solution contains 20 mg of abacavir (as sulfate) 
 
 

3. LIST OF EXCIPIENTS 
 
Contains amongst others: sorbitol (340 mg/ml, E420), methyl parahydroxybenzoate (E218) and propyl 
parahydroxybenzoate (E216). See leaflet for further information. 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
240 ml oral solution 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

8. EXPIRY DATE 
 
EXP {MM/YYYY} 
 
 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
Discard two months after first opening 
 

  



50 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/112/002  
 
 

13. BATCH NUMBER 
 
Lot 
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 

15. INSTRUCTIONS ON USE 
 
 

16.     INFORMATION IN BRAILLE 
 
 
17.     UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18.     UNIQUE IDENTIFIER – HUMAN READABLE DATA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALERT CARD TEXT 
 



51 

 
SIDE 1 

 
IMPORTANT  -  ALERT CARD 
ZIAGEN (abacavir) oral solution 

Carry this card with you at all times 
 
Since Ziagen contains abacavir some patients taking Ziagen may develop a hypersensitivity reaction 
(serious allergic reaction) which 
can be life-threatening if treatment with Ziagen is continued. CONTACT YOUR DOCTOR  
IMMEDIATELY for advice on whether you should stop taking Ziagen if: 
1) you get a skin rash OR 
2) you get one or more symptoms from at least TWO of the following groups 

- fever 
- shortness of breath, sore throat or cough 
- nausea or vomiting or diarrhoea or abdominal pain 
- severe tiredness or achiness or generally feeling ill 

If you have discontinued Ziagen due to this reaction, YOU MUST NEVER TAKE Ziagen or any 
other abacavir containing medicine (e.g. Kivexa, Trizivir or Triumeq) again, as within hours you may 
experience a life-threatening lowering of your blood pressure or death.       
                                                                                                              (see reverse of card) 
 
 
SIDE 2 
 
You should immediately contact your doctor if you think you are having a hypersensitivity reaction to 
Ziagen.  Write your doctor’s details below:  
 
 
Doctor:  .......................………………  Tel: ...................…………………………………………….. 
 
 
If your doctor is not available, you must urgently seek alternative medical advice (e.g. the 
emergency unit of the nearest hospital). 
 
 
For general Ziagen information enquiries, contact ……………….Tel …………… (local company 
name and telephone number will be inserted here). 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 



52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 



53 

Package leaflet: Information for the user 
 

Ziagen 300 mg Film-coated tablets 
Abacavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any further questions ask your doctor or pharmacist. 

-  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
even if their signs of illness are the same as yours. 

-  If you get any side effects talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

IMPORTANT - Hypersensitivity reactions 

Ziagen contains abacavir (which is also an active substance in medicines such as Kivexa, Triumeq 
and Trizivir). Some people who take abacavir may develop a hypersensitivity reaction (a serious 
allergic reaction), which can be life-threatening if they continue to take abacavir containing products. 
 

You must carefully read all the information under ‘Hypersensitivity reactions’ in the panel in 
Section 4. 

The Ziagen pack includes an Alert Card, to remind you and medical staff about abacavir 
hypersensitivity. Detach this card and keep it with you at all times. 
 
What is in this leaflet  

1. What Ziagen is and what it is used for 
2. What you need to know before you take Ziagen 
3. How to take Ziagen 
4. Possible side effects 
5. How to store Ziagen  
6. Contents of the pack and other information 
 
1. What Ziagen is and what it is used for 
 
Ziagen is used to treat HIV (human immunodeficiency virus) infection. 
 
Ziagen contains the active ingredient abacavir.  Abacavir belongs to a group of anti-retroviral 
medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs). 
 
Ziagen does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps 
it at a low level. It also increases the CD4 cell count in your blood. CD4 cells are a type of white blood 
cell that are important in helping your body to fight infection. 
  
Not everyone responds to treatment with Ziagen in the same way. Your doctor will monitor the 
effectiveness of your treatment. 
 
2. What you need to know before you take Ziagen  
 



54 

Do not take Ziagen: 
if you are allergic (hypersensitive) to abacavir (or any other medicine containing abacavir –such 
as Trizivir, Triumeq or Kivexa) or any of the other ingredients of this medicine (listed in Section 
6) 
Carefully read all the information about hypersensitivity reactions in Section 4. 

Check with your doctor if you think   this applies to you.  
 

 
Take special care with Ziagen 

Some people taking Ziagen for HIV are more at risk of serious side effects. You need to be aware of 
the extra risks: 
• if you have moderate or severe liver disease  
• if you have ever had liver disease, including hepatitis B or C 
• if you are seriously overweight (especially if you are a woman) 
• if you have severe kidney disease 

Talk to your doctor if any of these apply to you. You may need extra check-ups, including 
blood tests, while you are taking your medicine. See Section 4 for more information.  

 
Abacavir hypersensitivity reactions 
Even patients who don’t have the HLA-B*5701 gene may still develop a hypersensitivity reaction (a 
serious allergic reaction). 
 

Carefully read all the information about hypersensitivity reactions in Section 4 of this 
leaflet. 

 
Risk of heart attack 
It cannot be excluded that abacavir may increase the risk of having a heart attack. 

Tell your doctor if you have heart problems, if you smoke, or have other illnesses that may 
increase your risk of heart disease such as high blood pressure, or diabetes. Do not stop taking 
Ziagen unless your doctor advises you to do so. 

 
Look out for important symptoms 
Some people taking medicines for HIV infection develop other conditions, which can be serious. You 
need to know about important signs and symptoms to look out for while you are taking Ziagen. 

Read the information ‘Other possible side effects of combination therapy for HIV’ in 
Section 4 of this leaflet. 

 
Protect other people 
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of 
infected blood (for example, by sharing injection needles). You can still pass on HIV when taking this 
medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with your doctor the 
precautions needed to avoid infecting other people. 
 
Other medicines and Ziagen 
Tell your doctor or pharmacist if you are taking any other medicines, or if you have taken any 
recently, including herbal medicines or other medicines you bought without a prescription. Remember 
to tell your doctor or pharmacist if you begin taking a new medicine while you are taking Ziagen. 
 
Some medicines interact with Ziagen 
These include: 
 
• phenytoin, for treating epilepsy 

Tell your doctor if you are taking phenytoin. Your doctor may need to monitor you while you are 
taking Ziagen. 

 



55 

• methadone used as a heroin substitute.  Abacavir increases the rate at which methadone is 
removed from the body. If you are taking methadone, you will be checked for any withdrawal 
symptoms. Your methadone dose may need to be changed. 
Tell your doctor if you are taking methadone.  

 
 
Pregnancy 
Ziagen is not recommended for use during pregnancy. Ziagen and similar medicines may cause 
side effects in unborn babies. If you have taken Ziagen during your pregnancy, your doctor may 
request regular blood tests and other diagnostic tests to monitor the development of your child. In 
children whose mothers took NRTIs during pregnancy, the benefit from the protection against HIV 
outweighed the risk of side effects. 
 
Breast-feeding 
Women who are HIV-positive must not breast-feed, because HIV infection can be passed on to the 
baby in breast milk. A small amount of the ingredients in Ziagen can also pass into your breast milk. 
If you are breast-feeding, or thinking about breast-feeding: 

Talk to your doctor immediately. 
 
Driving and using machines 

Do not drive or operate machines unless you are feeling well. 
 
3. How to take Ziagen  
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 

Swallow the tablets with some water. Ziagen can be taken with or without food. 

If you cannot swallow the tablet(s), you may crush and combine them with a small amount of food or 
drink, and take all the dose immediately.  

Stay in regular contact with your doctor 
Ziagen helps to control your condition. You need to keep taking it every day to stop your illness 
getting worse. You may still develop other infections and illnesses linked to HIV infection. 

Keep in touch with your doctor, and do not stop taking Ziagen without your doctor’s advice. 
 

How much to take 

Adults, adolescents and children weighing at least 25 kg 

The usual dose of Ziagen is 600 mg a day.  This can be taken either as one 300 mg tablet twice a day 
or two 300 mg tablets once a day.  

Children from one year of age weighing less than 25 kg  

The dose given depends on the body weight of your child.  The recommended dose is: 

• Children weighing at least 20 kg and less than 25 kg: The usual dose of Ziagen is 450 mg a 
day. This can be given as 150 mg (half of a tablet) taken in the morning and 300 mg (one whole 
tablet) taken in the evening, or 450 mg (one and a half tablets) once a day as advised by your 
doctor.  



56 

• Children weighing at least 14 kg and less than 20 kg: The usual dose of Ziagen is 300 mg a 
day. This can be given as 150 mg (half of a  tablet) twice daily, or 300 mg (one whole tablet) once 
a day as advised by your doctor.  

The tablet can be divided into equal doses. 

An oral solution (20 mg abacavir/ml) is also available for the treatment of children over three months 
of age and weighing less than 14 kg, or for people who need a lower than usual dose, or who cannot 
take tablets.  

If you take more Ziagen than you should 
If you accidentally take too much Ziagen, tell your doctor or your pharmacist, or contact your nearest 
hospital emergency department for further advice. 
 
If you forget to take Ziagen 
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.  
Do not take a double dose to make up for a forgotten dose.  
 
It is important to take Ziagen regularly, because if you take it at irregular intervals, you may be more 
likely to have a hypersensitivity reaction. 
 
If you have stopped taking Ziagen 
If you have stopped taking Ziagen for any reason - especially because you think you are having side 
effects, or because you have other illness: 

Talk to your doctor before you start taking it again. Your doctor will check whether your 
symptoms were related to a hypersensitivity reaction. If the doctor thinks they may have been 
related, you will be told never again to take Ziagen, or any other medicine containing abacavir 
(e.g. Triumeq,Trizivir or Kivexa). It is important that you follow this advice. 

 
If your doctor advises that you can start taking Ziagen again, you may be asked to take your first doses 
in a place where you will have ready access to medical care if you need it. 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.  

 
Like all medicines, this medicine can cause side effects, although not everyone gets them. 
  
When you are being treated for HIV, it can be hard to tell whether a symptom is a side effect of Ziagen 
or other medicines you are taking, or an effect of the HIV disease itself. So it is very important to 
talk to your doctor about any changes in your health. 

Even patients who don’t have the HLA-B*5701 gene may still develop a hypersensitivity 
reaction (a serious allergic reaction), described in this leaflet in the panel headed ‘Hypersensitivity 
reactions’.  

 
It is very important that you read and understand the information about this serious 
reaction. 

 
As well as the side effects listed below for Ziagen, other conditions can develop during combination 
therapy for HIV.  
It is important to read the information later in this section under ‘Other possible side effects of 
combination therapy for HIV’. 

Hypersensitivity reactions 

Ziagen contains abacavir (which is also an active substance in Trizivir , Triumeq and Kivexa). 



57 

Abacavir can cause a serious allergic reaction known as a hypersensitivity reaction. 
These hypersensitivity reactions have been seen more frequently in people taking medicines that 
contain abacavir.  
 
 
Who gets these reactions? 
Anyone taking Ziagen could develop a hypersensitivity reaction to abacavir, which could be life 
threatening if they continue to take Ziagen. 

You are more likely to develop such a reaction if you have the HLA-B*5701 gene (but you can get a 
reaction even if you do not have this gene). You should have been tested for this gene before Ziagen 
was prescribed for you. If you know you have this gene, tell your doctor before you take Ziagen. 
About 3 to 4 in every 100 patients treated with abacavir in a clinical trial who did not have the HLA-
B*5701 gene developed a hypersensitivity reaction. 
 
What are the symptoms? 
The most common symptoms are: 
• fever (high temperature) and skin rash 
Other common symptoms are: 
• nausea (feeling sick), vomiting (being sick), diarrhoea, abdominal (stomach) pain, severe tiredness 
Other symptoms include: 
 
Pains in the joints or muscles, swelling of the neck, shortness of breath, sore throat, cough, occasional 
headaches, inflammation of the eye (conjunctivitis), mouth ulcers, low blood pressure, tingling or 
numbness of the hands or feet. 
 
When do these reactions happen? 
Hypersensitivity reactions can start at any time during treatment with Ziagen, but are more likely 
during the first 6 weeks of treatment. 
 
 
If you are caring for a child who is being treated with Ziagen, it is important that you 
understand the information about this hypersensitivity reaction. If your child gets the symptoms 
described below it is essential that you follow the instructions given. 
 
Contact your doctor immediately: 
1 if you get a skin rash, OR 
2 if you get symptoms from at least 2 of the following groups: 
 - fever  
 - shortness of breath, sore throat or cough 
 - nausea or vomiting, diarrhoea or abdominal pain 
 - severe tiredness or achiness, or generally feeling ill 
Your doctor may advise you to stop taking Ziagen. 
 

If you have stopped taking Ziagen 

If you have stopped taking Ziagen because of a hypersensitivity reaction, you must NEVER AGAIN 
take Ziagen, or any other medicine containing abacavir (e.g. Trizivir, Triumeq or Kivexa). If you 
do, within hours, your blood pressure could fall dangerously low, which could result in death. 

If you have stopped taking Ziagen for any reason - especially because you think you are having side 
effects, or because you have other illness: 

Talk to your doctor before you start again. Your doctor will check whether your symptoms were 
related to a hypersensitivity reaction. If the doctor thinks they may have been, you will then be told 



58 

never again to take Ziagen, or any other medicine containing abacavir (e.g. Trizivir, Triumeq or 
Kivexa). It is important that you follow this advice. 

Occasionally, hypersensitivity reactions have developed in people who start taking abacavir containing 
products again, but who had only one symptom on the Alert Card before they stopped taking it. 
 
Very rarely, patients who have taken medicines containing abacavir in the past without any symptoms 
of hypersensitivity have developed a hypersensitivity reaction when they start taking these medicines 
again.  
 
If your doctor advises that you can start taking Ziagen again, you may be asked to take your first doses 
in a place where you will have ready access to medical care if you need it. 
 
If you are hypersensitive to Ziagen, return all your unused Ziagen tablets for safe disposal. Ask 
your doctor or pharmacist for advice. 

The Ziagen pack includes an Alert Card, to remind you and medical staff about hypersensitivity 
reactions. Detach this card and keep it with you at all times. 
 

 
Common side effects 
These may affect up to 1 in 10 people: 
• hypersensitivity reaction  
• feeling sick (nausea) 
• headache 
• being sick (vomiting) 
• diarrhoea 
• loss of appetite 
• tiredness, lack of energy 
• fever (high temperature) 
• skin rash 
 
Rare side effects 
These may affect up to 1 in 1,000 people: 
• inflammation of the pancreas (pancreatitis) 
 
Very rare side effects 
These may affect up to 1 in 10,000 people: 
• skin rash, which may form blisters and  looks like small targets (central dark spots surrounded by 

a paler area, with a dark ring around the edge) (erythema multiforme) 
• a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 

genitals (Stevens–Johnson syndrome), and a more severe form causing skin peeling in more than 
30% of the body surface (toxic epidermal necrolysis) 

• lactic acidosis (excess lactic acid in the blood) 
 

 
 

If you notice any of these symptoms contact a doctor urgently. 

If you get side effects 

Tell your doctor or pharmacist if any of the side effects get severe or troublesome, or if you 
notice any side effects not listed in this leaflet. 

 
Other possible side effects of combination therapy for HIV 

Combination therapy including Ziagen may cause other conditions to develop during HIV treatment. 
 



59 

Symptoms of infection and inflammation  

Old infections may flare up 
People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to 
develop serious infections (opportunistic infections). When these people start treatment, they may find 
that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are 
probably caused by the body’s immune system becoming stronger, so that the body starts to fight these 
infections.  Symptoms usually include fever, plus some of the following: 

• headache 
• stomach ache 
• difficulty breathing 

 
In rare cases, as the immune system becomes stronger, it can also attack healthy body tissue 
(autoimmune disorders).  The symptoms of autoimmune disorders may develop many months after 
you start taking medicine to treat your HIV infection. Symptoms may include: 

• palpitations (rapid or irregular heartbeat) or tremor 
• hyperactivity (excessive restlessness and movement)  
• weakness beginning in the hands and feet and moving up towards the trunk of the body 

 
If you get any symptoms of infection while you are taking Ziagen: 

Tell your doctor immediately. Do not take other medicines for the infection without your doctor’s 
advice. 

 
 

You may have problems with your bones 

Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this 
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be 
more likely to get this condition: 
• if they have been taking combination therapy for a long time 
• if they are also taking anti-inflammatory medicines called corticosteroids 
• if they drink alcohol 
• if their immune systems are very weak 
• if they are overweight 
Signs of osteonecrosis include: 
• stiffness in the joints 
• aches and pains (especially in the hip, knee or shoulder) 
• difficulty moving 
If you notice any of these symptoms: 

Tell your doctor. 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
5. How to store Ziagen  
 
Keep this medicine out of the sight and reach of children. 
 
Do not take this medicine after the expiry date which is stated on the carton. The expiry date refers to 
the last day of that month. 
 
Do not store above 30°C. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


60 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures help protect the environment.  

6. Contents of the pack and other information

What Ziagen contains 
The active substance in each Ziagen film-coated, scored tablet is 300 mg of abacavir (as sulfate). 

The other ingredients are microcrystalline cellulose, sodium starch glycollate, magnesium stearate and 
colloidal anhydrous silica in the core of the tablet. The tablet coating contains triacetin, 
methylhydroxypropylcellulose, titanium dioxide, polysorbate 80 and iron oxide yellow. 

What Ziagen looks like and contents of the pack 
Ziagen film-coated tablets are engraved with ‘GX 623’ on both sides. The scored tablets are yellow 
and capsule-shaped and are provided in blister packs containing 60 tablets.  

Marketing Authorisation Holder:  
ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP Amersfoort, Netherlands 

Manufacturer:  
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations), Priory Street, Ware, 
Hertfordshire, SG 12 0DJ, United Kingdom. 

GlaxoSmithKline Pharmaceuticals S.A., ul., Grunwaldzka 189, 60-322 Poznan, Poland. 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 

België/Belgique/Belgien 
ViiV Healthcare srl/bv 
Tél/Tel: + 32 (0) 10 85 65 00 

България 
ГлаксоСмитКлайн ЕООД 
Teл.: + 359 2 953 10 34 

Česká republika 
GlaxoSmithKline s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 

Danmark 
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 

Deutschland 
ViiV Healthcare GmbH  
Tel.: + 49 (0)89 203 0038-10 
viiv.med.info@viivhealthcare.com

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 

Luxembourg/Luxemburg 
ViiV Healthcare srl/bv 
Belgique/Belgien 
Tél/Tel: + 32 (0) 10 85 65 00 

Magyarország 
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

Malta 
GlaxoSmithKline (Malta) 
Limited 
Tel: + 356 21 238131 

Nederland 
ViiV Healthcare BV  
Tel: + 31 (0) 33 2081199 

mailto:viiv.med.info@viivhealthcare.com
mailto:viiv.med.info@viivhealthcare.com


61 

Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 
 

Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
firmapost@gsk.no 

Ελλάδα 
GlaxoSmithKline  
Μονοπρόσωπη A.E.B.E. 
Τηλ: + 30 210 68 82 100 
 

Österreich 
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 
 

España 
Laboratorios ViiV Healthcare, S.L. 
Tel: +34 900 923 501 
es-ci@viivhealthcare.com 
 

Polska 
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 

France 
ViiV Healthcare SAS  
Tél.: + 33 (0)1 39 17 6969 
Infomed@viivhealthcare.com 
 
Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1 6051 999 
 

Portugal 
VIIV HEALTHCARE, UNIPESSOAL, LDA  
Tel: + 351 21 094 08 01 
FI.PT@gsk.com 
 
România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 
 

Ireland 
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 

Slovenija 
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
medical.x.si@gsk.com 
 

Ísland 
Vistor hf.  
Sími: +354 535 7000 
 

Slovenská republika 
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 
 

Italia 
ViiV Healthcare S.r.l  
Tel: + 39 (0)45 9212611 

Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00 
gskcyprus@gsk.com 

Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 
 

Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 

United Kingdom 
ViiV Healthcare UK Limited  
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com  
  

  
 
This leaflet was last revised in {MM/YYYY} 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

mailto:firmapost@gsk.no
mailto:es-ci@viivhealthcare.com
mailto:es-ci@viivhealthcare.com
mailto:Infomed@viivhealthcare.com
mailto:Infomed@viivhealthcare.com
http://www.ema.europa.eu/
http://www.ema.europa.eu/


62 

Package leaflet: Information for the user 
 

Ziagen 20 mg/ml oral solution 
Abacavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any further questions ask your doctor or pharmacist. 

-  This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 
even if their signs of illness are the same as yours. 

-  If you get any side effects talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 
IMPORTANT - Hypersensitivity reactions 

Ziagen contains abacavir (which is also an active substance in medicines such as Kivexa,Triumeq 
and Trizivir). Some people who take abacavir may develop a hypersensitivity reaction (a serious 
allergic reaction), which can be life-threatening if they continue to take abacavir. containing products. 
 
You must carefully read all the information under ‘Hypersensitivity reactions’ in the panel in 
Section 4. 

The Ziagen pack includes an Alert Card, to remind you and medical staff about abacavir 
hypersensitivity. Detach this card and keep it with you at all times. 
 
What is in this leaflet  

1. What Ziagen is and what it is used for 
2. What you need to know before you take Ziagen 
3. How to take Ziagen 
4. Possible side effects 
5. How to store Ziagen  
6. Contents of the pack and other information 
 
1. What Ziagen is and what it is used for 
 
Ziagen is used to treat HIV (human immunodeficiency virus) infection. 
 
Ziagen contains the active ingredient abacavir.  Abacavir belongs to a group of anti-retroviral 
medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs). 
 
Ziagen does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps 
it at a low level. It also increases the CD4 cell count in your blood. CD4 cells are a type of white blood 
cell that are important in helping your body to fight infection. 
  
Not everyone responds to treatment with Ziagen in the same way. Your doctor will monitor the 
effectiveness of your treatment. 
 
2. What you need to know before you take Ziagen  
 



63 

Do not take Ziagen: 
• if you are allergic (hypersensitive) to abacavir (or any other medicine containing abacavir - such 

as Triumeq, Trizivir or Kivexa) or any of the other ingredients of this medicine (listed in  
Section 6) 
Carefully read all the information about hypersensitivity reactions in Section 4. 

Check with your doctor if you think   this applies to you.  
 

 
Take special care with Ziagen 

Some people taking Ziagen for HIV are more at risk of serious side effects. You need to be aware of 
the extra risks: 
• if you have moderate or severe liver disease 
• if you have ever had liver disease, including hepatitis B or C 
• if you are seriously overweight (especially if you are a woman) 
• if you have severe kidney disease 

Talk to your doctor if any of these apply to you. You may need extra check-ups, including 
blood tests, while you are taking your medicine. See Section 4 for more information.  

Abacavir hypersensitivity reactions 
Even patients who don’t have the HLA-B*5701 gene may still develop a hypersensitivity reaction (a 
serious allergic reaction). 
 

Carefully read all the information about hypersensitivity reactions in Section 4 of this leaflet. 
 
Risk of heart attack 
It cannot be excluded that abacavir may increase the risk of having a heart attack. 

Tell your doctor if you have heart problems, if you smoke, or have other illnesses that may 
increase your risk of heart disease such as high blood pressure, or diabetes. Do not stop taking 
Ziagen unless your doctor advises you to do so. 

 
Look out for important symptoms 
Some people taking medicines for HIV infection develop other conditions, which can be serious. You 
need to know about important signs and symptoms to look out for while you are taking Ziagen. 

Read the information ‘Other possible side effects of combination therapy for HIV’ in 
Section 4 of this leaflet. 

 
Protect other people 
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of 
infected blood (for example, by sharing injection needles). You can still pass on HIV when taking this 
medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with your doctor the 
precautions needed to avoid infecting other people. 
 
Other medicines and Ziagen 
Tell your doctor or pharmacist if you are taking any other medicines, or if you have taken any 
recently, including herbal medicines or other medicines you bought without a prescription. Remember 
to tell your doctor or pharmacist if you begin taking a new medicine while you are taking Ziagen. 
 
Some medicines interact with Ziagen 
These include: 
 
• phenytoin, for treating epilepsy.  

Tell your doctor if you are taking phenytoin. Your doctor may need to monitor you while you are 
taking Ziagen. 

 
• methadone used as a heroin substitute.  Abacavir increases the rate at which methadone is 

removed from the body. If you are taking methadone, you will be checked for any withdrawal 
symptoms. Your methadone dose may need to be changed. 



64 

Tell your doctor if you are taking methadone. 
 
 
Pregnancy 
Ziagen is not recommended for use during pregnancy. Ziagen and similar medicines may cause 
side effects in unborn babies. If you have taken Ziagen during your pregnancy, your doctor may 
request regular blood tests and other diagnostic tests to monitor the development of your child. In 
children whose mothers took NRTIs during pregnancy, the benefit from the protection against HIV 
outweighed the risk of side effects. 
 

Breast-feeding 
Women who are HIV-positive must not breast-feed, because HIV infection can be passed on to the 
baby in breast milk. A small amount of the ingredients in Ziagen can also pass into your breast milk. 

If you are breast-feeding, or thinking about breast-feeding: 
Talk to your doctor immediately. 

 
Driving and using machines 

Do not drive or operate machines unless you are feeling well. 
 
Important information about some of the other ingredients of Ziagen oral solution 
 
This medicine contains the sweetener sorbitol (approximately 5g in each 15 ml dose), which may have 
a mild laxative effect. Do not take medicines containing sorbitol if you have hereditary fructose 
intolerance. The calorific value of sorbitol is 2.6 kcal/g. 
 
Ziagen also contains preservatives (parahydroxybenzoates) which may cause allergic reactions 
(possibly delayed).  
 
3. How to take Ziagen  
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  Ziagen can be taken with or without food.  

Stay in regular contact with your doctor 
Ziagen helps to control your condition. You need to keep taking it every day to stop your illness 
getting worse. You may still develop other infections and illnesses linked to HIV infection. 

Keep in touch with your doctor, and do not stop taking Ziagen without your doctor’s advice. 
 

How much to take 

Adults, adolescents and children weighing at least 25 kg 

The usual dose of Ziagen is 600 mg (30 ml) a day.  This can be taken either as 300 mg (15 ml) twice 
a day or 600 mg (30 ml) once a day.  

Children from 3 months of age weighing less than 25 kg  

The dose depends on the child’s body weight.  The recommended dose is 8 mg/kg twice a day or            
16 mg/kg once a day, up to a maximum total daily dose of 600 mg daily. 

How to measure the dose and take the medicine 

Use the oral dosing syringe supplied with the pack to measure your dose accurately.  When full, the 
syringe contains 10 ml of solution.   
 
 
 
1. Remove the bottle cap.  Keep it safely. 
2. Hold the bottle firmly.  Push the plastic adapter into the neck of the bottle 



65 

3. Insert the syringe firmly into the adapter 
4. Turn bottle upside down 
5. Pull out the syringe plunger until the syringe contains the first part of your full dose 
6. Turn the bottle the right way up.  Remove the syringe from the adapter 
7. Put the syringe into your mouth, placing the tip of the syringe against the inside of your 

cheek.  Slowly push the plunger in, allowing time to swallow. Don’t push too hard and squirt 
the liquid into the back of your throat, or you may choke 

8. Repeat steps 3 to 7 in the same way until you have taken your whole dose.  For example, if 
your dose is 30 ml, you need to take 3 syringe-fulls of medicine 

9. Take the syringe out of the bottle and wash it thoroughly in clean water.  Let it dry 
completely before you use it again 

10. Close the bottle tightly with the cap, leaving the adapter in place 
 
If you take more Ziagen than you should 
If you accidentally take too much Ziagen, tell your doctor or your pharmacist, or contact your nearest 
hospital emergency department for further advice. 
 
If you forget to take Ziagen 
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.  
Do not take a double dose to make up for a forgotten dose.  
 
It is important to take Ziagen regularly, because if you take it at irregular intervals, you may be more 
likely to have a hypersensitivity reaction. 
 
If you have stopped taking Ziagen 
If you have stopped taking Ziagen for any reason - especially because you think you are having side 
effects, or because you have other illness: 

Talk to your doctor before you start taking it again. Your doctor will check whether your 
symptoms were related to a hypersensitivity reaction. If the doctor thinks they may have been 
related, you will be told never again to take Ziagen, or any other medicine containing abacavir 
(e.g.Triumeq, Trizivir or Kivexa). It is important that you follow this advice. 

 
If your doctor advises that you can start taking Ziagen again, you may be asked to take your first doses 
in a place where you will have ready access to medical care if you need it. 
 
 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.  

 
Like all medicines, this medicine can cause side effects, although not everyone gets them. 
  
When you are being treated for HIV, it can be hard to tell whether a symptom is a side effect of Ziagen 
or other medicines you are taking, or an effect of the HIV disease itself. So it is very important to 
talk to your doctor about any changes in your health. 
 
Even patients who don’t have the HLA-B*5701 gene may still develop a hypersensitivity reaction (a 
serious allergic reaction), described in this leaflet in the panel headed ‘Hypersensitivity reactions’.  
 
It is very important that you read and understand the information about this serious reaction. 
 



66 

As well as the side effects listed below for Ziagen, other conditions can develop during combination 
therapy for HIV.  

It is important to read the information later in this section under ‘Other possible side effects of 
combination therapy for HIV’. 

Hypersensitivity reactions 

Ziagen contains abacavir (which is also an active substance in Kivexa, Triumeq and Trizivir). 
Abacavir can cause a serious allergic reaction known as a hypersensitivity reaction. 
These hypersensitivity reactions have been seen more frequently in people taking medicines that 
contain abacavir.  
 
Who gets these reactions? 
Anyone taking Ziagen could develop a hypersensitivity reaction to abacavir, which could be life 
threatening if they continue to take Ziagen. 

You are more likely to develop such a reaction if you have the HLA-B*5701 gene (but you can get a 
reaction even if you do not have this gene). You should have been tested for this gene before Ziagen 
was prescribed for you. If you know you have this gene, tell your doctor before you take Ziagen. 
 
About 3 to 4 in every 100 patients treated with abacavir in a clinical trial who did not have the HLA-
B*5701 gene developed a hypersensitivity reaction. 
 
 
What are the symptoms? 
 
The most common symptoms are: 
• fever (high temperature) and skin rash 
Other common symptoms are: 
• nausea (feeling sick), vomiting (being sick), diarrhoea, abdominal (stomach) pain, severe tiredness 
Other symptoms include: 
Pains in the joints or muscles, swelling of the neck, shortness of breath, sore throat, cough, occasional 
headaches, inflammation of the eye (conjunctivitis), mouth ulcers, low blood pressure, tingling or 
numbness of the hands or feet. 
 
 
When do these reactions happen? 
Hypersensitivity reactions can start at any time during treatment with Ziagen, but are more likely 
during the first 6 weeks of treatment. 
 
If you are caring for a child who is being treated with Ziagen, it is important that you 
understand the information about this hypersensitivity reaction. If your child gets the symptoms 
described below it is essential that you follow the instructions given. 
 
Contact your doctor immediately: 
1 if you get a skin rash, OR 
2 if you get symptoms from at least 2 of the following groups: 
 - fever  
 - shortness of breath, sore throat or cough 
 - nausea or vomiting, diarrhoea or abdominal pain 
 - severe tiredness or achiness, or generally feeling ill 
Your doctor may advise you to stop taking Ziagen. 
 



67 

If you have stopped taking Ziagen 

If you have stopped taking Ziagen because of a hypersensitivity reaction, you must NEVER AGAIN 
take Ziagen, or any other medicine containing abacavir (e.g. Trizivir, Triumeq or Kivexa). If you 
do, within hours, your blood pressure could fall dangerously low, which could result in death. 

 
If you have stopped taking Ziagen for any reason - especially because you think you are having side 
effects, or because you have other illness: 

Talk to your doctor before you start again. Your doctor will check whether your symptoms were 
related to a hypersensitivity reaction. If the doctor thinks they may have been, you will then be told 
never again to take Ziagen, or any other medicine containing abacavir (e.g. Trizivir , Triumeq 
or Kivexa). It is important that you follow this advice. 

Occasionally, hypersensitivity reactions have developed in people who start taking abacavir containing 
products again, but who had only one symptom on the Alert Card before they stopped taking it. 
 
Very rarely, patients who have taken medicines containing abacavir in the past without any symptoms 
of hypersensitivity have developed a hypersensitivity reaction when they start taking these medicines 
again.  
 
If your doctor advises that you can start taking Ziagen again, you may be asked to take your first doses 
in a place where you will have ready access to medical care if you need it. 
 
If you are hypersensitive to Ziagen, return all your unused Ziagen oral solution for safe disposal. 
Ask your doctor or pharmacist for advice. 

The Ziagen pack includes an Alert Card, to remind you and medical staff about hypersensitivity 
reactions. Detach this card and keep it with you at all times. 
 
 
Common side effects 
These may affect up to 1 in 10 people: 
• hypersensitivity reaction  
• feeling sick (nausea) 
• headache 
• being sick (vomiting) 
• diarrhoea 
• loss of appetite 
• tiredness, lack of energy 
• fever (high temperature) 
• skin rash  

 
Rare side effects 
These may affect up to 1 in 1,000 people: 
• inflammation of the pancreas (pancreatitis) 
 
Very rare side effects 
These may affect up to 1 in 10,000 people: 
• skin rash, which may form blisters and  looks like small targets (central dark spots surrounded by 

a paler area, with a dark ring around the edge) (erythema multiforme) 
• a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 

genitals (Stevens–Johnson syndrome), and a more severe form causing skin peeling in more than 
30% of the body surface (toxic epidermal necrolysis). 

• lactic acidosis (excess lactic acid in the blood) 
 

 
If you notice any of these symptoms contact a doctor urgently. 



68 

If you get side effects 

Tell your doctor or pharmacist if any of the side effects gets severe or troublesome, or if you 
notice any side effects not listed in this leaflet. 

 
Other possible side effects of combination therapy for HIV 

Combination therapy including Ziagen may cause other conditions to develop during HIV treatment. 
 

Symptoms of infection and inflammation  

Old infections may flare up 

People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to 
develop serious infections (opportunistic infections). When these people start treatment, they may find 
that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are 
probably caused by the body’s immune system becoming stronger, so that the body starts to fight these 
infections. Symptoms usually include fever, plus some of the following: 

• headache 
• stomach ache 
• difficulty breathing 

 
In rare cases, as the immune system becomes stronger, it can also attack healthy body tissue 
(autoimmune disorders).  The symptoms of autoimmune disorders may develop many months after 
you start taking medicine to treat your HIV infection. Symptoms may include: 

• palpitations (rapid or irregular heartbeat) or tremor 
• hyperactivity (excessive restlessness and movement)  
• weakness beginning in the hands and feet and moving up towards the trunk of the body 

 
 
If you get any symptoms of infection while you are taking Ziagen: 

Tell your doctor immediately. Do not take other medicines for the infection without your doctor’s 
advice. 
 

You may have problems with your bones 

Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this 
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be 
more likely to get this condition: 
• if they have been taking combination therapy for a long time 
• if they are also taking anti-inflammatory medicines called corticosteroids 
• if they drink alcohol 
• if their immune systems are very weak 
• if they are overweight 
Signs of osteonecrosis include: 
• stiffness in the joints 
• aches and pains (especially in the hip, knee or shoulder) 
• difficulty moving 
If you notice any of these symptoms: 

Tell your doctor. 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


69 

5. How to store Ziagen  
 
Keep this medicine out of the sight and reach of children. 
 
Do not take this medicine after the expiry date which is stated on the carton. The expiry date refers to 
the last day of that month. 
 
Do not store above 30°C. 
 
Discard oral solution two months after first opening. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures protect the environment. 
 
6. Contents of the pack and other information 
 
What Ziagen contains 
The active substance in Ziagen oral solution is 20 mg of abacavir (as sulfate) in each ml of the 
solution.  
 
The other ingredients are sorbitol 70% (E420), saccharin sodium, sodium citrate, citric acid 
anhydrous, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene 
glycol (E1520), maltodextrin, lactic acid, glyceryl triacetate, artificial strawberry and banana flavour, 
purified water, sodium hydroxide and/or hydrochloric acid for pH adjustment. 
 
What Ziagen looks like and contents of the pack 
Ziagen oral solution is clear to yellowish in colour which may turn into a brown colour over time with 
strawberry/banana flavouring. It is supplied in cartons containing a white polyethylene bottle, with a 
child resistant cap. The bottle contains 240 ml (20 mg abacavir/ml) of solution. A 10 ml oral dosing 
syringe and a plastic adapter for the bottle are included in the pack. 
 
 
Marketing Authorisation Holder: ViiV Healthcare BV, Van Asch van Wijckstraat 55H, 3811 LP 
Amersfoort, Netherlands 
 
Manufacturer: Glaxo Operations UK Ltd, (trading as GlaxoWellcome Operations) Harmire Road 
Barnard Castle Co. Durham DL12 8DT United Kingdom or ViiV Healthcare Trading Services UK 
Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
 

België/Belgique/Belgien 
ViiV Healthcare srl/bv 
 
Tél/Tel: + 32 (0) 10 85 65 00 
 

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

България 
ГлаксоСмитКлайн ЕООД 
Teл.: + 359 2 953 10 34 
 

Luxembourg/Luxemburg 
ViiV Healthcare srl/bv 
 
Belgique/Belgien 
Tél/Tel: + 32 (0) 10 85 65 00 
 



70 

Česká republika 
GlaxoSmithKline s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 

Danmark 
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 

Deutschland 
ViiV Healthcare GmbH  
Tel.: + 49 (0)89 203 0038-10 
viiv.med.info@viivhealthcare.com

Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 

Ελλάδα 
GlaxoSmithKline 
Μονοπρόσωπη A.E.B.E. 
Τηλ: + 30 210 68 82 100 

España 
Laboratorios ViiV Healthcare, S.L. 
Tel: +34 900 923 501 
es-ci@viivhealthcare.com 

France 
ViiV Healthcare SAS 
Tél.: + 33 (0)1 39 17 6969 
Infomed@viivhealthcare.com 

Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1 6051 999 

Ireland 
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 

Ísland 
Vistor hf.  
Sími: +354 535 7000 

Italia 
ViiV Healthcare S.r.l  
Tel: + 39 (0)45 9212611 

Magyarország 
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

Nederland 
ViiV Healthcare BV  
Tel: + 31 (0) 33 2081199 

Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
firmapost@gsk.no 

Österreich 
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 

Polska 
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 

Portugal 
VIIV HEALTHCARE, UNIPESSOAL, LDA 
Tel: + 351 21 094 08 01 
FI.PT@gsk.com 

România 
GlaxoSmithKline (GSK) S.R.L. 
Tel: + 4021 3028 208 

Slovenija 
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
medical.x.si@gsk.com 

Slovenská republika 
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 

Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 

mailto:cz.info@gsk.com
mailto:viiv.med.info@viivhealthcare.com
mailto:viiv.med.info@viivhealthcare.com
mailto:es-ci@viivhealthcare.com
mailto:es-ci@viivhealthcare.com
mailto:Infomed@viivhealthcare.com
mailto:Infomed@viivhealthcare.com


71 

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00 
gskcyprus@gsk.com 
 

Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 
 

Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 
 

 United Kingdom 
ViiV Healthcare UK Limited  
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com 

  
 
This leaflet was last revised in {MM/YYYY} 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site:  
http://www.ema.europa.eu 
 
 
 

 
 

  
 

  
 

mailto:gskcyprus@gsk.com
mailto:lv-epasts@gsk.com
mailto:lv-epasts@gsk.com
http://www.emea.europa.eu/
http://www.emea.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND40EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET