ZIAGEN 20mg / ml oral solution medication leaflet

Ziagen 20 mg/ml oral solution

Each ml of oral solution contains 20 mg of abacavir (as sulfate).

Sorbitol (E420) 340 mg/ml

Methyl parahydroxybenzoate (E218) 1.5 mg/ml

Propyl parahydroxybenzoate (E216) 0.18 mg/ml

Propylene glycol (E1520) 50 mg/ml

For the full list of excipients see section 6.1.

Oral solution

The oral solution is clear to slightly opalescent yellowish, aqueous solution which may turn into abrown colour over time

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 and5.1).

The demonstration of the benefit of Ziagen is mainly based on results of studies performed intreatment-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 beperformed in any HIV-infected patient, irrespective of racial origin(see section 4.4). Abacavir shouldnot be used in patients known to carry the HLA-B*5701 allele.

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).

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 atwice daily regimen is not feasible, a once daily regimen (16 mg/kg/day) could be considered. It shouldbe taken into account that data for the once daily regimen are very limited in this population (see sections5.1 and 5.2).

Children less than three months of age: the experience in children aged less than three months islimited (see section 5.2).

Patients changing from the twice daily dosing regimen to the once daily dosing regimen should takethe recomended once daily dose (as described above) approximately 12 hours after the last twice dailydose, and then continue to take the recomended once daily dose (as described above) approximatelyevery 24 hours. When changing back to a twice daily regimen, patients should take the recommendedtwice daily dose approximately 24 hours after the last once daily dose.

No dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen isnot recommended for patients with end-stage renal disease (see section 5.2).

Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made inpatients with mild hepatic impairment (Child-Pugh score 5-6). In patients with moderate or severehepatic impairment, no clinical data are available, therefore the use of abacavir is not recommendedunless judged necessary. If abacavir is used in patients with mild hepatic impairment, then closemonitoring is required, including monitoring of abacavir plasma levels if feasible (see sections 4.4and 5.2).

No pharmacokinetic data are currently available in patients over 65 years of age.

Hypersensitivity to abacavir or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8.

Hypersensitivity reactions (see also section 4.8):

Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) characterised byfever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observedwith abacavir, some of which have been life-threatening, and in rare cases fatal, when not managedappropriately.

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 thisallele.

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 patientswith 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 hypersensitivitymay result in a life-threatening reaction.

* After stopping treatment with Ziagen for reasons of a suspected HSR, Ziagen or any othermedicinal 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 aprompt return of symptoms within hours. This recurrence is usually more severe than on initialpresentation, and may include life-threatening hypotension and death.

* In order to avoid restarting abacavir, patients who have experienced a suspected HSR should beinstructed to dispose of their remaining Ziagen oral solution.

* 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 oftreatment 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 beenobserved as part of abacavir HSR are described in detail in section 4.8 (Description of selected adversereactions), including respiratory and gastrointestinal symptoms. Importantly, such symptoms may leadto misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), orgastroenteritis .

The symptoms related to HSR worsen with continued therapy and can be life-threatening. Thesesymptoms usually resolve upon discontinuation of abacavir.

Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have alsoexperienced 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 asetting where medical assistance is readily available.

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, whichis most pronounced with stavudine, didanosine and zidovudine. There have been reports ofmitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleosideanalogues ; these have predominantly concerned treatment with regimens containing zidovudine.Themain adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolicdisorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onsetneurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. These findingsshould be considered for any child exposed in utero to nucleotide and nucleotide analogues, whopresents with severe clinical findings of unknown etiology, particularly neurologic findings. Thesefindings do not affect current national recommendations to use antiretroviral therapy in pregnantwomen to prevent vertical transmission of HIV.

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

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 earlystage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once dailyregimen.

The safety and efficacy of Ziagen has not been established in patients with significant underlying liverdisorders. Ziagen is not recommended in patients with moderate or severe hepatic impairment (seesections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy, and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, 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 anincreased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant product information for these medicinalproducts.

Renal disease

Ziagen should not be administered to patients with end-stage renal disease (see section 5.2).

Ziagen oral solution contains 340 mg/ml of sorbitol. When taken according to the dosagerecommendations each 15 ml dose contains approximately 5 g of sorbitol. Patients with rare hereditaryproblems of fructose intolerance should not take this medicine. Sorbitol can have a mild laxativeeffect. The calorific value of sorbitol is 2.6 kcal/g.

Ziagen oral solution also contains methyl parahydroxybenzoate and propyl parahydroxybenzoatewhich may cause allergic reactions (possibly delayed).

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially‘sodium-free’.

Ziagen oral solution contains 50 mg/ml of propylene glycol. When taken according to the dosagerecommendations each 15 ml dose contains approximately 750 mg of propylene glycol.

* Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induceadverse effects in children less than 5 years old.

* While propylene glycol has not been shown to cause reproductive or developmental toxicity inanimals or humans, it may reach the foetus and was found in milk. As a consequence,administration of propylene glycol to pregnant or lactating patients should be considered followinga benefit risk assessment for an individual patient.

* Monitoring is required in patients with impaired renal or hepatic functions because variousadverse events attributed to propylene glycol have been reported such as renal dysfunction (acutetubular necrosis), acute renal failure and liver dysfunction.

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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 treatmentinstituted 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 toonset is more variable and these events can occur many months after initiation of treatment.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported 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, jointstiffness or difficulty in movement.

Patients receiving Ziagen or any other antiretroviral therapy may still develop opportunistic infectionsand other complications of HIV infection. Therefore patients should remain under close clinicalobservation by physicians experienced in the treatment of these associated HIV diseases.

Although the available data from clinical and observational studies with abacavir show inconsistentresults, several studies suggest an increased risk of cardiovascular events (notably myocardialinfarction) in patients treated with abacavir. Therefore, when prescribing Ziagen, action should betaken to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

In addition, alternative treatment options to the abacavir containing regimen should be consideredwhen treating patients with a high cardiovascular risk.

The potential for P450 mediated interactions with other medicinal products involving abacavir is low.

In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1).

P450 does not play a major role in the metabolism of abacavir, and abacavir shows limited potential toinhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit

CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolismhas not been observed in clinical studies. Therefore, there is little potential for interactions withantiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studieshave shown that there are no clinically significant interactions between abacavir, zidovudine, andlamivudine.

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 AUCof abacavir of about 41%. These findings are not considered clinically significant. Abacavir has noeffect on the metabolism of ethanol.

Methadone: in a pharmacokinetic study, co-administration of 600 mg abacavir twice daily withmethadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC wasunchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In thisstudy abacavir increased the mean methadone systemic clearance by 22%. The induction of drugmetabolising enzymes cannot therefore be excluded. Patients being treated with methadone andabacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, asoccasionally methadone re-titration may be required.

Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir ispossible but has not been studied.

Riociguat: In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose ofriociguat (0.5 mg) to HIV patients receiving the combination of abacavir/dolutegravir/lamivudine(600mg/50mg/300mg once daily) led to an approximately three-fold higher riociguat AUC(0-∞) whencompared to historical riociguat AUC(0-∞) reported in healthy subjects. Riociguat dose may need tobe reduced. Consult the riociguat prescribing information for dosing recommendations.

As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection inpregnant 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 (seesection 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinicalrelevance in human of these data is unknown. Placental transfer of abacavir and/or its relatedmetabolites has been shown to occur in human.

In pregnant women, more than 800 outcomes after first trimester exposure and more than 1000outcomes after second and third trimester exposure indicate no malformative and foetal /neonataleffect of abacavir. The malformative risk is unlikely in humans based on those data.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variabledegree 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).

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted intohuman milk. There are no data available on the safety of abacavir when administered to babies lessthan three months old. It is recommended that women living with HIV do not breast-feed their infantsin order to avoid transmission of HIV.

Studies in animals showed that abacavir had no effect on fertility (see section 5.3).

No studies on the effects on ability to drive and use machines have been performed.

For many adverse reactions reported, it is unclear whether they are related to Ziagen, to the widerange of medicinal products used in the management of HIV infection or as a result of the diseaseprocess.

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 thesesymptoms 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 necrolysishave been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinalproducts containing abacavir should be permanently discontinued.

Many of the adverse reactions have not been treatment limiting. The following convention has beenused for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000).

Common: anorexia

Very rare: lactic acidosis

Common: headache

Common: nausea, vomiting, diarrhoea

Rare: pancreatitis

Common: rash (without systemic symptoms)

Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

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 clinicalstudies or post marketing surveillance. Those reported in at least 10% of patients with ahypersensitivity reaction are in bold text.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usuallymaculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash orfever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such aslethargy 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

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 rareinstance, 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 restartingabacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior tostopping abacavir; and on very rare occasions have also been seen in patients who have restartedtherapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavirtolerant).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4)

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported to occur in the setting of immune reactivation; however, the reported time to onsetis more variable and these events can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (seesection 4.4).

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 population1206 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 section5.1). No additional safety issues have been identified in paediatric subjects receiving either once ortwice daily dosing compared to adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered topatients in clinical studies. No additional adverse reactions to those reported for normal doses werereported. The effects of higher doses are not known. If overdose occurs the patient should bemonitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied asnecessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.

Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code: J05AF06

Abacavir is a NRTI. It is a potent selective inhibitor of HIV-1 and HIV-2. Abacavir is metabolisedintracellularly to the active moiety, carbovir 5’- triphosphate (TP). In vitro studies have demonstratedthat its mechanism of action in relation to HIV is inhibition of the HIV reverse transcriptase enzyme, anevent which results in chain termination and interruption of the viral replication cycle. The antiviralactivity of abacavir in cell culture was not antagonized when combined with the nucleoside reversetranscriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir orzidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the proteaseinhibitor (PI) amprenavir.

In vitro resistance

Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specificgenotypic 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 mutationsfor 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 inpivotal 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%), andless common was the selection of L74V (5%), K65R (1%) and Y115F (1%). The inclusion ofzidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in thepresence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%).

Abacavir +

Therapy Abacavir + Abacavir +

Combivir1 lamivudine + lamivudine + Total

NNRTI PI (or

PI/ritonavir)

Number of

Subjects 282 1094 909 2285

Number of

Virological 43 90 158 291

Failures

Number of

On-Therapy 40 (100%) 51 (100%)2 141 (100%) 232 (100%)

Genotypes

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 zidovudine2.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 ofsix 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 isolatesof patients with uncontrolled viral replication, who have been pre-treated with and are resistant toother nucleoside inhibitors. In a meta-analysis of five clinical trials where abacavir was added tointensify 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 wereuncommon (≤3%). Logistic regression modelling of the predictive value for genotype (adjusted forbaseline plasma HIV-1 RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviraltherapies), showed that the presence of 3 or more NRTI resistance-associated mutations wasassociated 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 combinationwith A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir.

Week 4

Baseline Reverse (n = 166)

Transcriptase Mutation Median Percent withn Change vRNA <400 copies/ml(log10 c/ml) vRNA

None 15 -0.96 40%

M184V alone 75 -0.74 64%

Any one NRTI mutation 82 -0.72 65%

Any two NRTI-associatedmutations 22 -0.82 32%

Any three NRTI-associatedmutations 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 M184Imutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviralactivities 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 riseto cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115Fgives rise to cross-resistance between abacavir and lamivudine. Appropriate use of abacavir can beguided using currently recommended resistance algorithms.

Cross-resistance between abacavir and antiretrovirals from other classes (e.g. PIs or NNRTIs) isunlikely.

The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adulttreatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination withzidovudine and lamivudine.

Twice daily (300 mg) administration:

* Therapy naïve adults

In adults treated with abacavir in combination with lamivudine and zidovudine the proportion ofpatients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treatanalysis at 48 weeks) with corresponding rise in CD4 cells.

One randomised, double blind, placebo controlled clinical study in adults has compared thecombination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine andzidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinuedrandomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalencebetween the treatment regimens at week 48. Although a similar antiviral effect was observed betweenthe abacavir and indinavir containing regimens in terms of proportion of patients with undetectableviral 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 indinavircombination, 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, antiretroviraltherapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mgonce 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 zidovudinegroup, achieved a virologic response of plasma HIV-1 RNA ≤50 copies/ml by Week 48 (pointestimate for treatment difference: 0.8, 95% CI -6.3, 7.9). In the as treated (AT) analysis the differencebetween both treatment arms was more noticeable (88% of patients in the abacavir group, compared to95% 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 betweenboth treatment arms.

ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147antiretroviral 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 medianfollow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to bevirologically 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 4drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 theproportion 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 ofpatients with virologic failure. The remaining arms were continued in a blinded fashion. After amedian 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 significantdifference 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 32 weeks 26% 16% 13%

RNA >200 copies/ml) 144 weeks - 26% 25%

Virologic success (48 63% 80% 86%weeks HIV RNA < 50copies/ml)

* Therapy experienced adults

In adults moderately exposed to antiretroviral therapy the addition of abacavir to combinationantiretroviral therapy provided modest benefits in reducing viral load (median change0.44 log10 copies/ml at 16 weeks).

In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit as partof a new combination regimen will depend on the nature and duration of prior therapy which mayhave 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, controlledstudy (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 wererandomised to receive either abacavir 600 mg once daily or 300 mg twice daily, in combination withefavirenz and lamivudine given once daily. Similar clinical success (point estimate for treatmentdifference -1.7, 95% CI -8.4, 4.9) was observed for both regimens. From these results, it can beconcluded with 95% confidence that the true difference is no greater than 8.4% in favour of the twicedaily 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 theonce and twice daily treatment groups (10% and 8% respectively). In the small sample size forgenotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the oncedaily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limiteddata derived from this study. Long term data with abacavir used as a once daily regimen (beyond 48weeks) are currently limited.

* Therapy experienced adults

In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised andreceived treatment with either the fixed-dose combination of abacavir/lamivudine (FDC) once daily orabacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovirand a PI or an NNRTI for 48 weeks. Results indicate that the FDC group was non-inferior to theabacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average areaunder the curve minus baseline (AAUCMB, -1.65 log10 copies/ml versus -1.83 log10 copies/mlrespectively, 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, asthere were only moderately experienced patients included in this study with an imbalance in baselineviral 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 containingabacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, wererandomised to continue this regimen or switch to abacavir/lamivudine FDC plus a PI or NNRTI for 48weeks. 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).

The safety and efficacy of Ziagen in a number of different multidrug combination regimens is still notcompletely 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 seenwhen it was administered to patients with AIDS dementia complex.

A randomised comparison of a regimen including once daily vs twice daily dosing of abacavir andlamivudine 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 andchildren, 2006). After 36 weeks on a regimen including twice daily abacavir and lamivudine, 669eligible subjects were randomised to either continue twice daily dosing or switch to once dailyabacavir and lamivudine for at least 96 weeks. Of note, from this study clinical data were not availablefor 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 Week96 in the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW(Observed Analysis)

Twice Daily Once Daily

N (%) N (%)

Week 0 (After ≥36 Weeks on Treatment)

Plasma HIV-1 RNA 250/331 (76) 237/335 (71)<80 c/ml

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

Week 48

Plasma HIV-1 RNA 242/331 (73) 236/330 (72)<80 c/ml

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

Week 96

Plasma HIV-1 RNA 234/326 (72) 230/331 (69)<80 c/ml

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

The abacavir + lamivudine once daily dosing group was demonstrated to be non-inferior to the twicedaily 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. Subgroupanalyses 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 andzidovudine (60%) had HIV-1 RNA ≤400 copies/ml at 48 weeks, compared with those treated withlamivudine and zidovudine (47%)[ p=0.09, intention to treat analysis]. Similarly, greater proportionsof children treated with the abacavir containing combinations had HIV-1 RNA ≤50 copies/ml at 48weeks (53%, 42% and 28% respectively, p=0.07).

In a pharmacokinetic study (PENTA 15), four virologically controlled subjects less than 12 months ofage switched from abacavir plus lamivudine oral solution twice daily to a once daily regimen. Threesubjects had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48. Nosafety concerns were observed in these subjects.

Abacavir is rapidly and well absorbed following oral administration. The absolute bioavailability oforal abacavir in adults is about 83%. Following oral administration, the mean time (tmax) to maximalserum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour forthe solution formulation.

There are no differences observed between the AUC for the tablet or solution. At therapeutic dosagesa dosage of 300 mg twice daily, the mean (CV) steady state Cmax and Cmin of abacavir areapproximately 3.00 µg/ml (30%) and 0.01 µg/ml(99%), respectively. The mean (CV) AUC over adosing interval of 12 hours was 6.02 µg.h/ml (29%), equivalent to a daily AUC of approximately12.0 µg.h/ml. The Cmax value for the oral solution is slightly higher than the tablet. After a 600 mgabacavir 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.

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 toplasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 foldgreater than the IC50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twicedaily.

Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) tohuman plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactionswith other medicinal products through plasma protein binding displacement.

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose beingrenally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcoholdehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide whichaccount for about 66% of the administered dose. The metabolites are excreted in the urine.

The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mgtwice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepaticmetabolism with subsequent excretion of metabolites primarily in the urine. The metabolites andunchanged abacavir account for about 83% of the administered abacavir dose in the urine. Theremainder is eliminated in the faeces.

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mgdose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellularhalf-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life inthis study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TPexposures 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 useof abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacyand safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021-

See section 5.1 Clinical experience).

Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied inpatients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose; themedian (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 theelimination half-life. No definitive recommendation on dosage reduction is possible in patients withmild hepatic impairment due to the substantial variability of abacavir exposure.

Abacavir is not recommended in patients with moderate or severe hepatic impairment.

Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchangedin the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar topatients with normal renal function. Therefore no dosage reduction is required in patients with renalimpairment. Based on limited experience Ziagen should be avoided in patients with end-stage renaldisease.

According to clinical trials performed in children abacavir is rapidly and well absorbed from oralsolution and tablet formulations administered to children. Plasma abacavir exposure has been shown tobe the same for both formulations when administered at the same dose. Children receiving abacaviroral solution according to the recommended dosage regimen achieve plasma abacavir exposure similarto adults. Children receiving abacavir oral tablets according to the recommended dosage regimenachieve higher plasma abacavir exposure than children receiving oral solution because higher mg/kgdoses are administered with the tablet formulation.

There are insufficient safety data to recommend the use of Ziagen in infants less than three monthsold. The limited data available indicate that an oral solution dose of 2 mg/kg in neonates less than 30days old provides similar or greater AUCs, compared to the 8 mg/kg oral solution dose administeredto 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 tablebelow:

Summary of Stead-State Plasma Abacavir AUC (0-24) (µg.h/ml) and Statistical Comparisons for

Once and Twice-Daily Oral Administration Across Studies

Abacavir Abacavir Once-Versus

Study Age Group 16 mg/kg Once- 8 mg/kg Twice- Twice-Daily

Daily Dosing Daily Dosing Comparison

Geometric Mean Geometric Mean GLS Mean Ratio(95% Cl) (95% Cl) (90% Cl)

ARROW PK 3 to 12 years 15.3 15.6 0.98

Substudy (N=36) (13.3-17.5) (13.7-17.8) (0.89, 1.08)

Part 1

PENTA 13 2 to 12 years 13.4 9.91 1.35(N=14) (11.8-15.2) (8.3-11.9) (1.19-1.54)

PENTA 15 3 to 36 months 11.6 10.9 1.07(N=18) (9.89-13.5) (8.9-13.2) (0.92-1.23)

In PENTA 15 study, the geometric mean plasma abacavir AUC(0-24) (95% CI) of the four subjectsunder 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.

The pharmacokinetics of abacavir has not been studied in patients over 65 years of age.

Abacavir was not mutagenic in bacterial tests but showed activity in vitro in the human lymphocytechromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus test. This isconsistent with the known activity of other nucleoside analogues. These results indicate that abacavirhas a weak potential to cause chromosomal damage both in vitro and in vivo at high testconcentrations.

Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in theincidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial glandof males and the clitoral gland of females of both species, and in rats in the thyroid gland of males andthe 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 and600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3and 7 times the human systemic exposure during therapy. While the carcinogenic potential in humansis unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potentialclinical benefit.

In pre-clinical toxicology studies, abacavir treatment was shown to increase liver weights in rats andmonkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies thatabacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of themetabolism 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 ofabacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemicexposure 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 inrabbits. These findings included decreased foetal body weight, foetal oedema, and an increase inskeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can bedrawn 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.

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.

Not applicable

2 years

After first opening the container: 2 months

Do not store above 25°C.

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 apolypropylene barrel (with ml graduations) and a polyethylene plunger.

A plastic adapter and oral dosing syringe are provided for accurate measurement of the prescribeddose 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.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/99/112/002

Date of first authorisation: 8 July 1999

Date of latest renewal: 21 March 2014

Detailed information on this medicinal product is available on the website of the European Medicines

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