TRIZIVIR 300mg / 150mg / 300mg film-coated tablets medication leaflet

TRIZIVIR 300 mg/150 mg/300 mg film-coated tablets

Each film-coated tablet contains 300 mg of abacavir (as sulfate), 150 mg lamivudine and 300 mgzidovudine.

Each 300 mg/150 mg/300 mg tablet contains 2.7 mg sodium.

For the full list of excipients see section 6.1.

Film-coated tablet (tablet).

Blue-green capsule-shaped film-coated tablets engraved with “GX LL1” on one side.

Trizivir is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults(see sections 4.4 and 5.1). This fixed combination replaces the three components (abacavir,lamivudine and zidovudine) used separately in similar doses. It is recommended that treatment isstarted with abacavir, lamivudine, and zidovudine separately for the first 6-8 weeks (see section 4.4).

The choice of this fixed combination should be based not only on potential adherence criteria, butmainly on expected efficacy and risk related to the three nucleoside analogues.

The demonstration of the benefit of Trizivir is mainly based on results of studies performed intreatment naive patients or moderately antiretroviral experienced patients with non-advanced disease.

In patients with high viral load (> 100,000 copies/mL) choice of therapy needs special consideration(see section 5.1).

Overall, the virologic suppression with this triple nucleoside regimen could be inferior to thatobtained with other multitherapies notably including boosted Protease inhibitors or non-nucleosidereverse transcriptase inhibitors, therefore the use of Trizivir should only be considered under specialcircumstances (e.g. co-infection with tuberculosis).

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.

Therapy should be prescribed by a physician experienced in the management of HIV infection.

The recommended dose of Trizivir in adults (18 years and over) is one tablet twice daily.

Trizivir can be taken with or without food.

Where discontinuation of therapy with one of the active substances of Trizivir is indicated, or wheredose reduction is necessary separate preparations of abacavir, lamivudine and zidovudine areavailable.

Whilst no dose adjustment of abacavir is necessary in patients with renal dysfunction, lamivudine andzidovudine concentrations are increased in patients with renal impairment due to decreased clearance(see section 4.4). Therefore, as dose adjustments of these may be necessary, it is recommended thatseparate preparations of abacavir, lamivudine and zidovudine be administered to patients with severerenal impairment (creatinine clearance ≤ 30 mL/min). Physicians should refer to the individualsummary of product characteristics of these medicinal products. Trizivir should not be administered topatients with end-stage renal disease (see sections 4.3 and 5.2).

Abacavir is primarily metabolised by the liver. No clinical data are available in patients with moderateor severe hepatic impairment, therefore the use of Trizivir is not recommended unless judgednecessary. In patients with mild hepatic impairment (Child-Pugh score 5-6) close monitoring isrequired, including monitoring of abacavir plasma levels if feasible (see sections 4.4 and 5.2).

No pharmacokinetic data are currently available in patients over 65 years of age. Special care isadvised in this age group due to age associated changes such as the decrease in renal function andalteration of haematological parameters.

The safety and efficacy of Trizivir in adolescents and children has not been established. No data areavailable.

Dose adjustments in patients with haematological adverse reactions

Dose adjustment of zidovudine may be necessary if the haemoglobin level falls below 9 g/dl or5.59 mmol/l or the neutrophil count falls below 1.0 x 109/l (see sections 4.3 and 4.4). As doseadjustment of Trizivir is not possible, separate preparations of abacavir, lamivudine and zidovudineshould be used. Physicians should refer to the individual summary of product characteristics of thesemedicinal products.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. See sections4.4 and 4.8.

Patients with end-stage renal disease.

Due to the active substance zidovudine, Trizivir is contraindicated in patients with abnormally lowneutrophil counts (< 0.75 x 109/l), or abnormally low haemoglobin levels (< 7.5 g/dl or 4.65 mmol/l)(see section 4.4).

The special warnings and precautions relevant to abacavir, lamivudine and zidovudine are included inthis section. There are no additional precautions or warnings relevant to the combination Trizivir.

Hypersensitivity Reactions (see also section 4.8 )

Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) characterisedby fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have beenobserved with abacavir, some of which have been life-threatening, and in rare cases fatal, when notmanaged appropriately.

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.

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

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

* After stopping treatment with Trizivir for reasons of a suspected HSR, Trizivir or any othermedicinal product containing abacavir (e.g. Kivexa, Ziagen, 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 oninitial presentation, and may include life-threatening hypotension and death.

* In order to avoid restarting abacavir patients who have experienced a suspected HSR shouldbe instructed to dispose of their remaining Trizivir 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 initiationof 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 beenobserved as part of abacavir HSR are described in detail in section 4.8 (Description of selectedadverse reactions), including respiratory and gastrointestinal symptoms. Importantly, such symptomsmay lead to 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.

Lactic acidosis

Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with theuse of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestivesymptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss,respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including motorweakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renalfailure.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with zidovudine should be discontinued in the setting of symptomatic hyperlactatemia andmetabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering zidovudine to any patient (particularly obesewomen) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepaticsteatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C andtreated with alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely.

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which ismost 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 adverse reactions have often been transitory. Lateonset neurological 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.

Lipoatrophy

Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked tomitochondrial toxicity. The incidence and severity of lipoatrophy are related to cumulative exposure.

This fat loss, which is most evident in the face, limbs and buttocks, may not be reversible whenswitching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophyduring therapy with zidovudine and zidovudine-containing products (Combivir and Trizivir). Therapyshould be switched to an alternative regimen if there is suspicion of lipoatrophy development.

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.

Haematological adverse reactions

Anaemia, neutropenia and leukopenia (usually secondary to neutropenia) can be expected to occur inpatients receiving zidovudine. These occurred more frequently at higher zidovudine doses (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly withadvanced HIV disease. Haematological parameters should therefore be carefully monitored (seesection 4.3) in patients receiving Trizivir. These haematological effects are not usually observedbefore four to six week’s therapy. For patients with advanced symptomatic HIV disease, it is generallyrecommended that blood tests are performed at least every two weeks for the first three months oftherapy and at least monthly thereafter.

In patients with early HIV disease haematological adverse reactions are infrequent. Depending on theoverall condition of the patient, blood tests may be performed less often, for example every one tothree months. Additionally, dose adjustment of zidovudine may be required if severe anaemia ormyelosuppression occurs during treatment with Trizivir, or in patients with pre-existing bone marrowcompromise e.g. haemoglobin < 9 g/dl (5.59 mmol/l) or neutrophil count < 1.0 x 109/l (seesection 4.2). As dose adjustment of Trizivir is not possible separate preparations of zidovudine,abacavir and lamivudine should be used. Physicians should refer to the individual prescribinginformation for these medicinal products.

Cases of pancreatitis have occurred rarely in patients treated with abacavir, lamivudine andzidovudine. However, it is not clear whether these cases were due to treatment with these medicinalproducts or to the underlying HIV disease. Treatment with Trizivir should be stopped immediately ifclinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV)infection, additional information relating to the use of lamivudine in the treatment of HBV is availablein the Zeffix SmPC.

The safety and efficacy of Trizivir has not been established in patients with significant underlyingliver disorders. Trizivir is not recommended in patients with moderate or severe hepatic impairment(see sections 4.2 and 5.2).

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.

If Trizivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of bothliver function tests and markers of HBV replication is recommended, as withdrawal of lamivudinemay result in an acute exacerbation of hepatitis (see Zeffix SmPC).

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 hepatitis B or C virus

The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk ofanaemia (see section 4.5).

Children and adolescents

Because insufficient data are available, the use of Trizivir in children or adolescents is notrecommended. In this patient population, hypersensitivity reactions are particularly difficult toidentify.

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 jirovecii pneumonia. Any inflammatory symptoms should be evaluated andtreatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmunehepatitis) have also been reported to occur in the setting of immune reactivation; however, the reportedtime to onset is more variable and 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 combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint aches and pain, joint stiffness or difficulty in movement.

Patients should be advised that Trizivir or any other antiretroviral therapy does not cure HIV infectionand that they may still develop opportunistic infections and other complications of HIV infection.

Therefore, patients should remain under close clinical observation by physicians experienced in thetreatment 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 Trizivir, 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.

Patients with a creatinine clearance between 30 and 49 mL/min receiving Trizivir may experiencea 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance≥50 mL/min. There are no safety data from randomized, controlled trials comparing Trizivir to theindividual components in patients with a creatinine clearance between 30 and 49 mL/min whoreceived dose-adjusted lamivudine. In the original lamivudine registrational trials in combination withzidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities(neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in<1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepaticdisorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Trizivir shouldbe monitored for lamivudine-related adverse events, notably haematologic toxicities. If new orworsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudineprescribing information, is indicated, which cannot be achieved with Trizivir. Trizivir should bediscontinued and the individual components should be used to construct the treatment regimen.

Drug Interactions

To date there are insufficient data on the efficacy and safety of Trizivir given concomitantly with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or the protease inhibitors (PIs) (see section 5.1).

Trizivir should not be taken with any other medicinal products containing lamivudine or medicinalproducts containing emtricitabine.

The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

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

Trizivir contains abacavir, lamivudine and zidovudine, therefore any interactions identified for theseindividually are relevant to Trizivir. Clinical studies have shown that there are no clinically significantinteractions between abacavir, lamivudine and zidovudine.

Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase;co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated throughalcohol dehydrogenase could alter abacavir exposure. Zidovudine is primarily metabolised by UGTenzymes; co-administration of inducers or inhibitors of UGT enzymes could alter zidovudineexposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediatedthrough organic cation transporters (OCTs); co-administration of lamivudine with OCT inhibitors mayincrease lamivudine exposure.

Abacavir, lamivudine and zidovudine are not significantly metabolised by cytochrome P450 enzymes(such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they induce this enzyme system. Lamivudine andzidovudine do not inhibit cytochrome P450 enzymes. Abacavir shows limited potential to inhibitmetabolism mediated by CYP3A4 and has been shown in vitro not to inhibit CYP2C9 or CYP 2D6enzymes. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1(CYP1A1). Therefore, there is little potential for interactions with antiretroviral protease inhibitors,non-nucleosides and other medicinal products metabolised by major P450 enzymes.

Interaction studies have only been performed in adults. The list below should not be consideredexhaustive but is representative of the classes studied.

Drugs by Therapeutic Area Interaction Recommendation

Geometric mean change concerning co-(%) administration(Possible mechanism)

ANTIRETROVIRAL MEDICINAL PRODUCTS

Didanosine/Abacavir Interaction not studied. No dosage adjustment

Didanosine/Lamivudine Interaction not studied. necessary.

Didanosine/Zidovudine Interaction not studied.

Stavudine/Abacavir Interaction not studied. Combination not

Stavudine/Lamivudine Interaction not studied. recommended.

Stavudine/Zidovudine In vitro antagonism of anti-HIVactivity between stavudine andzidovudine could result indecreased efficacy of bothdrugs.

ANTI-INFECTIVE PRODUCTS

Atovaquone/Abacavir Interaction not studied. As only limited data available

Atovaquone/Lamivudine Interaction not studied. the clinical significance is

Atovaquone/Zidovudine Zidovudine AUC ↑33% unknown.(750 mg twice daily with Atovaquone AUC ↔food/200 mg thrice daily)

Clarithromycin/Abacavir Interaction not studied. Separate administration of

Clarithromycin/Lamivudine Interaction not studied. Trizivir and clarithromycin by

Clarithromycin/Zidovudine Zidovudine AUC ↓12% at least 2 hours(500 mg twice daily/100 mgevery 4 hours)

Trimethoprim/sulfamethoxazole Interaction not studied. No Trizivir dosage adjustment(Co-trimoxazole)/Abacavir necessary, unless patient has

Trimethoprim/sulfamethoxazole Lamivudine: AUC ↑40% renal impairment (See Section(Co-trimoxazole)/Lamivudine 4.2).(160mg/800mg once daily for 5 Trimethoprim: AUC ↔days/300mg single dose) Sulfamethoxazole: AUC ↔ When concomitantadministration with co-(organic cation transporter trimoxazole is warranted,inhibition) patients should be monitored

Trimethoprim/sulfamethoxazole Interaction not studied. clinically. High doses of(Co-trimoxazole)/Zidovudine trimethoprim/sulfamethoxazole for thetreatment of Pneumocystisjirovecii pneumonia (PCP) andtoxoplasmosis have not beenstudied and should be avoided.

ANTIFUNGALS

Fluconazole/Abacavir Interaction not studied. As only limited data are

Fluconazole/Lamivudine Interaction not studied. available the clinical

Fluconazole/Zidovudine Zidovudine AUC ↑74% significance is not known.(400 mg once daily/200 mg Monitor for signs ofthrice daily) (UGT inhibition) zidovudine toxicity (seesection 4.8).

ANTIMYCOBACTERIALS

Rifampicin/Abacavir Interaction not studied. Insufficient data torecommend dosage

Potential to slightly decrease adjustment.abacavir plasma concentrationsthrough UGT induction.

Drugs by Therapeutic Area Interaction Recommendation

Geometric mean change concerning co-(%) administration(Possible mechanism)

Rifampicin/Lamivudine Interaction not studied. Insufficient data to

Rifampicin/Zidovudine Zidovudine AUC ↓48% recommend dosageadjustment.

(600mg once daily/200 mg (UGT induction)thrice daily)

ANTICONVULSANTS

Phenobarbital/Abacavir Interaction not studied. Insufficient data torecommend dosage

Potential to slightly decrease adjustment.abacavir plasma concentrationsthrough UGT induction.

Phenobarbital/Lamivudine Interaction not studied.

Phenobarbital/Zidovudine Interaction not studied.

Potential to slightly decreasezidovudine plasmaconcentrations through UGTinduction.

Phenytoin/Abacavir Interaction not studied. Insufficient data torecommend dosage

Potential to slightly decrease adjustment.abacavir plasma concentrationsthrough UGT induction. Monitor phenytoin

Phenytoin/Lamivudine Interaction not studied. concentrations.

Phenytoin/Zidovudine Phenytoin AUC ↑↓

Valproic acid/Abacavir Interaction not studied. As only limited data are

Valproic acid/Lamivudine Interaction not studied. available the clinical

Valproic acid/Zidovudine Zidovudine AUC ↑80% significance is not known.(250 mg or 500 mg thrice Monitor for signs ofdaily/100 mg thrice daily) (UGT inhibition) zidovudine toxicity (seesection 4.8).

ANTIHISTAMINES (HISTAMINE H2 RECEPTOR ANTAGONISTS)

Ranitidine/Abacavir Interaction not studied. No dosage adjustment

Ranitidine/Lamivudine Interaction not studied. necessary.

Clinically significantinteraction unlikely. Ranitidineeliminated only in part by renalorganic cation transport system.

Ranitidine/Zidovudine Interaction not studied

Cimetidine/Abacavir Interaction not studied. No dosage adjustment

Cimetidine/Lamivudine Interaction not studied. necessary.

Clinically significantinteraction unlikely.

Cimetidine eliminated only inpart by renal organic cationtransport system.

Cimetidine/Zidovudine Interaction not studied.

Drugs by Therapeutic Interaction Recommendation

Area Geometric mean change concerning co-(%) administration(Possible mechanism)

CYTOTOXICS

Cladribine/Lamivudine Interaction not studied. Therefore, the concomitantuse of lamivudine with

In vitro lamivudine inhibits the cladribine is notintracellular phosphorylation of recommended (see sectioncladribine leading to a potential 4.4).risk of cladribine loss of efficacyin case of combination in theclinical setting. Some clinicalfindings also support a possibleinteraction between lamivudineand cladribine.

OPIOIDS

Methadone/Abacavir Abacavir: AUC ↔ As only limited data are(40 to 90mg once daily for 14 Cmax ↓35% available the clinicaldays/600mg single dose, then significance is not known.600mg twice daily for 14 days) Methadone: CL/F ↑22% Monitor for signs of

Methadone/Lamivudine Interaction not studied. zidovudine toxicity (see

Methadone/Zidovudine Zidovudine AUC ↑43% section 4.8).(30 to 90 mg once Methadone AUC ↔daily/200 mg every 4 hours) Methadone dosage adjustmentunlikely in majority ofpatients; occasionallymethadone re-titration may berequired.

RETINOIDS

Retinoid compounds Interaction not studied. Insufficient data to(e.g. isotretinoin)/Abacavir recommend dosage

Possible interaction given adjustment.common pathway of eliminationvia alcohol dehydrogenase.

Retinoid compounds Interaction not studied.(e.g. isotretinoin)/Lamivudine

No drug interaction studies

Retinoid compounds Interaction not studied.(e.g. isotretinoin)/Zidovudine

URICOSURIC

Probenecid/Abacavir Interaction not studied. As only limited data are

Probenecid/Lamivudine Interaction not studied. available the clinical

Probenecid/Zidovudine Zidovudine AUC ↑106% significance is not known.(500 mg four times Monitor for signs ofdaily/2mg/kg thrice daily) (UGT inhibition) zidovudine toxicity (seesection 4.8).

MISCELLANEOUS

Ethanol/Abacavir Abacavir: AUC ↑41% No dosage adjustment(0.7 g/kg single dose/600mg Ethanol: AUC ↔ necessary.single dose)(Inhibition of alcoholdehydrogenase)

Ethanol/Lamivudine Interaction not studied.

Ethanol/Zidovudine Interaction not studied.

Sorbitol solution (3.2 g, 10.2 g, Single dose lamivudine oral When possible, avoid chronic13.4 g)/ Lamivudine solution 300 mg coadministration of Trizivir

Lamivudine: with medicinal productscontaining sorbitol or other

AUC ↓ 14%; 32%; 36% osmotic acting poly-alcoholsor monosaccharide alcohols

Cmax ↓ 28%; 52%, 55%. (e.g. xylitol, mannitol,lactitol, maltitol). Considermore frequent monitoring of

HIV-1 viral load whenchronic coadministrationcannot be avoided.

Riociguat/Abacavir Riociguat ↑ Riociguat dose may need to

In vitro, abacavir inhibits be reduced. Consult the

CYP1A1. Concomitant riociguat prescribingadministration of a single dose information for dosingof riociguat (0.5 mg) to HIV recommendations.

patients receiving thecombination ofabacavir/dolutegravir/lamivudine(600mg/50mg/300mg oncedaily) led to an approximatelythree-fold higher riociguat

AUC(0-∞) when compared tohistorical riociguat AUC(0-∞)reported in healthy subjects.

Abbreviations: ↑ = Increase; ↓=decrease; ↔= no significant change; AUC=area under theconcentration versus time curve; Cmax=maximum observed concentration; CL/F=apparent oralclearance

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimenused to treat HIV although the exact mechanism remains to be elucidated. The concomitant use ofribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).

Consideration should be given to replacing zidovudine in a combination ART regimen if this isalready established. This would be particularly important in patients with a known history ofzidovudine induced anaemia.

Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressivemedicinal products (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole,amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may alsoincrease the risk of adverse reactions to zidovudine (see section 4.8). If concomitant therapy with

Trizivir and any of these medicinal products is necessary then extra care should be taken in monitoringrenal function and haematological parameters and, if required, the dosage of one or more agentsshould be reduced.

Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions tozidovudine with cotrimoxazole (see interaction information above relating to lamivudine and co-trimoxazole), aerosolised pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn,the animal data as well as the clinical experience in pregnant women should be taken into account. Inthe present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborninfants, has been shown to reduce the rate of maternal-foetal transmission of HIV. There are no dataon the use of Trizivir in pregnancy. A moderate amount of data on pregnant women taking theindividual actives abacavir, lamivudine and zidovudine in combination indicates no malformativetoxicity (more than 300 outcomes from first trimester exposures). A large amount of data on pregnantwomen taking lamivudine or zidovudine indicate no malformative toxicity (more than 3000 outcomesfrom first trimester exposure each, of which over 2000 outcomes involved exposure to bothlamivudine and zidovudine). Moderate amount of data (more than 600 outcomes from first trimester)indicates no malformative toxicity for abacavir. The malformative risk is unlikely in humans based onthe mentioned moderate amount of data.

The active ingredients of Trizivir may inhibit cellular DNA replication, zidovudine has been shown tobe transplacental carcinogen in one animal study and abacavir has been shown to be carcinogenic inanimal models (see section 5.3). The clinical relevance of these findings is unknown.

For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinalproduct such as Trizivir and subsequently become pregnant, consideration should be given to thepossibility of a recurrence of hepatitis on discontinuation of lamivudine.

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.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine inbreastfed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) andprogressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There areno data available on the safety of abacavir and lamivudine when administered to babies less than threemonths old.

After administration of a single dose of 200 mg zidovudine to HIV-infected women, the meanconcentration of zidovudine was similar in human milk and serum.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

Studies in animals showed that neither abacavir nor lamivudine nor zidovudine had any effect onfertility (see section 5.3). Zidovudine has been shown not to affect the number of sperm, spermmorphology and motility in man.

No studies on the effects on the ability to drive and use machines have been performed. The clinicalstatus of the patient and the adverse event profile of Trizivir should be borne in mind whenconsidering the patient’s ability to drive or operate machinery.

Adverse reactions have been reported with abacavir, lamivudine and zidovudine used separately or incombination for therapy of HIV disease. Because Trizivir contains abacavir, lamivudine andzidovudine, the adverse reactions associated with these compounds may be expected.

Tabulated list of adverse reactions reported with the individual substances

The adverse reactions reported with abacavir, lamivudine and zidovudine are presented in Table 2.

They are listed by body system, organ class and absolute frequency. Frequencies are defined as verycommon (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to< 1/1000), very rare (< 1/10,000). Care must be taken to eliminate the possibility of a hypersensitivityreaction if any of these symptoms occur.

Table 1: Adverse reactions reported with the individual components of Trizivir

Abacavir Lamivudine Zidovudine

IMPORTANT: for information on abacavir hypersensitivity see the information below,under the Description of selected adverse reactions

Uncommon: neutropenia, Common: anaemia, neutropeniaanaemia (both occasionally and leukopeniasevere), thrombocytopenia Uncommon: thrombocytopenia

Very rare: pure red cell aplasia and pancytopenia with marrowhypoplasia

Rare: pure red cell aplasia

Very rare: aplastic anaemia

Common: hypersensitivity

Common: anorexia Very Rare : lactic acidosis Rare: anorexia, lactic acidosis

Very Rare : lactic acidosis in the absence of hypoxaemia

Rare: anxiety, depression

Common: headache Common: headache, insomnia Very common: headache

Very rare: peripheral Common: dizzinessneuropathy (paraesthesiae)

Rare: insomnia, paraesthesia,somnolence, loss of mentalacuity, convulsions

Rare: cardiomyopathy

Common: cough, nasal Uncommon: dyspnoeasymptoms Rare: cough

Abacavir Lamivudine Zidovudine

Common: nausea, vomiting, Common: nausea, vomiting, Very common: Nauseadiarrhoea abdominal pain, diarrhoea Common: vomiting, abdominal

Rare: pancreatitis Rare: rises in serum amylase, pain, and diarrhoeapancreatitis Uncommon: flatulence

Rare: oral mucosapigmentation, taste disturbancedyspepsia, pancreatitis

Uncommon: transient rises inliver enzymes (AST, ALT) Common: raised blood levels

Rare: hepatitis of liver enzymes and bilirubin

Rare: liver disorders such assevere hepatomegaly withsteatosis,

Common: rash (without Common: rash, alopecia Uncommon: rash and pruritussystemic symptoms) Rare: nail and skin

Very rare: erythema pigmentation, urticaria andmultiforme, Stevens-Johnson sweatingsyndrome and toxic epidermalnecrolysis

Common: arthralgia, muscle Common: myalgiadisorders Uncommon: myopathy

Rare: rhabdomyolysis

Rare: urinary frequency

Rare: gynaecomastia

Common: fever, lethargy, Common: fatigue, malaise, Common: malaisefatigue fever Uncommon: fever, generalisedpain and asthenia

Rare: chills, chest pain, andinfluenza-like syndrome

Many of the adverse reactions listed in the table 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.

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).

Haematological adverse reactions with zidovudine

Anaemia, neutropenia and leukopenia occurred more frequently at higher doses (1,200-1,500 mg/day)and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior totreatment) and particularly in patients with CD4 cell counts less than 100/mm3. Dose reduction orcessation of therapy may become necessary (see section 4.4). The anaemia may necessitatetransfusions.

The incidence of neutropenia was also increased in those patients whose neutrophil counts,haemoglobin levels and serum vitamin B12 levels were low at the start of zidovudine therapy.

Lactic acidosis

Treatment with zidovudine has been associated with cases of lactic acidosis, sometimes fatal, usuallyassociated with severe hepatomegaly and hepatic steatosis, (see section 4.4).

Lipoatrophy

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident inthe face, limbs and buttocks. Patients receiving Trizivir should be frequently examined andquestioned for signs of lipoatrophy. When such development is found, treatment with Trizivir shouldnot be continued (see section 4.4).

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 combination antiretroviral therapy (CART).

The frequency of this is unknown (see section 4.4).

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.

There is limited experience of overdose with Trizivir. No specific symptoms or signs have beenidentified following acute overdose with abacavir, zidovudine or lamivudine apart from those listed asadverse reactions.

If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), andstandard supportive treatment applied as necessary. Since lamivudine is dialysable, continuoushaemodialysis could be used in the treatment of overdose, although this has not been studied.

Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine, butenhance the elimination of the glucuronide metabolite. It is not known whether abacavir can beremoved by peritoneal dialysis or haemodialysis.

Pharmacotherapeutic group

Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC Code:

J05AR04.

Abacavir, lamivudine and zidovudine are all NRTIs, and are potent selective inhibitors of HIV-1 and

HIV-2.All three medicinal products are metabolised sequentially by intracellular kinases to therespective 5′-triphosphate (TP). Lamivudine-TP, carbovir-TP (the active triphosphate form ofabacavir) and zidovudine-TP are substrates for and competitive inhibitors of HIV reverse transcriptase(RT). However, their main antiviral activity is through incorporation of the monophosphate form intothe viral DNA chain, resulting in chain termination. Abacavir, lamivudine and zidovudinetriphosphates show significantly less affinity for host cell DNA polymerases.

No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents:abacavir, didanosine and nevirapine). No antagonistic effects in vitro were seen with zidovudine andother antiretrovirals (tested agents: didanosine and interferon-alpha). The antiviral activity of abacavirin cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors(NRTIs) didanosine, emtricitabine, stavudine or tenofovir, the non-nucleoside reverse transcriptaseinhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

In vitro resistance

HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184Vamino acid change close to the active site of the viral RT.

Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specificgenotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). Viralresistance to abacavir develops relatively slowly in vitro, requiring multiple mutations for a clinicallyrelevant increase in EC50 over wild-type virus.

In vivo resistance (therapy naïve patients)

The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containingantiretroviral therapy. Most patients experiencing virological failure with a regimen containingabacavir in a pivotal clinical trial with Combivir (fixed dose combination of lamivudine andzidovudine) showed either no NRTI-related changes from baseline (15 %) or only M184V or M184Iselection (78 %). The overall selection frequency for M184V or M184I was high (85 %), and selectionof L74V, K65R and Y115F was not observed (see Table). Thymidine analogue mutations (TAMs)which are selected by zidovudine (ZDV) were also found (8%).

Therapy Abacavir + Combivir

Number of Subjects 282

Number of Virological Failures 43

Number of On-Therapy Genotypes 40 (100 %)

K65R 0

L74V 0

Y115F 0

M184V/I 34 (85 %)

TAMs1 3 (8 %)1. Number of subjects with ≥1 TAM.

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 addition, the selection of L74V and K65R was reduced when co-administered with

ZDV (K65R: without ZDV: 13/127, 10 %; with ZDV: 1/86, 1 %; L74V: without ZDV: 51/127, 40 %;with ZDV: 2/86, 2 %).

In vivo resistance (Therapy experienced patients)

The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containingantiretroviral therapy and confers high-level resistance to lamivudine. In vitro data tend to suggest thatthe continuation of lamivudine in anti-retroviral regimen despite the development of M184V mightprovide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevanceof these findings is not established. Indeed, the available clinical data are very limited and precludeany reliable conclusion in the field. In any case, initiation of susceptible NRTIs should always bepreferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despiteemergence of M184V mutation should only be considered in cases where no other active NRTIs areavailable. Similarly, the presence of TAMs gives rise to resistance to ZDV.

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 was associatedwith reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p≤0.012). Inaddition, 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.

Week 4

Baseline Reverse (n = 166)

Transcriptase Median

Mutation n Change vRNA Percent with(log c/mL) <400 copies/mL vRNA

None 15 -0.96 40 %

M184V alone 75 -0.74 64 %

Any one NRTImutation 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 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, lamivudine or zidovudine and antiretrovirals from other classese.g. PIs or NNRTIs is unlikely.

One randomised, double blind, placebo controlled clinical study has compared the combination ofabacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and zidovudine intreatment naive patients. Due to the high proportion of premature discontinuation (42% of patientsdiscontinued randomised treatment by week 48), no definitive conclusion can be drawn regarding theequivalence between the treatment regimens at week 48. Although a similar antiviral effect wasobserved between the abacavir and indinavir containing regimens in terms of proportion of patientswith undetectable viral load (≤400 copies/mL; intention to treat analysis (ITT), 47% versus 49%; astreated analysis (AT), 86% versus 94% for abacavir and indinavir combinations respectively), resultsfavoured 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 andindinavir respectively).

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 000copies/mL) with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and13% on the 4 drug arm categorised as having virological failure (HIV RNA >200 copies/mL). At week48 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 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)

In antiretroviral-naive patients treated with a combination of abacavir, lamivudine, zidovudine andefavirenz in a small, ongoing, open label pilot study, the proportion of patients with undetectable viralload (<400 copies/mL) was approximately 90% with 80% having <50 copies/mL after 24 weeks oftreatment.

Currently there are no data on the use of Trizivir in heavily pre-treated patients, patients failing onother therapies or patients with advanced disease (CD4 cells <50 cells/mm3).

The degree of benefit of this nucleoside combination in heavily pre-treated patients will depend on thenature and duration of prior therapy that may have selected for HIV-1 variants with cross-resistance toabacavir, lamivudine or zidovudine.

To date there are insufficient data on the efficacy and safety of Trizivir given concomitantly with

NNRTIs or PIs.

Abacavir, lamivudine and zidovudine are rapidly and well absorbed from the gastro-intestinal tractfollowing oral administration. The absolute bioavailability of oral abacavir, lamivudine andzidovudine in adults is about 83%, 80 - 85% and 60 - 70% respectively.

In a pharmacokinetic study in HIV-1 infected patients, the steady state pharmacokinetic parameters ofabacavir, lamivudine and zidovudine were similar when either Trizivir alone or the combination tabletlamivudine/zidovudine and abacavir in combination were administered, and also similar to the valuesobtained in the bioequivalence study of Trizivir in healthy volunteers.

A bioequivalence study compared Trizivir with abacavir 300 mg, lamivudine 150 mg and zidovudine300 mg taken together. The effect of food on the rate and extent of absorption was also studied.

Trizivir was shown to be bioequivalent to abacavir 300 mg, lamivudine 150 mg and zidovudine300 mg given as separate tablets for AUC0-∞ and Cmax. Food decreased the rate of absorption of

Trizivir (slight decrease Cmax (mean 18 - 32 %) and increase tmax (approximately 1 hour), but not theextent of absorption (AUC0-∞). These changes are not considered clinically relevant and no foodrestrictions are recommended for administration of Trizivir.

At a therapeutic dose (one Trizivir tablet twice daily) in patients, the mean (CV) steady-state Cmax ofabacavir, lamivudine and zidovudine in plasma are 3.49 µg/mL (45%), 1.33 µg/mL (33%) and1.56 µg/mL (83%), respectively. Corresponding values for Cmin could not be established for abacavirand are 0.14 µg/mL (70%) for lamivudine and 0.01 µg/mL (64%) for zidovudine. The mean (CV)

AUCs for abacavir, lamivudine and zidovudine over a dosing interval of 12 hours are 6.39 µg.h/mL(31%), 5.73 µg.h/mL (31%) and 1.50 µg.h/mL (47%), respectively.

A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine,however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on thepharmacokinetics of lamivudine. An effect of abacavir is observed on zidovudine (Cmax reduced with20%) and on lamivudine (Cmax reduced with 35%).

Intravenous studies with abacavir, lamivudine and zidovudine showed that the mean apparent volumeof distribution is 0.8, 1.3 and 1.6l/kg respectively. Lamivudine exhibits linear pharmacokinetics overthe therapeutic dose range and displays limited binding to the major plasma protein albumin (<36 %serum albumin in vitro). Zidovudine plasma protein binding is 34% to 38%. Plasma protein bindingstudies in vitro indicate that abacavir binds only low to moderately (~ 49%) to human plasma proteinsat therapeutic concentrations. This indicates a low likelihood for interactions with other medicinalproducts through plasma protein binding displacement.

Interactions involving binding site displacement are not anticipated with Trizivir.

Data show that abacavir, lamivudine and zidovudine penetrate the central nervous system (CNS) andreach the cerebrospinal fluid (CSF). The mean ratios of CSF/serum lamivudine and zidovudineconcentrations 2 - 4 hours after oral administration were approximately 0.12 and 0.5 respectively. Thetrue extent of CNS penetration of lamivudine and its relationship with any clinical efficacy isunknown.

Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observedvalues of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 µg/mL or0.26 µM when abacavir is given at 600 mg twice daily.

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared byrenal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions withlamivudine is low due to the small extent of hepatic metabolism (5 - 10%) and low plasma binding.

The 5’-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting forapproximately 50 - 80 % of the administered dose eliminated by renal excretion. 3’-amino-3’-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenousdosing.

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 dose excreted in the urine.

The observed lamivudine half-life of elimination is 18 to 19 hours. The mean systemic clearance oflamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (>70 %) via the organiccationic transport system. Studies in patients with renal impairment show lamivudine elimination isaffected by renal dysfunction. Dose reduction is required for patients with creatinine clearance≤ 30 mL/min (see section 4.2).

From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and themean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be 0.34 l/h/kg,indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine concentrationsare increased in patients with advanced renal failure.

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.

Pharmacokinetic data has been obtained for abacavir, lamivudine and zidovudine separately. Limiteddata in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients withhepatic impairment because of decreased glucuronidation. Data obtained in patients with moderate tosevere hepatic impairment show that lamivudine pharmacokinetics are not significantly affected byhepatic dysfunction.

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 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 theelimination half-life. No definitive recommendation on dose reduction is possible in patients with mildhepatic impairment due to substantial variability of abacavir exposure in this patient population.

Based on data obtained for abacavir, Trizivir is not recommended in patients with moderate or severehepatic impairment.

The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance oflamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70 %) via the organiccationic transport system. Studies in patients with renal impairment show lamivudine elimination isaffected by renal dysfunction.

From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and themean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be 0.34 l/h/kg,indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine concentrationsare increased in patients with advanced renal failure.

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, and, therefore, no dose reduction is required in patients with renalimpairment.

As dose adjustments of lamivudine and zidovudine may be necessary it is recommended that separatepreparations of abacavir, lamivudine and zidovudine be administered to patients with severe renalimpairment (creatinine clearance ≤ 30 mL/min). Trizivir is contraindicated in patients with end-stagerenal disease (see section 4.3).

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

There are no data available on treatment with the combination of abacavir, lamivudine and zidovudinein animals. The clinically relevant toxicological effects of these three medicinal products are anaemia,neutropenia and leukopenia.

Neither abacavir, lamivudine nor zidovudine is mutagenic in bacterial tests, but consistent with othernucleoside analogues, they inhibit cellular DNA replication in in vitro mammalian tests such as themouse lymphoma assay.

Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasmaconcentrations up to 40 - 50 times higher than clinical plasma levels. Zidovudine showed clastogeniceffects in oral repeated dose micronucleus tests in mice and rats. Peripheral blood lymphocytes from

AIDS patients receiving zidovudine treatment have also been observed to contain higher numbers ofchromosome breakages.

A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults,including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the preventionof mother to child viral transmission. Zidovudine was also incorporated into DNA from cord bloodleukocytes of infants from zidovudine-treated mothers. A transplacental genotoxicity study conductedin monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated that foetuses exposed in utero to the combinationsustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, andshowed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinicalsignificance of these findings is unknown.

Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high testconcentrations and therefore any potential risk to man must be balanced against the expected benefitsof treatment.

The carcinogenic potential of a combination of abacavir, lamivudine and zidovudine has not beentested. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show anycarcinogenic potential. In oral carcinogenicity studies with zidovudine in mice and rats, late appearingvaginal epithelial tumours were observed. A subsequent intravaginal carcinogenicity study confirmedthe hypothesis that the vaginal tumours were the result of long term local exposure of the rodentvaginal epithelium to high concentrations of unmetabolised zidovudine in urine. There were no otherzidovudine-related tumours observed in either sex of either species.

In addition, two transplacental carcinogenicity studies have been conducted in mice. In one study, bythe US National Cancer Institute, zidovudine was administered at maximum tolerated doses topregnant mice from day 12 to 18 of gestation. One year postnatally, there was an increase in theincidence of tumours in the lung, liver and female reproductive tract of offspring exposed to thehighest dose level (420 mg/kg term body weight).

In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, withexposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as inthe standard oral carcinogenicity study. The second study thus provided no evidence that zidovudineacts as a transplacental carcinogen.

It is concluded that as the increase in incidence of tumours in the first transplacental carcinogenicitystudy represents a hypothetical risk, this should be balanced against the proven therapeutic benefit.

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 andand in 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 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 clinical relevance of these findings is unknown, these data suggest that a carcinogenic riskto humans is outweighed by the potential clinical benefit.

In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinicalrelevance 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 medicinalproducts 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.

Lamivudine was not teratogenic in animal studies but there were indications of an increase in earlyembryonic deaths in the rabbit at relatively low systemic exposures, comparable to those achieved inhumans. A similar effect was not seen in rats even at very high systemic exposure.

Zidovudine had a similar effect in both species, but only at very high systemic exposures. Atmaternally toxic doses, zidovudine given to rats during organogenesis resulted in an increasedincidence of malformations, but no evidence of foetal abnormalities was observed at lower doses.

Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. Thesefindings included decreased foetal body weight, foetal oedema, and an increase in skeletalvariations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn withregard 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. Likewise,neither lamivudine nor zidovudine had any effect on fertility. Zidovudine has not been shown to affectthe number of sperm, sperm morphology and motility in man.

Tablet Core:

microcrystalline cellulose,sodium starch glycollate (type A),magnesium stearate.

Tablet Coating:

Opadry Green 03B11434 containing: hypromellose, titanium dioxide, polyethylene glycol, indigocarmine aluminium lake, iron oxide yellow.

Not applicable

2 years

Do not store above 30°C

Trizivir tablets are available in opaque white PCTFE/PVC-Al blister packs or child-resistant foil

PVC/PCTFE/PVC-Al/Paper blister packs containing 60 tablets, or child resistant HDPE bottlescontaining 60 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/00/156/002 - opaque white PCTFE/PVC-Al Blister pack (60 Tablets)

EU/1/00/156/003 -Bottle pack (60 Tablets)

EU/1/00/156/004 - child-resistant foil PVC/PCTFE/PVC-Al/Paper Blister pack (60 Tablets)

Date of first authorisation: 28 December 2000

Date of latest renewal: 29 November 2010

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

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