- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults, adolescents and children weighing at least 25 kg:The recommended dose of Abacavir/Lamivudine is one tablet once daily.Children Under 25 kg:Abacavir/Lamivudine should not be administered to children who weigh less than 25 kg because it is a fixed-dose tablet that cannot be dose reduced.Abacavir/Lamivudine is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments. Separate preparations of abacavir or lamivudine are available in cases where discontinuation or dose adjustment of one of the active substances is indicated. In these cases the physician should refer to the individual product information for these medicinal products.Special Populations:
Elderly:No pharmacokinetic data are currently available in patients over 65 years of age. Special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.
Renal impairment:Abacavir/Lamivudine is not recommended for use in patients with a creatinine clearance < 50 ml/min as necessary dose adjustment cannot be made (see section 5.2).
Hepatic impairment:No data are available in patients with moderate hepatic impairment, therefore the use of abacavir/l;amivudine is not recommended unless judged necessary. In patients with mild and moderate hepatic impairment close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended (see sections 4.4 and 5.2). Abacavir/lamivudine is contraindicated in patients with severe hepatic impairment (see section 4.3).
Paediatric population:The safety and efficacy of abacavir/lamivudine in children weighing less than 25 kg has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on posology can be made.
Method of administrationOral use.Abacavir/Lamivudine can be taken with or without food.
|Hypersensitivity reactions (see also section 4.8 ) Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section 4.8) characterised by fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed with abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed appropriately. The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele. However, abacavir HSRs have been reported at a lower frequency in patients who do not carry this allele. Therefore the following should be adhered to: • HLA-B*5701 status must always be documented prior to initiating therapy. • Abacavir/Lamivudine should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen. (e.g. Ziagen, Trizivir, Triumeq) • Abacavir/Lamivudine 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 Abacavir/Lamivudine after the onset of hypersensitivity may result in a life-threatening reaction. • After stopping treatment with Abacavir/Lamivudine for reasons of a suspected HSR, Abacavir/Lamivudine or any other medicinal product containing abacavir (e.g. Ziagen, Trizivir, Triumeq) must never be re-initiated. • Restarting abacavir containing products following a suspected abacavir HSR can result in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death. • In order to avoid restarting abacavir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining Abacavir/Lamivudine tablets. • Clinical Description of abacavir HSR Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up. Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Almost all HSR to abacavir include fever and/or rash. Other signs and symptoms that have been observed as part of abacavir HSR are described in detail in section 4.8 (Description of selected adverse reactions), including respiratory and gastrointestinal symptoms. Importantly, such symptoms may lead to misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. The symptoms related to HSR worsen with continued therapy and can be life-threatening. These symptoms usually resolve upon discontinuation of abacavir. Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have also experienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8 Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting where medical assistance is readily available.|
|Lactic acidosis Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely.|
LipodystrophyCombination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
PancreatitisPancreatitis has been reported, but a causal relationship to lamivudine and abacavir is uncertain.
Risk of virological failure⁻ Triple nucleoside therapy: There have been reports of a high rate of virological failure, and of emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir disoproxil fumarate as a once daily regimen.⁻ The risk of virological failure with abacavir/lamivudine might be higher than with other therapeutic options (see section 5.1).
Liver diseaseThe safety and efficacy of abacavir/lamivudine has not been established in patients with significant underlying liver disorders. Abacavir/lamivudine is contraindicated in patients with severe hepatic impairment (see section 4.3).Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Patients co-infected with chronic hepatitis B or C virusPatients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV), additional information relating to the use of lamivudine in the treatment of hepatitis B infection can be found in the Summary of Product Characteristics for products containing lamivudine that are indicated for the treatment of HBV.If Abacavir/Lamivudine is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see the Summary of Product Characteristics for products containing lamivudine that are indicated for the treatment of HBV).As abacavir and ribavirin share the same phosphorylation pathways, a possible intracellular interaction between these medicinal products has been postulated, which could lead to a reduction in intracellular phosphorylated metabolites of ribavirin and, as a possible consequence, a reduced chance of sustained virological response (SVR) for hepatitis C (HCV) in HCV co-infected patients treated with pegylated interferon plus RBV. Conflicting clinical findings are reported in literature on co-administration between abacavir and ribavirin. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when medicinal products containing abacavir and ribavirin are co-administered. (see section 4.5).
Mitochondrial dysfunctionNucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation SyndromeIn HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
OsteonecrosisAlthough the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Opportunistic infectionsPatients should be advised that abacavir/lamivudine or any other antiretroviral therapy does not cure HIV infection and 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 the treatment of these associated HIV diseases.
Myocardial infarctionObservational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing Abacavir/Lamivudine, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Drug InteractionsAbacavir/Lamivudine should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.The combination of lamivudine with cladribine is not-recommended (see section 4.5).
ExcipientsAbacavir/Lamivudine contains the azo colouring agent sunset yellow, which may cause allergic reactions.
|Drugs by Therapeutic Area||Interaction Geometric mean change (%) (Possible mechanism)||Recommendation concerning co-administration|
|ANTIRETROVIRAL MEDICINAL PRODUCTS|
|Didanosine /Abacavir||Interaction not studied.||No dosage adjustment necessary.|
|Didanosine/Lamivudine||Interaction not studied.|
|Zidovudine/Abacavir||Interaction not studied.|
|Zidovudine/Lamivudine Zidovudine 300 mg single dose Lamivudine 150 mg single dose||Lamivudine: AUC ↔ Zidovudine : AUC ↔|
|Emtricitabine/Lamivudine||Due to similarities, Abacavir/Lamivudine should not be administered concomitantly with other cytidine analogues, such as emtricitabine.|
|Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Abacavir||Interaction not studied.||No Abacavir/Lamivudine dosage adjustment necessary. When concomitant administration with co-trimoxazole is warranted, patients should be monitored clinically. High doses of trimethoprim/sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis have not been studied and should be avoided.|
|Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Lamivudine (160 mg/800 mg once daily for 5 days/300 mg single dose)||Lamivudine: AUC ↑40% Trimethoprim: AUC ↔ Sulfamethoxazole: AUC ↔ (organic cation transporter inhibition)|
|Rifampicin/Abacavir||Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.||Insufficient data to recommend dosage adjustment.|
|Rifampicin/Lamivudine||Interaction not studied.|
|Phenobarbital/Abacavir||Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.||Insufficient data to recommend dosage adjustment.|
|Phenobarbital/Lamivudine||Interaction not studied.|
|Phenytoin/Abacavir||Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.||Insufficient data to recommend dosage adjustment. Monitor phenytoin concentrations.|
|Phenytoin/Lamivudine||Interaction not studied.|
|ANTIHISTAMINES (HISTAMINE H2 RECEPTOR ANTAGONISTS)|
|Ranitidine/Abacavir||Interaction not studied.||No dosage adjustment necessary.|
|Ranitidine/Lamivudine||Interaction not studied. Clinically significant interaction unlikely. Ranitidine eliminated only in part by renal organic cation transport system.|
|Cimetidine/Abacavir||Interaction not studied.||No dosage adjustment necessary.|
|Cimetidine/Lamivudine||Interaction not studied. Clinically significant interaction unlikely. Cimetidine eliminated only in part by renal organic cation transport system.|
|Cladribine/Lamivudine||Interaction not studied. In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine.||Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section 4.4).|
|Methadone/Abacavir (40 to 90 mg once daily for 14 days/600 mg single dose, then 600 mg twice daily for 14 days)||Abacavir: AUC ↔ Cmax ↓35% Methadone: CL/F ↑22%||No Abacavir/Lamivudine dosage adjustment necessary. Methadone dosage adjustment unlikely in majority of patients; occasionally methadone re-titration may be required.|
|Methadone/Lamivudine||Interaction not studied.|
|Retinoid compounds (e.g. isotretinoin)/Abacavir||Interaction not studied. Possible interaction given common pathway of elimination via alcohol dehydrogenase.||Insufficient data to recommend dosage adjustment.|
|Retinoid compounds (e.g. isotretinoin)/Lamivudine No drug interaction studies||Interaction not studied.|
|Ribavirin/Abacavir||Interaction not studied. Theoretical potential to reduce intracellular phosphorylated metabolites.||Caution should be exercised when both drugs are co-administered (see section 4.4).|
|Ethanol/Abacavir (0.7 g/kg single dose/600 mg single dose)||Abacavir: AUC ↑41% Ethanol: AUC ↔ (Inhibition of alcohol dehydrogenase)||No dosage adjustment necessary.|
|Ethanol/Lamivudine||Interaction not studied.|
Paediatric populationInteraction studies have only been performed in adults.
PregnancyAs a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant 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. Animal studies with abacavir have shown toxicity to the developing embryo and foetus in rats, but not in rabbits. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats. (see section 5.3). The active ingredients of abacavir/lamivudine may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown. Placental transfer of abacavir and lamivudine has been shown to occur in humans.In pregnant women treated with abacavir, more than 800 outcomes after first trimester exposure and more than 1000 outcomes after second and third trimester exposure indicate no malformative and foeto/neonatal effect. In pregnant women treated with lamivudine, more than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure indicate no malformative and foeto/neonatal effect. There are no data on the use of abacavir/lamivudine in pregnancy, however the malformative risk is unlikely in humans based on those data.For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinal product such as Abacavir/Lamivudine and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.
Mitochondrial dysfunctionNucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).
Breast-feedingAbacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk.Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of abacavir and lamivudine when administered to babies less than three months old.It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
FertilityStudies in animals showed that neither abacavir nor lamivudine had any effect on fertility (see section 5.3).
Summary of the safety profileThe adverse reactions reported for abacavir/lamivudine were consistent with the known safety profiles of abacavir and lamivudine when given as separate medicinal products. For many of these adverse reactions it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process.Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.
Tabulated list of adverse reactionsThe adverse reactions considered at least possibly related to abacavir or lamivudine are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (> 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).
|Blood and lymphatic systems disorders||Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia Very rare: Pure red cell aplasia|
|Immune system disorders||Common: hypersensitivity|
|Metabolism and nutrition disorders||Common: anorexia|
|Nervous system disorders||Common: headache||Common: Headache, insomnia. Very rare: Cases of peripheral neuropathy (or paraesthesia) have been reported.|
|Respiratory, thoracic and mediastinal disorders||Common: Cough, nasal symptoms|
|Gastrointestinal disorders||Common: nausea, vomiting, diarrhoea Rare: pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain||Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea Rare: Rises in serum amylase. Cases of pancreatitis have been reported|
|Hepatobiliary disorders||Uncommon: Transient rises in liver enzymes (AST, ALT), Rare: Hepatitis|
|Skin and subcutaneous tissue disorders||Common: rash (without systemic symptoms) Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis||Common: Rash, alopecia Rare: Angioedema|
|Musculoskeletal and connective tissue disorders||Common : Arthralgia, muscle disorders Rare: Rhabdomyolysis|
|General disorders and administration site conditions||Common: fever, lethargy, fatigue.||Common: fatigue, malaise, fever.|
|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|
|Liver/pancreas||Elevated liver function tests, hepatitis, hepatic failure|
|Musculoskeletal||Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase|
|Urology||Elevated creatinine, renal failure|
Lactic acidosisCases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4).
LipodystrophyCombination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Metabolic abnormalitiesCART has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).
Immune reactivation syndromeIn HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
OsteonecrosisCases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).
Paediatric populationThe safety database to support once daily dosing in paediatric patients comes from the ARROW Trial (COL105677) in which 669 HIV-1 infected paediatric subjects (from 12 months to ≤17 years old) received abacavir and lamivudine either once or twice daily (see section 5.1). Within this population, 104 HIV-1 infected paediatric subjects weighing at least 25 kg received abacavir and lamivudine as abacavir/lamivudine once daily. No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).
In vivo resistanceAbacavir-resistant isolates of HIV-1 have been selected in-vitro in wild-type strain HIV-1 (HXB2) and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115). Selection for the M184V mutation occurred first and resulted in a two fold increase in IC50. Continued passage in increasing concentrations of drug resulted in selection for double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7- to 8-fold change in abacavir susceptibility and combinations of three mutations were required to confer more than an 8-fold change in susceptibility. Passage with a zidovudine resistant clinical isolate RTMC also selected for the 184V mutation.HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184V amino acid change close to the active site of the viral RT. Passage of HIV-1 (HXB2) in the presence of increasing 3TC concentrations results in high-level (>100 to >500-fold) lamivudine-resistant viruses and the RT M184I or V mutation is rapidly selected. The IC50 for wild-type HXB2 is 0.24 to 0.6 μM, while the IC50 for M184V containing HXB2 is >100 to 500 μM.
Antiviral therapy According to Genotypic/Phenotypic Resistance
In vivo resistance (Therapy-naïve patients)The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy.Isolates from most patients experiencing virological failure with a regimen containing abacavir in pivotal clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or M184I selection (45%). The overall selection frequency for M184V or M184I was high (54%), and less common was the selection of L74V (5%), K65R (1%) and Y115F (1%) (see table below). The inclusion of zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in the presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%).
|Therapy||Abacavir + Combivir1||Abacavir + lamivudine + NNRTI||Abacavir + lamivudine + PI (or PI/ritonavir)||Total|
|Number of Subjects||282||1094||909||2285|
|Number of Virological Failures||43||90||158||306|
|Number of On- Therapy Genotypes||40 (100%)||51 (100%)2||141 (100%)||232 (100%)|
|K65R||0||1 (2%)||2 (1%)||3 (1%)|
|L74V||0||9 (18%)||3 (2%)||12 (5%)|
|Y115F||0||2 (4%)||0||2 (1%)|
|M184V/I||34 (85%)||22 (43%)||70 (50%)||126 (54%)|
|TAMs3||3 (8%)||2 (4%)||4 (3%)||9 (4%)|
In vivo resistance (Therapy experienced patients)The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy and confer high-level resistance to lamivudine. In vitro data tend to suggest that the continuation of lamivudine in anti- retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible NRTIs should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTIs are available.Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to other nucleoside inhibitors. In a meta-analysis of five clinical trials where ABC was added to intensify therapy, of 166 subjects, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had M41L, 30 (18%) had K70R and 25 (15%) had D67N. K65R was absent and L74V and Y115F were uncommon (≤3%). Logistic regression modelling of the predictive value for genotype (adjusted for baseline plasma HIV-1RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral therapies) showed that the presence of 3 or more NRTI resistance-associated mutations was associated with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p≤0.012). In addition, the 69 insertion complex or the Q151M mutation, usually found in combination with A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir.
|Baseline Reverse Transcriptase Mutation||Week 4 (n = 166)|
|n||Median Change vRNA (log10 c/mL)||Percent with <400 copies/mL vRNA|
|Any one NRTI mutation||82||-0.72||65%|
|Any two NRTI- associated mutations||22||-0.82||32%|
|Any three NRTI- associated mutations||19||-0.30||5%|
|Four or more NRTI- associated mutations||28||-0.07||11%|
Phenotypic resistance and cross-resistancePhenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation, or M184V with multiple TAMs. Phenotypic cross- resistance to other NRTIs with M184V or M184I mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviral activities against such HIV-1 variants. The presence of M184V with K65R does give rise to cross-resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives rise to cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F gives rise to cross-resistance between abacavir and lamivudine. Readily available genotypic drug resistance interpretation algorithms and commercially available susceptibility tests have established clinical cut offs for reduced activity for abacavir and lamivudine as separate drug entities that predict susceptibility, partial susceptibility or resistance based upon either direct measurement of susceptibility or by calculation of the HIV-1 resistance phenotype from the viral genotype. Appropriate use of abacavir and lamivudine can be guided using these currently recommended resistance algorithms.Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or NNRTIs is unlikely.
Clinical experienceClinical experience with the combination of abacavir and lamivudine as a once daily regimen is mainly based on four studies in treatment-naïve subjects, CNA30021, EPZ104057 (HEAT study), ACTG5202, and CNA109586 (ASSERT study) and two studies in treatment-experienced subjects, CAL30001 and ESS30008.
Therapy-naïve patientsThe combination of abacavir and lamivudine as a once daily regimen is supported by a 48 weeks multi-centre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults. These were primarily asymptomatic HIV infected patients (CDC stage A). They were randomised to receive either abacavir (ABC) 600 mg once daily or 300 mg twice daily, in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The results are summarised by subgroup in the table below:
Efficacy Outcome at Week 48 in CNA30021 by baseline HIV-1 RNA and CD4 Categories (ITTe TLOVR ART naïve subjects).
|ABC QD +3TC+EFV (n=384)||ABC BID +3TC+EFV (n=386)|
|ITT-E Population TLOVR analysis||Proportion with HIV-1 RNA <50 copies/ml|
|All Subjects||253/384 (66%)||261/386 (68%)|
|Baseline RNA category <100,000 copies/mL||141/217 (65%)||145/217 (67%)|
|Baseline RNA category >=100,000 copies/mL||112/167 (67%)||116/169 (69%)|
|Baseline CD4 category <50||3/ 6 (50%)||4/6 (67%)|
|Baseline CD4 category 50-100||21/ 40 (53%)||23/37 (62%)|
|Baseline CD4 category 101-200||57/ 85 (67%)||43/67 (64%)|
|Baseline CD4 category 201-350||101/143 (71%)||114/170 (67%)|
|Baseline CD4 category >350||71/109 (65%)||76/105 (72%)|
|>1 log reduction in HIV RNA or <50 cp/mL All Patients||372/384 (97%)||373/386 (97%)|
ITT-Exposed Population M=F switch included
|Virologic Response||ABC/3TC +LPV/r (N = 343)||TDF/FTC + LPV/r (N = 345)|
|Week 48||Week 96||Week 48||Week 96|
|Overall response (stratified by baseline HIV-1 RNA)||231/343 (68%)||205/343 (60%)||232/345 (67%)||200/345 (58%)|
|Response by Baseline HIV-1 RNA <100,000 c/ml||134/188 (71%)||118/188 (63%)||141/205 (69%)||119/205 (58%)|
|Response by Baseline HIV-1 RNA ≥100,000 c/ml||97/155 (63%)||87/155 (56%)||91/140 (65%)||81/140 (58%)|
|ABC/3TC + EFV (N =192)||TDF/FTC + EFV (N =193)|
|Overall response||114/192 (59%)||137/193 (71%)|
|Response by Baseline HIV-1 RNA <100,000 c/mL||61/95 (64%)||62/83 (75%)|
|Response by Baseline HIV-1 RNA ≥100,000 c/mL||53/97 (55%)||75/110 (68%)|
Therapy-experienced patientsData from two studies, CAL30001 and ESS30008 demonstrated that abacavir/lamivudine once daily has similar virological efficacy to abacavir 300 mg twice daily plus lamivudine 300 mg once daily or 150 mg twice daily in therapy-experienced patients.In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and received treatment with either abacavirlamivudine once daily or abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks. Similar reductions in HIV-1 RNA as measured by average area under the curve minus baseline were observed, indicating that the abacavir/lamivudine group was non-inferior to the abacavir plus lamivudine twice daily group (AAUCMB, -1.65 log10 copies/ml versus -1.83 log10 copies/ml respectively, 95% CI -0.13, 0.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%) and < 400 copies/ml (54% versus 57%) at week 48 were also similar in each group (ITT population). However, as there were only moderately experienced patients included in this study with an imbalance in baseline viral load between the arms, these results should be interpreted with caution.In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were randomised to continue this regimen or switch to abacavir/lamivudine plus a PI or NNRTI for 48 weeks. Results at 48 weeks indicated that the abacavir/lamivudine 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).A genotypic sensitivity score (GSS) has not been established by the MAH for the abacavir/lamivudine combination. The proportion of treatment-experienced patients in the CAL30001 study with HIV- RNA <50 copies/mL at Week 48 by genotypic sensitivity score in optimized background therapy (OBT) are tabulated. The impact of major IAS-USA defined mutations to abacavir or lamivudine and multi-NRTI resistance associated mutations to the number of baseline mutations on response was also evaluated. The GSS was obtained from the Monogram reports with susceptible virus ascribed the values '1-4' based upon the numbers of drugs in the regimen and with virus with reduced susceptibility ascribed the value '0'. Genotypic sensitivity scores were not obtained for all patients at baseline. Similar proportions of patients in the once-daily and twice-daily abacavir arms of CAL30001 had GSS scores of <2 or ≥2 and successfully suppressed to <50 copies/mL by Week 48.
Proportion of Patients in CAL30001 with <50 copies/mL at Week 48 by Genotypic Sensitivity Score in OBT and Number of Baseline Mutations
|ABC/3TC FDC QD (n=94) Number of Baseline Mutations1||ABC BID +3TC QD (n=88)|
|Genotypic SS in OBT||All||0-1||2-5||6+||All|
|≤2||10/24 (42%)||3/24 (13%)||7/24 (29%)||0||12/26 (46%)|
|>2||29/56 (52%)||21/56 (38%)||8/56 (14%)||0||27/56 (48%)|
|Unknown||8/14 (57%)||6/14 (43%)||2/14 (14%)||0||2/6 (33%)|
|All||47/94 (50%)||30/94 (32%)||17/94 (18%)||0||41/88 (47%)|
Proportion of Patients in CNA30021with <50 cps/mL at Week 48 by Genotypic Sensitivity Score in OBT and Number of Baseline Mutations
|ABC QD + 3TC QD + EFV QD (N=384) Number of Baseline Mutations1||ABC BID+ 3TC QD + EFV QD (N=386)|
|Genotypic SS in OBT||All||0-1||2-5||6+||All|
|≤2||2/6 (33%)||2/6 (33%)||0||0||3/6 (50%)|
|>2||58/119 (49%)||57/119 (48%)||1/119 (<1%)||0||57/114 (50%)|
|All||60/125 (48%)||59/125 (47%)||1/125 (<1%)||0||60/120 (50%)|
AbsorptionAbacavir and lamivudine are rapidly and well absorbed from the gastro-intestinal tract following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hour for abacavir and lamivudine, respectively. Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 µg/ml (28%) and the mean (CV) AUC∞ is 11.95 µg.h/ml (21%). Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 µg/ml (26%) and the mean (CV) AUC24 is 8.87 µg.h/ml (21%).
DistributionIntravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 36%). This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid (CSF). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
BiotransformationAbacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%).
EliminationThe mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Abacavir/Lamivudine is not recommended for use in patients with a creatinine clearance < 50 ml/min as necessary dose adjustment cannot be made (see section 4.2).
Intracellular pharmacokineticsIn a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP exposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32 %, Cmax24,ss + 99 % and Ctrough + 18 %) compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma lamivudine half-life of 5-7 hours. In a crossover study in 60 healthy volunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC24,ss and Cmax24,ss) or lower (Ctrough 24 %) for the lamivudine 300 mg once daily regimen compared to the lamivudine 150 mg twice daily regimen. Overall, these data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021- See Clinical experience).
Special patient populations
Hepatic impairmentThere are no data available on the use of abacavir/lamivudine in hepatically impaired patients. Pharmacokinetic data has been obtained for abacavir and lamivudine alone.Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose. The results showed that there was a mean increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure.Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.
Renal impairmentPharmacokinetic data have been obtained for lamivudine and abacavir alone. Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function. Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Abacavir/Lamivudine is not recommended for use in patients with a creatinine clearance < 50 ml/min as necessary dose adjustment cannot be made.
ElderlyNo pharmacokinetic data are available in patients over 65 years of age.
ChildrenAbacavir is rapidly and well absorbed from oral formulations when administered to children. Paediatric pharmacokinetic studies have demonstrated that once daily dosing provides equivalent AUC24 to twice daily dosing of the same total daily dose for both oral solution and tablet formulations. The absolute bioavailability of lamivudine (approximately 58 to 66%) was lower and more variable in paediatric patients under 12 years of age. However, paediatric pharmacokinetic studies with tablet formulations have demonstrated that once daily dosing provides equivalent AUC24 to twice daily dosing of the same total daily dose.
Mutagenicity and carcinogenicityNeither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleoside analogues, they inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasma concentrations up to 40-50 times higher than clinical plasma concentrations. Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.The carcinogenic potential of a combination of abacavir and lamivudine has not been tested. In long- term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential. Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and 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 and 600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the human systemic exposure during therapy. While the clinical relevance of these findings is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.
Repeat-dose toxicityIn toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinal products hepatically metabolised has not been observed in man.Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
Reproductive toxicologyIn reproductive toxicity studies in animals, lamivudine and abacavir were shown to cross the placenta.Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. These findings included decreased foetal body weight, foetal oedema, and an increase in skeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.A fertility study in rats has shown that abacavir and lamivudine had no effect on male or female fertility.
Tablet coremagnesium stearatemicrocrystalline cellulose crospovidone (Type A)povidone (K-30)iron oxide yellow (E172)
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