Kivexa

Kivexa

abacavir + lamivudine

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Abacavir sulfate, lamivudine.
Description
Each tablet contains abacavir 600 mg as abacavir sulfate and lamivudine 300 mg.
Kivexa is a combination of 2 nucleoside analogues (abacavir and lamivudine).
Each tablet also contains the following excipients: Core: Magnesium stearate, microcrystalline cellulose, sodium starch glycollate. Coating: Opadry orange YS-1-13065-A containing: Hypromellose (E464), titanium dioxide (E171), polyethylene glycol 400, polysorbate 80 (E433) and sunset yellow aluminium lake (E110).
Action
Pharmacotherapeutic Group: Nucleoside reverse transcriptase inhibitor (NRTI). ATC Code: J05AR02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Abacavir and lamivudine are NRTIs and are potent, selective inhibitors of human immunodeficiency virus (HIV) -1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which are the active moieties. Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However, their main antiviral activity is through incorporation of the monophosphate form into the viral deoxyribonucleic acid (DNA) chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300-mg dose taken prior to the 24-hr sampling period, the geometric mean terminal carbovir-TP intracellular half-life (t½) at steady-state was 20.6 hrs, compared to the geometric mean abacavir plasma t½ in this study of 2.6 hrs. The steady-state pharmacokinetic properties of abacavir 600 mg once daily was compared to abacavir 300 mg twice daily in a crossover study in 27 HIV-infected patients. Intracellular carbovir triphosphate exposures in peripheral blood mononuclear cells were higher for abacavir 600 mg once daily with respect to AUC24,ss (32% higher), Cmax 24,ss (99% higher) and trough values (18% higher), compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300 mg once daily, the terminal intracellular t½ of lamivudine-TP was prolonged to 16-19 hrs, compared to the plasma lamivudine t½ of 5-7 hrs. The steady-state pharmacokinetic properties of lamivudine 300 mg once daily for 7 days compared to lamivudine 150 mg twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were similar with respect to AUC24,ss and Cmax 24,ss; however, trough values were lower compared to the 150 mg twice daily regimen. Intersubject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. 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 abacavir/lamivudine combination given once daily has been demonstrated in a pivotal clinical study.
Pharmacodynamic Effects: The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (Tested Agents: Abacavir, didanosine, nevirapine, zalcitabine and zidovudine).
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral RT. This variant arises both in vitro and in HIV-1-infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. Studies in vitro indicate that zidovudine-resistant virus isolates can become zidovudine-sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). Viral resistance to abacavir develops relatively slowly in vitro and in vivo, requiring multiple mutations to reach an 8-fold increase in IC50 over wild-type virus, which may be a clinically relevant level. Isolates resistant to abacavir might also show reduced sensitivity to lamivudine, zalcitabine, tenofovir, emtricitabine and/or didanosine, but remain sensitive to zidovudine and stavudine.
Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes eg, protease inhibitors (PI) or NNRTIs, is unlikely. Reduced 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.
Clinical isolates with ≥3 mutations associated with NRTIs are unlikely to be susceptible to abacavir. Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine, stavudine, abacavir and tenofovir maintain their antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation.
Pharmacokinetics: Kivexa has been shown to be bioequivalent to abacavir and lamivudine administered separately. This was demonstrated in a single-dose, 3-way crossover bioequivalence study of Kivexa (fasted) versus abacavir tablets 2 x 300 mg plus lamivudine tablets (fasted) 2 x 150 mg versus Kivexa administered with a high-fat meal, in healthy volunteers (n=30).
In the fasted state, there was no significant difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component. There was also no clinically significant food effect observed between administration of Kivexa in the fasted or fed state. These results indicate that Kivexa can be taken with or without food.
The pharmacokinetic properties of lamivudine and abacavir are described as follows.
Absorption: Abacavir and lamivudine are rapidly and well-absorbed following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is 83% and 80-85%, respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hrs and 1 hr for abacavir and lamivudine, respectively. Following a single oral dose of abacavir 600 mg, the mean Cmax is 4.26 mcg/mL and the mean AUC is 11.95 mcg·hr/mL. Following multiple-dose oral administration of lamivudine 300 mg once daily for 7 days, the mean steady-state Cmax is 2.04 mcg/mL and the mean AUC24 is 8.87 mcg·hr/mL.
Distribution: Intravenous 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 (approximately 49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein-binding (<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 30-44%. The observed values of the peak concentrations are 9-fold greater than the IC50 of abacavir of 0.08 mcg/mL or 0.26 micromolar when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hrs after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
Metabolism: Abacavir is primarily metabolised by the liver with <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 predominantly cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (<10%).
Elimination: The mean t½ of abacavir is about 1.5 hr. 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 t½ of elimination is 5-7 hrs. The mean systemic clearance of lamivudine is approximately 0.32 L/hr/kg, predominantly by renal clearance (>70%) via the organic cationic transport system.
Special Patient Populations: Hepatically Impaired: 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 scores 5-6). The results showed that there was a mean increase of 1.89-fold in the abacavir AUC and 1.58-fold in the t½ of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased.
Dosage reduction of abacavir is likely to be required in patients with mild hepatic impairment. The separate preparation of abacavir (Ziagenavir) should therefore, be used to treat these patients. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and substantially increased in these patients. Kivexa is therefore, contraindicated in patients with moderate and severe hepatic impairment.
Data obtained for lamivudine in patients with moderate to severe hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction.
Renally Impaired: Pharmacokinetic data have been obtained for abacavir and lamivudine 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. Dose reduction is required for patients with creatinine clearance (CrCl) of <50 mL/min, therefore, the separate preparation of lamivudine (Epivir) should be used to treat these patients.
Toxicology: Preclinical Safety Data: With the exception of a negative in vivo rat micronucleus test, there are no data available on the effects of the combination of abacavir and lamivudine in animals.
Carcinogenesis & Mutagenesis: Neither abacavir nor lamivudine were mutagenic in bacterial tests, but like many nucleoside analogues, they show activity in the in vitro mammalian tests eg, the mouse lymphoma assay. This is consistent with the known activity of other nucleoside analogues. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.
Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species and in the liver, urinary bladder, lymph nodes and the subcutis of female rats.
The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. These dose levels were equivalent to 24-33 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg. This is equivalent to 6 times the expected human systemic exposure. There is no structural counterpart for this gland in humans. While the carcinogenic potential in humans is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.
Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasma concentrations of up to 30-40 times higher than clinical plasma levels. The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential.
Repeat-Dose Toxicity: Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for 2 years. The systemic exposures were equivalent to 7-24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.
Reproductive Toxicology: In reproductive toxicity studies in animals, abacavir and lamivudine were shown to cross the placenta.
Abacavir demonstrated toxicity to the developing embryo and foetus only in rats at maternally toxic doses of ≥500 mg/kg/day. This dose is equivalent to 33 times the human therapeutic exposure based on AUC. The findings included foetal oedema, variations and malformations, resorptions, decreased foetal body weight and an increase in still births. The dose at which there were no effects on the pre- or postnatal development was 160 mg/kg/day. This dose is equivalent to an exposure of about 10 times that in humans. Similar findings were not observed in rabbits.
Lamivudine was not teratogenic in animal studies, but there were indications of an increase in early embryonic deaths in rabbits at exposure levels comparable to those achieved in man. However, there was no evidence of embryonic loss in rats at exposure levels of approximately 33 times the clinical exposure (based on Cmax).
Fertility studies in the rat have shown that abacavir and lamivudine had no effect on male or female fertility.
Indications/Uses
Antiretroviral combination therapy for the treatment of human immunodeficiency virus (HIV) infection in adults and adolescents from 12 years.
Dosage/Direction for Use
Therapy should be initiated by a physician experienced in the management of HIV infection.
Kivexa is a fixed-dose tablet and it should not be prescribed for patients requiring dosage adjustments eg, those with CrCl <50 mL/min or with mild hepatic impairment. Separate preparations of abacavir (Ziagenavir) or lamivudine (Epivir) should be administered in cases where discontinuation or dose adjustment is indicated. In these cases, the physician should refer to the individual product information for these medicinal products.
Adults and Adolescents: Recommended Dose: 1 tablet once daily.
Elderly: The pharmacokinetics of abacavir and lamivudine have not been studied in patients >65 years. When treating the elderly patients, consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, concomitant medicinal products or disease.
Children: Kivexa is not recommended for treatment in children <12 years as the necessary dose adjustment cannot be made. Physicians should refer to the individual product information for lamivudine and abacavir.
Renal Impairment: Whilst no dosage adjustment of abacavir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance. Therefore, Kivexa is not recommended for use in patients with a CrCl <50 mL/min (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: A dose reduction of abacavir is likely to be required for patients with mild hepatic impairment. As dose reduction is not possible with Kivexa, the separate preparation of abacavir should be used when this is judged necessary. Kivexa is contraindicated in patients with moderate and severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Administration: Kivexa should not be administered to adults or adolescents who weigh <40 kg because it is a fixed-dose tablet that cannot be reduced.
Kivexa can be taken with or without food.
Overdosage
Symptoms: No specific symptoms or signs have been identified following acute overdose with abacavir or lamivudine, apart from those listed as adverse effects.
Treatment: If overdose occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.
Contraindications
Hypersensitivity to abacavir or lamivudine, or to any of the excipients of Kivexa.
Patients with moderate and severe hepatic impairment.
Warnings
Hypersensitivity to Abacavir: Overall, in clinical studies conducted before, the introduction of screening for the HLA-B*5701 allele, approximately 5% of subjects receiving abacavir developed a hypersensitivity reaction, which in rare cases, has proved fatal.
Risk Factors: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. In the prospective study CNA106030 (PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding abacavir in patients with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66 of 847) to 3.4% (27 of 803) (p<0.0001) and the incidence of hypersensitivity reactions confirmed by skin patch testing from 2.7% (23 of 842) to 0% (0 of 802) (p<0.0001). Based on this study, it is estimated that 48-61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0-4% of patients who do not have the HLA-B*5701 allele.
Clinicians should consider screening for carriage of the HLA-B*5701 allele in any HIV-infected patient without prior exposure to abacavir. Screening is recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see Special Considerations Following an Interruption of Kivexa Therapy as follows). Use of abacavir in patients known to carry the HLA-B*5701 allele is not recommended and should be considered only under exceptional circumstances where potential benefit outweighs the risk and with close medical supervision.
In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must remain the basis of clinical decision making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
Clinical Description: The hypersensitivity reaction is characterised by the appearance of symptoms indicating multiorgan involvement. The majority of patients have fever and/or rash as part of the syndrome.
Some of the other symptoms of hypersensitivity may include fatigue, malaise, gastrointestinal symptoms eg, nausea, vomiting, diarrhoea or abdominal pain and respiratory signs and symptoms eg, dyspnoea, sore throat, cough and abnormal chest x-ray findings (predominantly infiltrates, which can be localised). The symptoms of this hypersensitivity reaction can occur at any time during treatment with abacavir, but usually occur within the first 6 weeks of therapy. The symptoms worsen with continued therapy and can be life-threatening. These symptoms usually resolve upon discontinuation of abacavir.
Clinical Management: Regardless of their HLA-B*5701 status, any patient developing signs or symptoms of hypersensitivity must contact a physician immediately for advice. If hypersensitivity reaction is diagnosed, Kivexa must be discontinued immediately. Kivexa, or any other medicinal product containing abacavir (eg, Ziagenavir, Trizivir) must never be restarted following a hypersensitivity reaction, as more severe symptoms will recur within hours and may include life-threatening hypotension and death.
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Kivexa should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications). Kivexa, or any other medicinal product containing abacavir (eg, Ziagenavir, Trizivir), should not be restarted even if a recurrence of symptoms occurs following rechallenge with alternative medication(s).
An alert card with information for the patient about this hypersensitivity reaction is included in the Kivexa pack.
Special Considerations Following an Interruption of Kivexa Therapy: Regardless of a patient's HLA-B*5701 status, if therapy with any abacavir containing product has been discontinued and restarting therapy with Kivexa is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, Kivexa or any other medicinal product containing abacavir (eg, Ziagenavir, Trizivir) should not be restarted.
There have been infrequent reports of hypersensitivity reaction following reintroduction of abacavir where the interruption was preceded by a single key symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or respiratory symptoms). If a decision is made to restart Kivexa in these patients, this should be done only under direct medical supervision.
On very rare occasions, hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction. If a decision is made to restart Kivexa, this must be done only if medical care can be accessed readily by the patient or others.
Screening for carriage of the HLA-B*5701 allele is recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. Reinitiation of abacavir in such patients who test positive for HLA-B*5701 allele is not recommended and should be considered only under exceptional circumstances where potential benefit outweighs the risk and with close medical supervision.
Essential Patient Information: Physicians must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction: Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life-threatening reaction or death and that the risk of a hypersensitivity reaction is increased if they are HLA-B*5701 positive.
Patients must also be informed that HLA-B*5701 negative patients can also experience abacavir hypersensitivity reaction. Therefore, any patient who develops signs or symptoms consistent with a possible hypersensitivity reaction to abacavir must contact the physician immediately.
Patients who are hypersensitive to abacavir should be reminded that they must never take Kivexa or any other medicinal product containing abacavir (eg, Ziagenavir, Trizivir) again, regardless of their HLA-B*5701 status.
In order to avoid restarting Kivexa, patients who have experienced a hypersensitivity reaction should be asked to return the remaining Kivexa tablets to the pharmacy.
Patients who have stopped Kivexa for any reason and particularly due to possible adverse reactions or illness, must be advised to contact a physician before restarting.
Each patient should be reminded to read the package leaflet included in the Kivexa pack. They should be reminded of the importance of removing the alert card included in the pack and should keep it with them at all times.
Special Precautions
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including abacavir and lamivudine. A majority of these cases have been reported in women.
Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia and sudden unexplained weight loss, gastrointestinal and respiratory symptoms (dyspnoea and tachypnoea).
Caution should be exercised when administering Kivexa particularly to those with known risk factors for liver disease. Treatment with Kivexa should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Lipodystrophy: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy (see Adverse Reactions).
Whilst all members of the protease and NRTI classes of medicinal products have been associated with ≥1 of these specific adverse events, linked to a general syndrome commonly referred to as lipodystrophy, data indicate that there are differences in the risk between individual members of the respective therapeutic classes.
In addition, the lipodystrophy syndrome has a multifactorial aetiology eg, HIV disease status, older age and duration of antiretroviral treatment all playing important, possibly synergistic roles.
The long-term consequences of these events are currently unknown.
Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions or aggravation of symptoms. Typically, such reactions have been observed within the 1st few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (eg, Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable and can occur many months after initiation of treatment and sometimes can be an atypical presentation.
Patients Co-Infected with Hepatitis B Virus (HBV): Clinical study and marketed use of lamivudine have shown that some patients with chronic HBV disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If Kivexa is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication should be considered.
Opportunistic Infections: Patients receiving Kivexa or any other ART may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
Transmission of Infection: Patients should be advised that current ART, including Kivexa, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.
Myocardial Infarction: In a prospective, observational epidemiological study designed to investigate the rate of myocardial infarction in patients on combination ART, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction. In a pooled analysis of GSK-sponsored clinical trials, no excess risk of myocardial infarction was observed with abacavir use. There is no known biological mechanism to explain a potential increase. In totality, the available data from observational cohorts and from controlled clinical trials are inconclusive in regard to the relationship between abacavir treatment and risk of myocardial infarction.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing ARTs, including abacavir and action taken to minimize all modifiable risk factors (eg, hypertension, hyperlipidaemia, diabetes mellitus and smoking).
Effects on the Ability to Drive or Operate Machinery: There have been no studies to investigate the effect of abacavir or lamivudine on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of these medicinal products. The clinical status of the patient and the adverse event profile of Kivexa should be borne in mind when considering the patient's ability to drive or operate machinery.
Use in Pregnancy: There are no adequate and well-controlled trials in pregnant women and the safe use of abacavir, lamivudine or ALFDC (abacavir-lamivudine fixed-dose combination) in human pregnancy has not been established. Therefore, administration of ALFDC in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the foetus.
Abacavir has been evaluated in the antiretroviral pregnancy registry in over 2,000 women during pregnancy and postpartum. Available human data from the antiretroviral pregnancy registry do not show an increased risk of major birth defects for abacavir compared to the background rate. Lamivudine has been evaluated in the antiretroviral pregnancy registry in over 11,000 women during pregnancy and postpartum. Available human data from the antiretroviral pregnancy registry do not show an increased risk of major birth defects for lamivudine compared to the background rate.
Abacavir and lamivudine have been associated with findings in animal reproductive studies (see Pharmacology: Toxicology under Actions).
There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peripartum to NRTIs. The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peripartum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Use in Lactation: Health experts recommend that, when possible, HIV-infected women do not breastfeed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breastfeeding during ART. In a study following repeat oral dose of either lamivudine 150 mg twice daily (given in combination with zidovudine 300 mg twice daily) or lamivudine 300 mg twice daily, lamivudine was excreted in human breast milk (0.5-8.2 mcg/mL) at similar concentrations to those found in serum. In other studies following repeat oral dose of lamivudine 150 mg twice daily (given either in combination with zidovudine 300 mg or as Combid 300 or Trizivir) the breast milk: Maternal plasma ratio ranged between 0.6 and 3.3. In a study after repeat oral administration of abacavir 300 mg twice daily (given as Trizivir), the breast milk: Maternal plasma ratio was 0.9. No pharmacokinetic studies were conducted with abacavir once daily oral administration. Lamivudine median infant serum concentrations ranged between 18 and 28 ng/mL and were not detectable in 1 of the studies (assay sensitivity 7 ng/mL). Most infants (8 out of 9) had non-detectable levels of abacavir (assay sensitivity 16 ng/mL). Intracellular carbovir and lamivudine triphosphate (active metabolites of abacavir and lamivudine) levels in breastfed infants were not measured therefore, the clinical relevance of the serum concentrations of the parent compounds measured is unknown.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate and well-controlled trials in pregnant women and the safe use of abacavir, lamivudine or ALFDC (abacavir-lamivudine fixed-dose combination) in human pregnancy has not been established. Therefore, administration of ALFDC in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the foetus.
Abacavir has been evaluated in the antiretroviral pregnancy registry in over 2,000 women during pregnancy and postpartum. Available human data from the antiretroviral pregnancy registry do not show an increased risk of major birth defects for abacavir compared to the background rate. Lamivudine has been evaluated in the antiretroviral pregnancy registry in over 11,000 women during pregnancy and postpartum. Available human data from the antiretroviral pregnancy registry do not show an increased risk of major birth defects for lamivudine compared to the background rate.
Abacavir and lamivudine have been associated with findings in animal reproductive studies (see Pharmacology: Toxicology under Actions).
There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peripartum to NRTIs. The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peripartum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Use in Lactation: Health experts recommend that, when possible, HIV-infected women do not breastfeed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breastfeeding during ART. In a study following repeat oral dose of either lamivudine 150 mg twice daily (given in combination with zidovudine 300 mg twice daily) or lamivudine 300 mg twice daily, lamivudine was excreted in human breast milk (0.5-8.2 mcg/mL) at similar concentrations to those found in serum. In other studies following repeat oral dose of lamivudine 150 mg twice daily (given either in combination with zidovudine 300 mg or as Combid 300 or Trizivir) the breast milk: Maternal plasma ratio ranged between 0.6 and 3.3. In a study after repeat oral administration of abacavir 300 mg twice daily (given as Trizivir), the breast milk: Maternal plasma ratio was 0.9. No pharmacokinetic studies were conducted with abacavir once daily oral administration. Lamivudine median infant serum concentrations ranged between 18 and 28 ng/mL and were not detectable in 1 of the studies (assay sensitivity 7 ng/mL). Most infants (8 out of 9) had non-detectable levels of abacavir (assay sensitivity 16 ng/mL). Intracellular carbovir and lamivudine triphosphate (active metabolites of abacavir and lamivudine) levels in breastfed infants were not measured therefore, the clinical relevance of the serum concentrations of the parent compounds measured is unknown.
Adverse Reactions
Kivexa contains abacavir and lamivudine, therefore, the adverse events associated with these may be expected.
Hypersensitivity to Abacavir: Overall, in clinical studies conducted before the introduction of screening for HLA-B*5701 allele, approximately 5% of subjects receiving abacavir developed a hypersensitivity reaction which, in rare cases, has proved fatal. This reaction is characterised by the appearance of symptoms indicating multiorgan/body system involvement (see also Warnings and Precautions).
Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome; however, reactions have occurred without rash or fever.
Symptoms can occur at any time while being treated with abacavir, but usually appear within the first 6 weeks of initiation of treatment (median time to onset is 11 days).
The signs and symptoms of this hypersensitivity reaction are listed as follows.
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*, fatigue*, malaise*, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis.
Neurological/Psychiatry: Headache*, paraesthesia.
Haematological: Lymphopenia.
Liver/Pancreas: Elevated liver function tests*, hepatic failure.
Musculoskeletal: Myalgia*; rarely, myolysis, arthralgia, elevated creatine phosphokinase.
Urology: Elevated creatinine, renal failure.
*Reported in at least 10% of patients with a hypersensitivity reaction.
Some patients with hypersensitivity were initially thought to have respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis or reactions to other medications. This delay in diagnosis of hypersensitivity has resulted in abacavir being continued or reintroduced, leading to a more severe hypersensitivity reaction or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases. If hypersensitivity reaction cannot be ruled out, Kivexa or any other medicinal product containing abacavir (eg, Ziagenavir, Trizivir) should not be restarted.
The symptoms related to this hypersensitivity reaction worsen with continued therapy and usually resolve upon discontinuation of abacavir.
Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction may be more severe than on initial presentation and may include life-threatening hypotension and death. Regardless of their HLA-B*5701 status, patients who develop this hypersensitivity reaction must discontinue Kivexa and must never be rechallenged with Kivexa or any other medicinal product containing abacavir (eg, Ziagenavir, Trizivir).
There have been infrequent reports of hypersensitivity reactions following reintroduction of abacavir, where the interruption was preceded by a single key symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or respiratory symptom).
On very rare occasions, hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction.
For many of the adverse events listed, it is unclear whether they are related to abacavir or lamivudine, 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 events listed 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 reaction. If Kivexa has been discontinued in patients due to experiencing any 1 of these symptoms and a decision is made to restart abacavir, this must be done only under direct medical supervision (see Warnings and Precautions). (See Table 1.)

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Post-Marketing Data: In addition to the adverse events included from clinical trial data, the following adverse events have been identified during post-approval use of abacavir and lamivudine. These events have been chosen for inclusion due to a potential causal connection to abacavir and/or lamivudine (see Table 2).

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Redistribution/accumulation of body fat has been observed in some patients receiving combination ART (see Warnings and Precautions). The incidence of this event is dependent on multiple factors including the particular antiretroviral drug combination.
Drug Interactions
As Kivexa contains abacavir and lamivudine, any interactions that have been identified with these agents individually may occur with Kivexa. Clinical studies have shown that there are no clinically significant interactions between abacavir and lamivudine. Abacavir and lamivudine are not significantly metabolised by cytochrome P-450 enzymes (eg, CYP3A4, CYP2C9 or CYP2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major P-450 enzymes.
The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma protein-binding and almost complete renal clearance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is renal.
Interactions Relevant to Abacavir: Ethanol: The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. Given the safety profile of abacavir, these findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.
Methadone: In a pharmacokinetic study, co-administration of abacavir 600 mg twice daily with methadone showed a 35% reduction in abacavir Cmax and a 1-hr delay in tmax, but AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study, abacavir increased the mean methadone systemic clearance by 22%. This change is not considered clinically relevant for the majority of patients, however, occasionally, methadone dose re-titration may be required.
Interactions Relevant to Lamivudine: Trimethoprim: Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see Dosage & Administration). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. The effect of co-administration of lamivudine with higher doses of co-trimoxazole used for the treatment of Pneumocystis jiroveci (P. carinii) pneumonia and toxoplasmosis has not been studied.
Zalcitabine: Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the 2 medicinal products are used concurrently. Kivexa is therefore, not recommended to be used in combination with zalcitabine.
Emtricitabine: Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the 2 medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral reverse transcriptase gene (M184V) and therefore, the therapeutic efficacy of these drugs in combination therapy may be limited. Lamivudine is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed-dose combinations.
Caution For Usage
Instructions for Use and Handling: Since Kivexa contains abacavir, some patients may develop a hypersensitivity reaction (serious allergic reaction) which can be life-threatening if treatment with Kivexa is continued. Contact the physician immediately for advice on whether to stop taking Kivexa in cases of skin rash; ≥1 symptoms from at least 2 of the following groups: Fever; shortness of breath, sore throat or cough; nausea, vomiting, diarrhoea or abdominal pain; severe tiredness, achiness or generally ill feeling.
If the patient discontinued Kivexa due to the previously mentioned reactions, the patient must never take Kivexa or any other medicine containing abacavir (Ziagenavir or Trizivir) again, as within hours the patient may experience a life-threatening lowering of blood pressure or death.
Storage
Do not store above 30°C.
MIMS Class
ATC Classification
J05AR02 - lamivudine and abacavir ; Belongs to the class of antivirals for treatment of HIV infections, combinations.
Presentation/Packing
FC tab (orange, modified capsule-shaped, debossed with 'GS FC2' on one side) 3 x 10's.
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