Summary of medicine characteristics - ABACAVIR MILPHARM 300 MG FILM-COATED TABLETS
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Abacavir Milpharm 300 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 300 mg of abacavir (as sulfate).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Yellow colored, biconvex, capsule shaped, coated tablet, debossed with ‘D’ and ‘300’ on either side of the score line on one side and plain with a score line on other side. The tablet can be divided into equal doses. [Size: about 18.6 × 7.3 mm]
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Abacavir is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults, adolescents and children (see sections 4.4 and 5.1).
The demonstration of the benefit of abacavir is mainly based on results of studies performed with a twice daily regimen, in treatment-naïve adult patients on combination therapy (see section 5.1).
Before initiating treatment with abacavir, screening for carriage of the HLAB*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin (see section 4.4). Abacavir should not be used in patients known to carry the HLA-B*5701 allele.
4.2 Posology and method of administration
Abacavir should be prescribed by physicians experienced in the management of HIV infection.
Abacavir may also available as an oral solution for use in children over three months of age and weighing less than 14 kg and for those patients for whom the tablets are inappropriate.
Adults, adolescents and children (weighing at least 25 kg):
The recommended dose of abacavir is 600 mg daily. This may be administered as either 300 mg (one tablet) twice daily or 600 mg (two tablets) once daily (see sections 4.4 and 5.1).
Children (weighing less than 25 kg):
Dosing according to weight bands is recommended for Abacavir tablets.
Children weighing > 20 kg to < 25 kg: The recommended dose is 450 mg daily. This may be administered as either one 150 mg (one half of a tablet) taken in the morning and 300 mg (one whole tablet) taken in the evening, or 450 mg (one and a half tablets) taken once daily.
Children weighing 14 to < 20 kg: The recommended dose is 300 mg daily. This may be administered as either 150 mg (one half of a tablet) twice daily or 300 mg (one whole tablet) once daily.
Children less than three months of age: The clinical experience in children aged less than three months is limited and are insufficient to propose specific dosage recommendations (see section 5.2).
Patients changing from the twice daily dosing regimen to the once daily dosing regimen should take the recommended once daily dose (as described above) approximately 12 hours after the last twice daily dose, and then continue to take the recommended once daily dose (as described above) approximately every 24 hours. When changing back to a twice daily regimen, patients should take the recommended twice daily dose approximately 24 hours after the last once daily dose.
No dosage adjustment of abacavir is necessary in patients with renal dysfunction. However, abacavir is not recommended for patients with end-stage renal disease (see section 5.2).
Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made in patients with mild hepatic impairment (Child-Pugh score 5–6). In patients with moderate or severe hepatic impairment, no clinical data are available, therefore the use of abacavir is not recommended unless judged necessary. If abacavir is used in patients with mild hepatic impairment, then close monitoring is required, including monitoring of abacavir plasma levels if feasible (see sections 4.4 and 5.2).
No pharmacokinetic data are currently available in patients over 65 years of age.
Method of administration
Abacavir can be taken with or without food.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.
Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).
Hypersensitivity to abacavir or to any of the excipients listed in section 6.1. See sections 4.4 and 4.8.
4.4 Special warnings and precautions for use4.4 Special warnings and precautions for use
Hypersensitivity reactions (see also section 4.8)
Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) characterised by fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have been observed with abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed appropriately.
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 should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen. (e.g. Kivexa, Trizivir, Triumeq)
Abacavir 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 after the onset of hypersensitivity may result in a life-threatening reaction.
After stopping treatment with Abacavir for reasons of a suspected HSR, Abacavir or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir, Triumeq) must never be re-initiated.
Restarting abacavir containing products following a suspected abacavir HSR can result in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death.
In order to avoid restarting abacavir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining Abacavir 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 lifethreatening. 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 reinitiating abacavir therapy (see Section 4.8 Description of selected adverse reactions). Restarting abacavir in such patients must be done in a setting where medical assistance is readily available.
Mitochondrial dysfunction following exposure in utero
Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleotide and nucleotide analogues, who presents with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain.
Triple nucleoside therapy
In patients with high viral load (>100,000 copies/ml) the choice of a triple combination with abacavir, lamivudine and zidovudine needs special consideration (see section 5.1).
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily regimen.
The safety and efficacy of abacavir has not been established in patients with significant underlying liver disorders. Abacavir is not recommended in patients with moderate or severe hepatic impairment (see sections 4.2 and 5.2).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Patients co-infected with chronic hepatitis B or C virus
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
Abacavir should not be administered to patients with end-stage renal disease (see section 5.2).
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Patients receiving abacavir or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing abacavir, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Abacavir contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per each film-coated tablet, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction4.5 Interaction with other medicinal products and other forms of interaction
The potential for P450 mediated interactions with other medicinal products involving abacavir is low. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). P450 does not play a major role in the metabolism of abacavir, and abacavir shows limited potential to inhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.
Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. These findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.
Methadone: in a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean methadone systemic clearance by 22%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally methadone retitration may be required.
Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.
Riociguat: In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving the combination of abacavir/dolutegravir/lamivudine (600mg/50mg/300mg once daily) led to an approximately three-fold higher riociguat AUC(O-co) when compared to historical riociguat AUC(0-co) reported in healthy subjects. Riociguat dose may need to be reduced. Consult the riociguat prescribing information for dosing recommendations.
4.6 Fertility, pregnancy and lactation
As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, both animal data as well as clinical experience in pregnant women should be taken into account.
Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical relevance in human of these data is unknown. Placental transfer of abacavir and/or its related metabolites has been shown to occur in human.
In pregnant women, more than 800 outcomes after first trimester exposure and more than 1000 outcomes after second and third trimester exposure indicate no malformative and foetal/neonatal effect of abacavir. The malformative risk is unlikely in humans based on those data.
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).
Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk. There are no data available on the safety of abacavir when administered to babies less than three months old. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Studies in animals showed that abacavir had no effect on fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on ability to drive and use machines have been performed.
4.8 Undesirable effects
For many adverse reactions reported, it is unclear whether they are related to abacavir, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process.
Many of the adverse reactions listed below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.
Many of the adverse reactions have not been treatment limiting. The following convention has been used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000).
Metabolism and nutrition disorders
Very rare: lactic acidosis
Nervous system disorders
Common: nausea, vomiting, diarrhoea
Skin and subcutaneous tissue disorders
Common: rash (without systemic symptoms)
Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
General disorders and administration site conditions
Common: fever, lethargy, fatigue
Description of Selected Adverse Reactions
Abacavir hypersensitivity reactions
The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at
least 10% of patients with a hypersensitivity reaction are in bold text.
Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.
Rash (usually maculopapular or urticarial)
Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration
Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure
Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis
Elevated liver function tests, hepatitis, hepatic failure
Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase
Elevated creatinine, renal failure
Symptoms related to this HSR worsen with continued therapy and can be lifethreatening and in rare instance, have been fatal.
Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Similar reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).
Weight and levels of blood lipids and glucose may increase during antiretroviral
therapy (see section 4.4)
Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART) an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).
Changes in laboratory chemistries
In controlled clinical studies laboratory abnormalities related to abacavir treatment were uncommon, with no differences in incidence observed between abacavir treated patients and the control arms.
1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial (COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section 5.1). No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
Abacavir is rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir in adults is about 83%. Following oral administration, the mean time (tmax) to maximal serum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour for the solution formulation.
At therapeutic dosages a dosage of 300 mg twice daily, the mean (CV) steady state Cmaxand Cmin of abacavir are approximately 3.00 pg/ml (30%) and 0.01 pg/ml (99%), respectively. The mean (CV) AUC over a dosing interval of 12 hours was 6.02 pg.h/ml (29%), equivalent to a daily AUC of approximately 12.0 pg.h/ml. The Cmax value for the oral solution is slightly higher than the tablet. After a 600 mg abacavir tablet dose, the mean (CV) abacavir Cmax was approximately 4.26 pg/ml (28%) and the mean (CV) AUC® was 11.95 pg.h/ml (21%).
Food delayed absorption and decreased Cmax but did not affect overall plasma concentrations (AUC). Therefore abacavir can be taken with or without food.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Following intravenous administration, the apparent volume of distribution was about 0.8 l/kg, indicating that abacavir penetrates freely into body tissues.
Studies in HIV infected patients have shown good penetration of abacavir into the CSF, with a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 pg/ml or 0.26 pM when abacavir is given at 600 mg twice daily.
Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.
Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide which account for about 66% of the administered dose. The metabolites are excreted in the urine.
The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.
In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP exposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32 %, Cmax24,ss + 99% and Ctrough + 18 %) compared to the 300 mg twice daily regimen. Overall, these data support the use of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy and safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021– See section 5.1 Clinical experience).
Special patient populations
Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5–6) receiving a single 600 mg dose; the median (range) AUC value was 24.1 (10.4 to 54.8) ug.h/ml. The results showed that there was a mean (90%CI) increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No definitive recommendation on dosage reduction is possible in patients with mild hepatic impairment due to the substantial variability of abacavir exposure.
Abacavir is not recommended in patients with moderate or severe hepatic impairment.
Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function. Therefore no dosage reduction is required in patients with renal impairment. Based on limited experience abacavir should be avoided in patients with end-stage renal disease.
According to clinical trials performed in children abacavir is rapidly and well absorbed from oral solution and tablet formulations administered to children. Plasma abacavir exposure has been shown to be the same for both formulations when administered at the same dose. Children receiving abacavir oral solution according to the recommended dosage regimen achieve plasma abacavir exposure similar to adults. Children receiving abacavir oral tablets according to the recommended dosage regimen achieve higher plasma abacavir exposure than children receiving oral solution because higher mg/kg doses are administered with the tablet formulation.
There are insufficient safety data to recommend the use of abacavir in infants less than three months old. The limited data available indicate that an oral solution dose of 2 mg/kg in neonates less than 30 days old provides similar or greater AUCs, compared to the 8 mg/kg oral solution dose administered to older children.
Pharmacokinetic data were derived from 3 pharmacokinetic studies (PENTA 13, PENTA 15 and ARROW PK sub study) enrolling children under 12 years of age. The data are displayed in the table below:
Summary of Stead-State Plasma Abacavir AUC (0-24) (gg.h/ml) and Statistical Comparisons for Once and Twice-Daily Oral Administration Across Studies
Abacavir 16 mg/kg Once-Daily Dosing Geometric Mean (95% Cl)
Abacavir 8 mg/kg Twice-Daily Dosing Geometric Mean (95% Cl)
Once-Versus Twice-Daily Comparison GLS Mean Ratio (90% Cl)
ARROW PK Substudy Part 1
3 to 12 years (N=36)
0.98 (0.89, 1.08)
2 to 12 years (N=14)
3 to 36 months (N=18)
In PENTA 15 study, the geometric mean plasma abacavir AUC (0–24) (95% CI) of the four subjects under 12 months of age who switch from a twice daily to a once daily regimen (see section 5.1) are 15.9 (8.86, 28.5) pg.h/ml in the once-daily dosing and 12.7 (6.52, 24.6) pg.h/ml in the twice-daily dosing.
The pharmacokinetics of abacavir has not been studied in patients over 65 years of age.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.3 Shelf life
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Abacavir film-coated tablets are available in clear PVC/aluminum foil containing 60 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements