Abacavir Mylan 300 mg Film-covered Tablets
2. Qualitative and quantitative composition
Each film-coated tablet consists of 300 mg of abacavir.
For the entire listing of excipients, see segment 6.1.
3. Pharmaceutical form
Film-lined pill (pill).
Yellow, pill formed, biconvex, film-covered tablet (approximately 18.5 x 7.3 mm), debossed with 'H' on one side with a score line and 'A' and '26' separated through a rating line on the other side.
The tablet may be divided into identical doses.
Four. Clinical details
Four.1 Therapeutic indicators
Abacavir Mylan is indicated in antiretroviral combination remedy for the remedy of Human Immunodeficiency Virus (HIV) contamination in adults, teens and children (see sections four.4 and five.1).
The demonstration of the gain of abacavir is in particular based totally on results of studies accomplished with a twice each day routine, in treatment-naïve adult sufferers on mixture therapy (see section 5.1).
Before beginning remedy with abacavir, screening for carriage of the HLA-B*5701 allele have to be executed in any HIV-infected affected person, regardless of racial origin (see section four.Four). Abacavir must now not be used in patients recognised to hold the HLA-B*5701 allele.
4.2 Posology and approach of administration
Posology
Abacavir Mylan have to be prescribed with the aid of physicians experienced within the management of HIV contamination.
Adults, kids and children (weighing at least 25 kg):
The advocated dose of abacavir is 600 mg daily. This can be administered as either 300 mg (one tablet) twice each day or six hundred mg ( capsules) as soon as every day (see sections 4.4 and five.1).
Children (weighing less than 25 kg):
Dosing consistent with weight bands is usually recommended for abacavir capsules.
Children weighing ≥ 20 kg to < 25 kg: The recommended dose is 450 mg day by day. This may be administered as both one one hundred fifty mg (one half of a tablet) taken inside the morning and three hundred mg (one entire pill) taken in the evening, or 450 mg (one and a 1/2 capsules) taken once every day.
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).
Abacavir may also be available as a 20 mg/ml oral solution for the treatment of children over three months of age and weighing less than 14 kg and for those patients for whom the tablets are inappropriate.
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.
Special populations
Renal impairment
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).
Hepatic impairment
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).
Elderly
No pharmacokinetic data are currently available in patients over 65 years of age.
Method of administration
For oral use.
Abacavir Mylan can be taken with or without food.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Hypersensitivity reactions (see also section 4.8)
Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see 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 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. Abacavir/lamivudine, abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine).
• 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 Mylan or any other medicinal product containing abacavir (e.G. Abacavir/lamivudine, abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine) 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, 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). 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 postnatally 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 aetiology, 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
Pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain.
Triple nucleoside therapy
In patients with high viral load (>a hundred,000 copies/ml) the selection of a triple mixture with abacavir, lamivudine and zidovudine needs special consideration (see segment 5.1).
There have been reviews of a excessive rate of virological failure and of emergence of resistance at an early degree while abacavir became mixed with tenofovir disoproxil fumarate and lamivudine as a once day by day regimen.
Liver disease
The protection and efficacy of abacavir has now not been mounted in sufferers with great underlying liver disorders. Abacavir isn't always encouraged in sufferers with slight or excessive hepatic impairment (see sections four.2 and five.2).
Patients with pre-present liver disorder, which include persistent lively hepatitis, have an expanded frequency of liver characteristic abnormalities throughout combination antiretroviral therapy, and need to be monitored according to conventional practice. If there's proof of worsening liver disorder in such sufferers, interruption or discontinuation of treatment must be considered.
Patients co-inflamed with chronic hepatitis B or C virus
Patients with continual hepatitis B or C and treated with combination antiretroviral remedy are at an increased chance of excessive and probably fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer additionally to the applicable product data for those medicinal products.
Renal disease
Abacavir need to not be administered to sufferers with give up-level renal disorder (see section 5.2).
Immune Reactivation Syndrome
In HIV-inflamed sufferers with extreme immune deficiency at the time of institution of aggregate antiretroviral remedy (CART), an inflammatory response to asymptomatic or residual opportunistic pathogens may additionally get up and cause extreme medical conditions, or aggravation of signs. Typically, such reactions have been found inside 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 must be evaluated and remedy instituted when essential. Autoimmune disorders (which includes Graves' disease and autoimmune hepatitis) have additionally been pronounced to occur within the putting of immune reactivation; but, the said time to onset is more variable and these activities can occur many months after initiation of treatment.
Osteonecrosis
Although the aetiology is taken into consideration to be multifactorial (along with corticosteroid use, alcohol consumption, extreme immunosuppression, better body mass index), instances of osteonecrosis had been stated particularly in sufferers with advanced HIV-disorder and/or lengthy-time period publicity to CART. Patients must be recommended to are looking for clinical advice in the event that they experience joint aches and pain, joint stiffness or problem in movement.
Opportunistic infections
Patients receiving abacavir or every other antiretroviral therapy may additionally nonetheless broaden opportunistic infections and other complications of HIV infection. Therefore patients should continue to be below close scientific commentary by using physicians skilled inside the remedy of those associated HIV illnesses.
Transmission
While powerful viral suppression with antiretroviral therapy has been demonstrated to considerably lessen the risk of sexual transmission, a residual danger cannot be excluded. Precautions to prevent transmission ought to be taken in accordance with country wide tips.
Myocardial Infarction
Observational studies have shown an association among myocardial infarction and the use of abacavir. Those studied had been in particular antiretroviral experienced patients. Data from scientific trials confirmed constrained numbers of myocardial infarction and could not exclude a small boom in hazard. Overall the to be had information from observational cohorts and from randomised trials show some inconsistency so can neither verify nor refute a causal relationship between abacavir treatment and the threat of myocardial infarction. To date, there's no mounted organic mechanism to explain a ability growth in chance. When prescribing abacavir, motion need to be taken to try to minimise all modifiable hazard elements (e.G. Smoking, high blood pressure, and hyperlipidaemia).
4.Five Interaction with different medicinal products and different sorts of interaction
Based at the results of in vitro experiments and the regarded main metabolic pathways of abacavir, the ability for P450 mediated interactions with different medicinal products concerning abacavir is low. P450 does no longer play a main position within the metabolism of abacavir, and abacavir does now not inhibit metabolism mediated via CYP 3A4. Abacavir has also been proven in vitro now not to inhibit CYP 3A4, CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism has now not been determined in medical research. Therefore, there may be little capacity for interactions with antiretroviral PIs and other medicinal merchandise metabolised by means of major P450 enzymes. Clinical research have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
Potent enzymatic inducers together with rifampicin, phenobarbital and phenytoin may additionally through their movement on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.
Ethanol: the metabolism of abacavir is altered via concomitant ethanol ensuing in an boom in AUC of abacavir of approximately 41%. These findings aren't taken into consideration clinically sizable. Abacavir has no impact on the metabolism of ethanol.
Methadone: in a pharmacokinetic examine, co-management of six hundred mg abacavir twice every day with methadone confirmed a 35% discount in abacavir Cmax and a one hour postpone in tmax however the AUC turned into unchanged. The modifications in abacavir pharmacokinetics are not considered clinically applicable. In this examine abacavir expanded the imply methadone systemic clearance with the aid of 22%. The induction of drug metabolising enzymes can not consequently be excluded. Patients being treated with methadone and abacavir ought to be monitored for proof of withdrawal symptoms indicating beneath dosing, as occasionally methadone re-titration can be required.
Retinoids: retinoid compounds are eliminated thru alcohol dehydrogenase. Interaction with abacavir is feasible however has not been studied.
Four.6 Fertility, being pregnant and lactation
Pregnancy
As a widespread rule, when figuring out to use antiretroviral sellers for the treatment HIV infection in pregnant women and therefore for decreasing the danger of HIV vertical transmission to the newborn, both animal statistics as well as clinical enjoy in pregnant women have to be taken under consideration. Animal studies have shown toxicity to the growing embryo and foetus in rats, however now not in rabbits (see phase five.3). Abacavir has been shown to be carcinogenic in animal fashions (see phase 5.Three). Clinical relevance in human of these statistics is unknown. Placental switch of abacavir and/or its associated metabolites has been proven to arise in human.
In pregnant ladies, greater than 800 effects after first trimester exposure and more than 1,000 results after 2d and 1/3 trimester publicity indicate no malformative and foetal/neonatal effect of abacavir. The malformative threat is not going in human beings based totally on the ones records.
Mitochondrial disorder
Nucleoside and nucleotide analogues had been demonstrated in vitro and in vivo to purpose a variable diploma of mitochondrial damage. There have been reports of mitochondrial disorder in HIV-bad toddlers uncovered in utero and/or submit-natally to nucleoside analogues (see segment 4.4).
Breast-feeding
Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk. There are not any facts to be had on the protection of abacavir whilst administered to infants less than 3 months old. It is suggested that HIV inflamed women do now not breast-feed their toddlers under any occasions so one can keep away from transmission of HIV.
Fertility
Studies in animals confirmed that abacavir had no effect on fertility (see segment 5.Three).
4.7 Effects on potential to pressure and use machines
No studies on the results on ability to power and use machines have been performed.
4.Eight Undesirable effects
For many adverse reactions mentioned, it is doubtful whether they are related to abacavir, to the wide variety of medicinal merchandise used in the control of HIV contamination or as a result of the disease procedure.
Many of the damaging reactions indexed under occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, sufferers with any of those symptoms ought to be cautiously evaluated for the presence of this allergic reaction (see segment 4.Four). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been said in which abacavir allergic reaction could not be dominated out. In such instances medicinal merchandise containing abacavir must be permanently discontinued.
Many of the adverse reactions have no longer been treatment limiting. The following convention has been used for his or her class: very not unusual (>1/10), not unusual (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) and very uncommon (<1/10,000).
Metabolism and vitamins problems
Common: anorexia
Very uncommon: lactic acidosis
Nervous machine disorders
Common: headache
Gastrointestinal problems
Common: nausea, vomiting, diarrhoea
Rare: pancreatitis
Skin and subcutaneous tissue disorders
Common: rash (without systemic signs)
Very uncommon: erythema multiforme, Stevens-Johnson syndrome and poisonous epidermal necrolysis
General disorders and administration site situations
Common: fever, lethargy, fatigue
Description of selected destructive reactions
Abacavir hypersensitive reaction reactions
The symptoms and symptoms of this HSR are indexed underneath. These have been recognized either from clinical studies or submit advertising surveillance. Those mentioned in at least 10% of sufferers with a allergic reaction reaction are in formidable text.
Almost all patients growing hypersensitivity reactions could have fever and/or rash (typically maculopapular or urticarial) as part of the syndrome, however reactions have passed off without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional signs and symptoms such as lethargy and malaise.
Skin
Rash (commonly maculopapular or urticarial)
Gastrointestinal tract
Nausea, vomiting, diarrhoea, stomach pain, mouth ulceration
Respiratory tract
Dyspnoea, cough, sore throat, grownup respiration distress syndrome, respiratory failure
Miscellaneous
Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis
Neurological/Psychiatry
Headache, paraesthesia
Haematological
Lymphopenia
Liver/pancreas
Elevated liver function exams, hepatitis, hepatic failure
Musculoskeletal
Myalgia, hardly ever myolysis, arthralgia, expanded creatine phosphokinase
Urology
Elevated creatinine, renal failure
Symptoms related to this HSR worsen with continued remedy and may be lifestyles-threatening and in uncommon instance, were fatal.
Restarting abacavir following an abacavir HSR results in a set off go back of symptoms inside hours. This recurrence of the HSR is generally extra extreme than on initial presentation, and can consist of existence-threatening hypotension and loss of life. Similar reactions have additionally came about every now and then after restarting abacavir in patients who had simplest one of the key symptoms of hypersensitive reaction (see above) prior to stopping abacavir; and on very uncommon events have also been seen in sufferers who have restarted therapy with out a previous signs and symptoms of a HSR (i.E., sufferers previously taken into consideration to be abacavir tolerant).
Metabolic parameters
Weight and levels of blood lipids and glucose may additionally increase at some point of antiretroviral therapy (see segment four.Four)
Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART) an inflammatory response to asymptomatic or residual opportunistic infections might also rise up. Autoimmune disorders (along with Graves' sickness and autoimmune hepatitis) have also been suggested; but, the mentioned time to onset is extra variable and those activities can occur many months after initiation of remedy (see section four.Four).
Osteonecrosis
Cases of osteonecrosis have been said, specially in sufferers with normally recounted chance elements, advanced HIV sickness or lengthy-term exposure to CART. The frequency of this is unknown (see phase 4.Four).
Changes in laboratory chemistries
In managed clinical research laboratory abnormalities related to abacavir remedy have been uncommon, with out a differences in incidence discovered between abacavir dealt with patients and the manage fingers.
Paediatric populace
1,206 HIV-inflamed paediatric patients aged 3 months to 17 years have been enrolled in the ARROW Trial (COL105677), 669 of whom received abacavir and lamivudine either a couple of times day by day (see phase 5.1). No extra safety troubles had been diagnosed in paediatric topics receiving either once or twice every day dosing in comparison to adults.
Reporting of suspected unfavourable reactions
Reporting suspected negative reactions after authorisation of the medicinal product is essential. It permits continued monitoring of the gain/hazard balance of the medicinal product. Healthcare professionals are asked to report any suspected unfavorable reactions via the Yellow Card Scheme at www.Mhra.Gov.United kingdom/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.Nine Overdose
Single doses up to one,200 mg and every day doses up to one,800 mg of abacavir had been administered to patients in scientific studies. No extra negative reactions to the ones stated for regular doses have been stated. The results of higher doses are not acknowledged. If overdose happens the affected person need to be monitored for proof of toxicity (see section 4.8), and general supportive treatment carried out as essential. It isn't acknowledged whether or not abacavir may be eliminated by means of peritoneal dialysis or haemodialysis.
Five. Pharmacological residences
Five.1 Pharmacodynamic houses
Pharmacotherapeutic organization: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF06.
Mechanism of movement
Abacavir is a nucleoside opposite transcriptase inhibitor (NRTI). It is a powerful selective inhibitor of HIV-1 and HIV-2. Abacavir is metabolised intracellularly to the lively moiety, carbovir five'- triphosphate (TP). In vitro studies have proven that its mechanism of movement when it comes to HIV is inhibition of the HIV reverse transcriptase enzyme, an occasion which results in chain termination and interruption of the viral replication cycle. The antiviral activity of abacavir in cell tradition become not antagonised whilst blended with the NRTIs didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.
Resistance
In vitro resistance
Abacavir-resistant isolates of HIV-1 have been selected in vitro and are related to precise genotypic modifications inside the opposite transcriptase (RT) codon region (codons M184V, K65R, L74V and Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations for a clinically relevant boom in EC50 over wild-kind virus.
In vivo resistance (Therapy naïve sufferers)
Isolates from most sufferers experiencing virological failure with a routine containing abacavir in pivotal medical trials confirmed either no NRTI-related changes from baseline (forty five%) or simplest M184V or M184I selection (45%). The usual choice frequency for M184V or M184I become high (54%), and much less common turned into the choice of L74V (five%), K65R (1%) and Y115F (1%). The inclusion of zidovudine in the regimen has been discovered to lessen the frequency of L74V and K65R selection in the presence of abacavir (with zidovudine: 0/forty, without zidovudine: 15/192, 8%).
Therapy
Abacavir + combination of lamivudine and zidovudine1
Abacavir + lamivudine + NNRTI
Abacavir + lamivudine + PI (or PI/ritonavir)
Total
Number of Subjects
282
1,094
909
2,285
Number of Virological Failures
43
Ninety
158
291
Number of On-Therapy Genotypes
40 (a hundred%)
51 (a hundred%)2
141 (100%)
232 (a hundred%)
K65R
0
1 (2%)
2 (1%)
Three (1%)
L74V
Zero
9 (18%)
Three (2%)
12 (five%)
Y115F
Zero
2 (4%)
0
2 (1%)
M184V/I
34 (eighty five%)
22 (43%)
70 (50%)
126 (54%)
TAMs3
Three (8%)
2 (four%)
Four (three%)
9 (four%)
1 A fixed dose combination of lamivudine and zidovudine
2 Includes three non-virological failures and four unconfirmed virological failures.
Three Number of topics with ≥ 1 Thymidine Analogue Mutations (TAMs).
TAMs is probably decided on while thymidine analogs are associated with abacavir. In a meta-analysis of six scientific trials, TAMs had been not decided on via regimens containing abacavir with out zidovudine (zero/127), however have been decided on via regimens containing abacavir and the thymidine analogue zidovudine (22/86, 26%).
In vivo resistance (Therapy skilled sufferers)
Clinically good sized reduction of susceptibility to abacavir has been demonstrated in scientific isolates of patients with uncontrolled viral replication, who have been pre-treated with and are proof against different nucleoside inhibitors. In a meta-evaluation of 5 medical trials where abacavir become brought to heighten remedy, of 166 subjects, 123 (seventy four%) 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 have been uncommon (≤3%). Logistic regression modelling of the predictive value for genotype (adjusted for baseline plasma HIV-1 RNA [vRNA], CD4+ mobile remember, range and length of prior antiretroviral cures), confirmed that the presence of three or more NRTI resistance-associated mutations turned into associated with decreased reaction at Week four (p=0.Half) or 4 or extra mutations at median Week 24 (p≤zero.012). In addition, the sixty nine insertion complicated or the Q151M mutation, normally found in aggregate with A62V, V75I, F77L and F116Y, motive a high stage 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
None
15
-zero.Ninety six
40%
M184V on my own
75
-zero.Seventy four
Sixty four%
Any one NRTI mutation
Eighty two
-0.Seventy two
Sixty five%
Any NRTI-associated mutations
22
-0.Eighty two
32%
Any three NRTI-related mutations
19
-0.30
5%
Four or more NRTI-related mutations
28
-zero.07
11%
Phenotypic resistance and cross-resistance
Phenotypic resistance to abacavir calls for M184V with as a minimum a different abacavir-selected mutation, or M184V with more than one TAMs. Phenotypic go-resistance to different NRTIs with M184V or M184I mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir hold their antiretroviral activities in opposition to such HIV-1 variations. The presence of M184V with K65R does provide upward thrust to cross-resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V offers rise to move-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F gives upward thrust to move-resistance among abacavir and lamivudine. Appropriate use of abacavir can be guided the usage of presently recommended resistance algorithms.
Cross-resistance between abacavir and antiretrovirals from different classes (e.G. PIs or NNRTIs) is unlikely.
Clinical efficacy and safety
The demonstration of the gain of abacavir is specifically based totally on effects of research completed in adult treatment-naïve sufferers the usage of a regimen of abacavir 300 mg two times each day in combination with zidovudine and lamivudine.
Twice day by day (three hundred mg) administration:
• Therapy naïve adults
In adults handled with abacavir in aggregate with lamivudine and zidovudine the proportion of patients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treat analysis at 48 weeks) with corresponding rise in CD4 cells.
One randomised, double blind, placebo controlled clinical study in adults has compared the combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and zidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinued randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence between the treatment regimens at week 48. Although a similar antiviral effect was observed between the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable viral load (≤400 copies/ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT), 86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir combination, particularly in the subset of patients with high viral load (>100,000 copies/ml at baseline; ITT, forty six% versus 55%; AT, 84% as opposed to 93% for abacavir and indinavir respectively).
In a multicentre, double-blind, controlled look at (CNA30024), 654 HIV-infected, antiretroviral therapy-naïve patients had been randomised to obtain either abacavir three hundred mg two times every day or zidovudine 300 mg two times day by day, each in aggregate with lamivudine 150 mg twice daily and efavirenz six hundred mg once day by day. The period of double-blind remedy became at least 48 weeks. In the intent-to-deal with (ITT) population, 70% of patients within the abacavir institution, in comparison to sixty nine% of patients within the zidovudine institution, done a virologic reaction of plasma HIV-1 RNA ≤50 copies/ml by Week 48 (point estimate for treatment distinction: zero.8, 95% CI -6.3, 7.Nine). In the as dealt with (AT) analysis the difference between each treatment hands was extra sizeable (88% of sufferers inside the abacavir institution, compared to 95% of patients in the zidovudine institution (factor estimate for remedy distinction: -6.8, 95% CI -eleven.8; -1.7). However, each analyses had been like minded with a end of non-inferiority among each treatment palms.
ACTG5095 became a randomised (1:1:1), double-blind, placebo-controlled trial finished in 1,147 antiretroviral naïve HIV-1 infected adults, comparing three regimens: zidovudine (ZDV), lamivudine (3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median comply with-up of 32 weeks, the tritherapy with the 3 nucleosides ZDV/3TC/ABC turned into shown to be virologically not so good as the 2 other palms no matter baseline viral load (< or > a hundred,000 copies/ml) with 26% of topics at the ZDV/3TC/ABC arm, 16% at the ZDV/3TC/EFV arm and 13% at the 4 drug arm labeled as having virological failure (HIV RNA >200 copies/ml). At week 48 the share of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of patients with virologic failure. The remaining arms were continued in a blinded fashion. After a median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study, addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy.
ZDV/3TC/ABC
ZDV/3TC/EFV
ZDV/3TC/ABC/EFV
Virologic failure (HIV RNA >2 hundred copies/ml)
32 weeks
26%
16%
13%
144 weeks
-
26%
25%
Virologic achievement (48 weeks HIV RNA <50 copies/ml)
63%
80%
86%
• Therapy experienced adults
In adults moderately exposed to antiretroviral therapy the addition of abacavir to combination antiretroviral therapy provided modest benefits in reducing viral load (median change 0.44 log10 copies/ml at 16 weeks).
In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit as part of a new combination regimen will depend on the nature and duration of prior therapy which may have selected for HIV-1 variants with cross-resistance to abacavir.
Once daily (600 mg) administration:
• Therapy naïve adults
The once daily regimen of abacavir is supported by a 48 weeks multi-centre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults. These were primarily asymptomatic HIV infected patients - Centre for Disease Control and Prevention (CDC) stage A. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, in combination with efavirenz and lamivudine given once daily. Similar clinical success (point estimate for treatment difference -1.7, 95% CI -8.4, 4.9) was observed for both regimens. From these results, it can be concluded with 95% confidence that the true difference is no greater than 8.4% in favour of the twice daily regimen. This potential difference is sufficiently small to draw an overall conclusion of non-inferiority of abacavir once daily over abacavir twice daily.
There was a low, similar overall incidence of virologic failure (viral load >50 copies/ml) in both the once and twice each day treatment organizations (10% and eight% respectively). In the small pattern size for genotypic evaluation, there has been a fashion in the direction of a higher rate of NRTI-associated mutations within the as soon as every day as opposed to the two times day by day abacavir regimens. No firm end may be drawn due to the restrained information derived from this study. Long term information with abacavir used as a as soon as daily routine (past forty eight weeks) are presently limited.
• Therapy experienced adults
In take a look at CAL30001, 182 treatment-experienced patients with virologic failure were randomised and acquired treatment with both the fixed-dose combination of abacavir/lamivudine (FDC) as soon as each day or abacavir three hundred mg two times day by day plus lamivudine 300 mg once day by day, each in combination with tenofovir and a PI or an NNRTI for 48 weeks. Results suggest that the FDC organization turned into non-not so good as the abacavir two times each day organization, based on comparable reductions in HIV-1 RNA as measured by means of average area under the curve minus baseline (AAUCMB, -1.Sixty five log10 copies/ml as opposed to -1.83 log10 copies/ml respectively, ninety five% CI -0.13, zero.38). Proportions with HIV-1 RNA < 50 copies/ml (50% versus 47%) and < four hundred copies/ml (fifty four% versus fifty seven%) were additionally comparable in each group (ITT population). However, as there have been simplest reasonably skilled sufferers protected in this study with an imbalance in baseline viral load among the arms, these consequences must be interpreted with caution.
In study ESS30008, 260 patients with virologic suppression on a first line remedy routine containing abacavir three hundred mg plus lamivudine a hundred and fifty mg, both given two times daily and a PI or NNRTI, had been randomised to hold this regimen or switch to abacavir/lamivudine FDC plus a PI or NNRTI for 48 weeks.
Results imply that the FDC group became associated with a comparable virologic outcome (non-inferior) compared to the abacavir plus lamivudine group, primarily based on proportions of topics with HIV-1 RNA < 50 copies/ml (ninety% and 85% respectively, ninety five% CI -2.7, thirteen.5).
Additional statistics:
The protection and efficacy of abacavir in a number of distinct multidrug combination regimens continues to be not absolutely assessed (specifically in mixture with NNRTIs).
Abacavir penetrates the cerebrospinal fluid (CSF) (see segment 5.2), and has been shown to lessen HIV-1 RNA degrees inside the CSF. However, no consequences on neuropsychological performance were visible whilst it become administered to sufferers with AIDS dementia complicated.
Paediatric populace:
A randomised comparison of a routine consisting of once daily vs two times daily dosing of abacavir and lamivudine become undertaken within a randomised, multicentre, managed have a look at of HIV-infected, paediatric patients. 1,206 paediatric sufferers elderly 3 months to 17 years enrolled inside the ARROW Trial (COL105677) and were dosed in line with the load - band dosing pointers within the World Health Organisation remedy tips (Antiretroviral therapy of HIV infection in infants and children, 2006). After 36 weeks on a regimen which includes two times day by day abacavir and lamivudine, 669 eligible topics had been randomised to either hold twice each day dosing or switch to once each day abacavir and lamivudine for as a minimum 96 weeks. Of be aware, from this study scientific facts were no longer available for children underneath twelve months old. The effects are summarised within the table under:
Virological Response Based on Plasma HIV-1 RNA less than 80 copies/ml at Week forty eight and Week ninety six in the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW (Observed Analysis)
Twice Daily N (%)
Once Daily N (%)
Week 0 (After ≥36 Weeks on Treatment)
Plasma HIV-1 RNA <eighty c/ml
250/331 (76)
237/335 (71)
Risk difference (as soon as every day-twice day by day)
-four.Eight% (ninety five% CI -11.Five% to +1.Nine%), p=0.Sixteen
Week forty eight
Plasma HIV-1 RNA <80 c/ml
242/331 (seventy three)
236/330 (72)
Risk distinction (once daily-two times each day)
-1.6% (ninety five% CI -8.4% to +5.2%), p=zero.Sixty five
Week 96
Plasma HIV-1 RNA <80 c/ml
234/326 (72)
230/331 (69)
Risk distinction (once each day-twice every day)
-2.3% (95% CI -9.3% to +four.7%), p=zero.Fifty two
The abacavir + lamivudine as soon as daily dosing group become tested to be non-inferior to the twice day by day organization in step with the pre-special non-inferiority margin of -12%, for the number one endpoint of <80 c/ml at Week forty eight as well as at Week 96 (secondary endpoint) and all different thresholds examined (<two hundred c/ml, <400 c/ml, <1,000 c/ml), which all fell well within this non-inferiority margin. Subgroup analyses checking out for heterogeneity of as soon as vs two times daily proven no sizeable effect of sex, age, or viral load at randomisation. Conclusions supported non-inferiority regardless of evaluation technique.
In a separate look at comparing the unblinded NRTI combos (without or with blinded nelfinavir) in children, a extra share dealt with with abacavir and lamivudine (seventy one%) or abacavir and zidovudine (60%) had HIV-1 RNA ≤ 400 copies/ml at 48 weeks, in comparison with the ones handled with lamivudine and zidovudine (47%)[p=0.09, intention to treat analysis]. Similarly, more proportions of kids handled with the abacavir containing mixtures had HIV-1 RNA ≤50 copies/ml at forty eight weeks (fifty three%, forty two% and 28% respectively, p=0.07).
In a pharmacokinetic have a look at (PENTA 15), four virologically managed topics much less than twelve months of age switched from abacavir plus lamivudine oral answer two times each day to a once day by day regimen. Three topics had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48. No protection issues had been located in those subjects.
Five.2 Pharmacokinetic properties
Absorption
Abacavir is hastily and nicely absorbed following oral management. 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 set 1.Five hours for the pill components and approximately 1.Zero hour for the answer formulation.
At healing dosages a dosage of 300 mg twice day by day, the mean (CV) regular kingdom Cmax and Cmin of abacavir are approximately three.00 μg/ml (30%) and zero.01 μg/ml (99%), respectively. The mean (CV) AUC over a dosing c programming language of 12 hours changed into 6.02 μg.H/ml (29%), equal to a each day AUC of about 12.Zero μg.H/ml. The Cmax price for the oral solution is slightly better than the pill. After a six hundred mg abacavir tablet dose, the mean (CV) abacavir Cmax changed into about 4.26 μg/ml (28%) and the imply (CV) AUC∞ changed into eleven.Ninety five μg.H/ml (21%).
Food delayed absorption and reduced Cmax however did now not have an effect on standard plasma concentrations (AUC). Therefore abacavir can be considering or without food.
Distribution
Following intravenous administration, the obvious volume of distribution changed into approximately 0.8 l/kg, indicating that abacavir penetrates freely into frame tissues.
Studies in HIV inflamed sufferers have proven exact penetration of abacavir into the CSF, with a CSF to plasma AUC ratio of among 30 to 44%. The found values of the peak concentrations are nine fold greater than the IC50 of abacavir of zero.08 μg/ml or zero.26 μM when abacavir is given at 600 mg twice each day.
Plasma protein binding research in vitro imply that abacavir binds only low to reasonably (~49%) to human plasma proteins at healing concentrations. This shows a low probability for interactions with different medicinal products via plasma protein binding displacement.
Biotransformation
Abacavir is on the whole metabolised through the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The number one pathways of metabolism in guy are by means of alcohol dehydrogenase and by way of glucuronidation to provide the five'-carboxylic acid and 5'-glucuronide which account for about sixty six% of the administered dose. The metabolites are excreted in the urine.
Elimination
The imply 1/2-existence of abacavir is about 1.Five hours. Following multiple oral doses of abacavir three hundred mg twice an afternoon there may be no enormous accumulation of abacavir. Elimination of abacavir is through hepatic metabolism with next excretion of metabolites usually inside the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose inside the urine. The remainder is eliminated within the faeces.
Intracellular pharmacokinetics
In a look at of 20 HIV-infected patients receiving abacavir three hundred mg twice every day, with simplest one three hundred mg dose taken previous to the 24 hour sampling duration, the geometric suggest terminal carbovir-TP intracellular half of-life at consistent-nation was 20.6 hours, in comparison to the geometric mean abacavir plasma half-existence in this study of two.6 hours. In a crossover take a look at in 27 HIV-inflamed patients, intracellular carbovir-TP exposures have been higher for the abacavir six hundred mg as soon as daily regimen (AUC24,ss + 32%, Cmax24,ss + 99% and Ctrough + 18%) in comparison to the 300 mg two times every day regimen. Overall, these statistics guide the use of abacavir 600 mg as soon as each day for the remedy of HIV inflamed patients. Additionally, the efficacy and protection of abacavir given once each day has been confirmed in a pivotal clinical take a look at (CNA30021- see phase 5.1).
Special affected person populations
Hepatic impairment
Abacavir is metabolised more often than not by the liver. The pharmacokinetics of abacavir have been studied in sufferers with slight hepatic impairment (Child-Pugh rating five-6) receiving a single six hundred mg dose; the median (variety) AUC cost became 24.1 (10.Four to fifty four.Eight) ug.H/ml. The outcomes showed that there was a mean (ninety% CI) boom of one.89 fold [1.32; 2.70] within the abacavir AUC, and 1.Fifty eight [1.22; 2.04] fold within the elimination half-lifestyles. No definitive advice on dosage reduction is possible in patients with moderate hepatic impairment due to the sizable variability of abacavir publicity.
Abacavir is not advocated in sufferers with moderate or extreme hepatic impairment.
Renal impairment
Abacavir is in the main metabolised by the liver with about 2% of abacavir excreted unchanged within the urine. The pharmacokinetics of abacavir in patients with give up-stage renal sickness is just like sufferers with normal renal characteristic. Therefore no dosage reduction is needed in patients with renal impairment. Based on restrained enjoy abacavir must be averted in sufferers with stop-stage renal disorder.
Paediatric population
According to medical trials performed in children abacavir is rapidly and well absorbed from pill formulations administered to children. Children receiving abacavir oral pills consistent with the recommended dosage regimen reap better plasma abacavir exposure than youngsters receiving oral solution because higher mg/kg doses are administered with the pill system.
There are inadequate protection facts to propose the usage of abacavir in infants much less than three months vintage.
Pharmacokinetic information were derived from three pharmacokinetic research (PENTA 13, PENTA 15 and ARROW PK substudy) enrolling children underneath 12 years of age. The data are displayed inside the desk underneath:
Summary of Stead-State Plasma Abacavir AUC(0-24) (μg.H/ml) and Statistical Comparisons for Once and Twice-Daily Oral Administration Across Studies
Study
Age Group
Abacavir sixteen mg/kg Once-Daily Dosing Geometric Mean (95% CI)
Abacavir eight mg/kg Twice-Daily Dosing Geometric Mean (ninety five% CI)
Once-Versus Twice-Daily Comparison GLS Mean Ratio (ninety% CI)
ARROW PK Substudy
Part 1
Three to 12 years
(N=36)
15.3 (13.Three-17.Five)
15.6 (13.7-17.Eight)
0.98 (zero.89, 1.08)
PENTA thirteen
2 to 12 years
(N=14)
Thirteen.Four
(eleven.Eight-15.2)
9.Ninety one
(8.Three-11.9)
1.35
(1.19-1.54)
PENTA 15
3 to 36 months
(N=18)
Eleven.6
(9.89-thirteen.Five)
10.Nine
(eight.Nine-13.2)
1.07
(0.Ninety two-1.23)
In PENTA 15 look at, the geometric mean plasma abacavir AUC(0-24) (ninety five% CI) of the four topics beneath 365 days of age who switch from a two times each day to a once day by day regimen (see phase five.1) are 15.Nine (8.86, 28.5) μg.H/ml inside the as soon as-daily dosing and 12.7 (6.Fifty two, 24.6) μg.H/ml within the twice-each day dosing.
Elderly
The pharmacokinetics of abacavir has not been studied in patients over 65 years of age.
5.Three Preclinical protection statistics
Abacavir became no longer mutagenic in bacterial checks however showed interest in vitro inside the human lymphocyte chromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus check. This is consistent with the recognized interest of other nucleoside analogues. These outcomes imply that abacavir has a susceptible capability to motive chromosomal harm both in vitro and in vivo at high check concentrations.
Carcinogenicity studies with orally administered abacavir in mice and rats confirmed an increase within the prevalence of malignant and non-malignant tumours. Malignant tumours passed off within the preputial gland of males and the clitoral gland of girls of each species, and in rats inside the thyroid gland of men and the liver, urinary bladder, lymph nodes and the subcutis of girls.
The majority of those tumours befell at the highest abacavir dose of 330 mg/kg/day in mice and six hundred mg/kg/day in rats. The exception changed into the preputial gland tumour which befell at a dose of one hundred ten mg/kg in mice. The systemic exposure on the no effect level in mice and rats turned into equal to three and seven times the human systemic exposure in the course of therapy. While the carcinogenic potential in people is unknown, those facts advise that a carcinogenic danger to human beings is outweighed by way of the ability clinical benefit.
In pre-clinical toxicology research, abacavir treatment become shown to boom liver weights in rats and monkeys. The medical relevance of that is unknown. There is not any proof from medical studies that abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the metabolism of different medicinal products hepatically metabolised has no longer been discovered in man.
Mild myocardial degeneration in the coronary heart of mice and rats became located following management of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the predicted systemic publicity in human beings. The clinical relevance of this locating has not been determined.
In reproductive toxicity research, embryo and foetal toxicity have been discovered in rats however not in rabbits. These findings protected decreased foetal frame weight, foetal oedema, and an increase in skeletal variations/malformations, early intra-uterine deaths and nevertheless births. No conclusion may be drawn with reference to the teratogenic capability of abacavir due to this embryo-foetal toxicity.
A fertility observe in the rat has shown that abacavir had no effect on male or lady fertility.
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