英文药名:Triumeq(dolutegravir/abacavir/lamivudine film-coated tablets) 中文药名:复方dolutegravir和阿巴卡韦/拉米夫定片 生产厂家:葛兰素史克和辉瑞合资公司
Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. There are no data on the use of Triumeq in pregnancy. There are no or limited amount of data from the use of dolutegravir in pregnant women. The effect of dolutegravir on human pregnancy is unknown. A moderate amount of data on pregnant women taking the individual actives abacavir and lamivudine in combination indicates no malformative toxicity (more than 400 outcomes from first trimester exposures). Concerning lamivudine, a large amount of data (more than 3000 outcomes from first trimester) indicates no malformative toxicity. Moderate amount of data (more than 600 outcomes from first trimester) indicates no malformative toxicity for abacavir. In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Abacavir and lamivudine may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown. Triumeq should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. For patients co-infected with hepatitis B who are being treated with a lamivudine containing medicinal product such as Triumeq and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine. Mitochondrial dysfunction 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). Breast-feeding Lamivudine is excreted in human milk at similar concentrations to those found in serum. It is expected that dolutegravir and abacavir will also be excreted into human milk based on animal data, although this has not been confirmed in humans. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV. Fertility There are no data on the effects of dolutegravir, abacavir or lamivudine on human male or female fertility. Animal studies indicate no effects of dolutegravir, abacavir or lamivudine on male or female fertility (see section 5.3). 4.7 Effects on ability to drive and use machines Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of Triumeq should be borne in mind when considering the patient's ability to drive or operate machinery. 4.8 Undesirable effects Summary of the safety profile Clinical safety data with Triumeq are limited. The most frequently reported adverse reactions considered possibly or probably related to dolutegravir and abacavir/lamivudine [pooled data from 679 anti retroviral naïve subjects receiving this combination in the Phase IIb to IIIb clinical trials, see section 5.1], were nausea (12%), insomnia (7%), dizziness (6%) and headache (6%). Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued. The most severe adverse event possibly related to the treatment with dolutegravir and abacavir/lamivudine, seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4 and Description of selected adverse reactions in this section). Tabulated list of adverse reactions The adverse reactions considered at least possibly related to treatment with the components of Triumeq from clinical study and post-marketing experience are listed in Table 2 by body system, organ class and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000). The adverse reactions observed for the combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from Phase IIb to Phase IIIb clinical trials were generally consistent with the adverse reaction profiles for the individual components dolutegravir, abacavir and lamivudine. There was no difference between the combination and the individual components in severity for any observed adverse reactions. Table 2: Tabulated summary of adverse reactions associated with the combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from Phase IIb to Phase IIIb clinical trials and adverse reactions to treatment with abacavir and lamivudine from clinical studies and post-marketing experience, when used with other antiretrovirals
Hypersensitivity reactions Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR), which were observed more commonly with abacavir. Hypersensitivity reaction observed for each of these medicinal products (described below) share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Time to onset was typically 10-14 days for both abacavir and dolutegravir-associated reactions, although reactions to abacavir may occur at any time during therapy. Treatment with Triumeq must be stopped without delay if HSR cannot be ruled out on clinical grounds, and therapy with Triumeq or other abacavir or dolutegravir containing products must never be re-initiated. Please refer to section 4.4 for further details on patient management in the event of a suspected HSR to Triumeq. Dolutegravir hypersensitivity Symptoms have included rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Abacavir hypersensitivity 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 sympotoms such as lethargy and malaise. Skin Rash (usually maculopapular or urticarial) Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure Miscellaneous Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis Neurological/Psychiatry Headache, paraesthesia Haematological Lymphopenia Liver/pancreas Elevated liver function tests, hepatitis, hepatic failure Musculoskeletal Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase Urology Elevated creatinine, renal failure Symptoms related to this HSR worsen with continued therapy and can be life- threatening and in 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). Lactic acidosis Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4). Lipodystrophy Combination antiretroviral therapy (CART) has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). Metabolic abnormalities CART has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4). Osteonecrosis 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). Immune reactivation syndrome In HIV-infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). Changes in laboratory chemistries Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 96 weeks. In the SINGLE study a mean change from baseline of 12.6 μmol/L was observed after 96 weeks of treatment. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate. Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy. Co-infection with Hepatitis B or C In dolutegravir Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Paediatric population There are no clinical study data on the effects of Triumeq in the paediatric population. Individual components have been investigated in adolescents (12 to 17 years). Based on limited available data with the dolutegravir single entity used in combination with other antiretroviral agents to treat adolescents (12 to 17 years), there were no additional types of adverse reactions beyond those observed in the adult population. The individual preparations of abacavir and lamivudine have been investigated separately, and as a dual nucleoside backbone, in combination antiretroviral therapy to treat ART- naive and ART- experienced HIV- infected paediatric patients (data available on the use of abacavir and lamivudine in infants less than three months are limited). No additional types of adverse reactions have been observed beyond those characterised for the adult population. 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: United Kingdom the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard Ireland HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie 4.9 Overdose No specific symptoms or signs have been identified following acute overdose with dolutegravir, abacavir or lamivudine, apart from those listed as adverse reactions. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of Triumeq. If overdose occurs, the patient should be treated supportively with appropriate monitoring, 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. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC code: J05AR13 Mechanism of action Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Abacavir and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective 5'-triphosphate (TP) which are the active moieties with extended intracellular half-lives supporting once daily dosing (see section 5.2). Lamivudine-TP (an analogue for cytidine) and carbovir-TP (the active triphosphate form of abacavir, an analogue for guanosine) 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 DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases. Pharmacodynamic effects Antiviral activity in vitro Dolutegravir, abacavir and lamivudine have been shown to inhibit replication of lab-strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood mononuclear cells (PMBCs) and monocyte/macrophages. The concentration of drug necessary to effect viral replication by 50% (IC50 - half maximal inhibitory concentration) varied according to virus and host cell type. The IC50 for dolutegravir in various lab-strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61). The mean IC50 for abacavir against lab-strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to 5.8 μM. The median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 μM. The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 1.57 to 7.5 μM for abacavir and from 0.16 to 0.51 μM for lamivudine. The IC50 values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 μM, against Group O from 0.022 to 1.21 μM, and against HIV-2 isolates, from 0.024 to 0.49 μM. For lamivudine, the IC50 values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 μM, against Group O from 0.030 to 0.160 μM and against HIV-2 isolates from 0.002 to 0.120 μM in peripheral blood mononuclear cells. HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreated patients in Africa and Asia were susceptible to abacavir (IC50 fold changes < 2.5), and lamivudine (IC50 fold changes < 3.0), except for two CRF02_AG isolates with fold changes of 2.9 and 3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive. The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Antiviral activity in combination with other antiviral agents No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals (tested agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir). In addition, ribavirin had no apparent effect on dolutegravir activity. 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). Effect of human serum In 100% human serum, the mean fold shift for dolutegravir activity was 75 fold, resulting in protein adjusted IC90 of 0.064 ug/mL. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%). Resistance Resistance in vitro: (dolutegravir) Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIVIII during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F. These mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432 mutations E92Q (fold change 3) and G193E (fold change 3) were selected. These mutations have been selected in patients with pre-existing raltegravir resistance and who were then treated with dolutegravir (listed as secondary mutations for dolutegravir). In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two individual patients with subtype B and subtype C in the clinical program for ART experienced, INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (fold change 10), but was not detected in patients receiving dolutegravir in the Phase III program. Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to primary mutations (excluding at Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravir fold change is seen as the number of secondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no further selection of resistance was seen (fold change unchanged around 1). In contrast, starting passage with mutants with mutation Q148H (fold change 1), a variety of raltegravir associated secondary mutations accumulated with a consequent increase of fold change to values >10. A clinically relevant phenotypic cut-off value (fold change vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome. Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for susceptibility to dolutegravir. Dolutegravir has a <10 fold change against 94% of the 705 clinical isolates. Resistance in vivo: (dolutegravir) In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48-96 weeks). In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum fold change of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum fold change of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission. The R263K mutation was also selected in vitro (see above). Resistance in vitro and in vivo: (abacavir and lamivudine) Abacavir-resistant isolates of HIV-1 have been selected in vitro and in vivo and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). During in vitro abacavir selection the M184V mutation occurred first and resulted in about a 2 fold increase in IC50, below the abacavir clinical cut-off of 4.5 fold change. Continued passage in increasing concentrations of drug resulted in selection for double RT mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7- to 8-fold change in abacavir susceptibility and combinations of three mutations were required to confer more than an 8-fold change in susceptibility. HIV-1 resistance to lamivudine involves the development of a M184I or 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. M184V is associated with about a 2 fold increase in abacavir resistance but does not confer clinical resistance for abacavir. Isolates resistant to abacavir may also show reduced sensitivity to lamivudine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65R with or without the M184V/I substitution, and to viruses with L74V plus the M184V/I substitution. Cross-resistance between dolutegravir or abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or NNRTIs is unlikely. Effects on electrocardiogram No relevant effects were seen on the QTc interval, with doses of dolutegravir exceeding the clinical dose by approximately 3 fold. Similar studies were not conducted with either abacavir or lamivudine. Clinical efficacy and safety The efficacy of Triumeq in HIV-infected, therapy naive subjects is based on the analyses of data from two randomized, international, double-blind, active-controlled trials, SINGLE (ING114467) and SPRING-2 (ING113086) and the international, open-label, active-controlled trial FLAMINGO (ING114915). In SINGLE, 833 patients were treated with dolutegravir 50 mg once daily plus fixed-dose abacavir-lamivudine (DTG + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar between treatment groups. Week 48 outcomes (including outcomes by key baseline covariates) are shown in Table 3. Table 3: Virologic Outcomes of Randomized Treatment of SINGLE at 48 Weeks (Snapshot algorithm)
In SPRING-2, 822 patients were treated with either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily (blinded), both with fixed-dose ABC/3TC (around 40%) or TDF/FTC (around 60%), given open label. Baseline demographics and outcomes are summarised in Table 4. Dolutegravir was non-inferior to raltegravir, including within the subset of patients with the abacavir/lamivudine background regimen. Table 4: Demographics and virologic outcomes of randomized treatment of SPRING-2 (snapshot algorithm)
Table 5: Demographics and virologic outcomes of randomized treatment of FLAMINGO (snapshot algorithm)
De novo resistance was not detected to the integrase class or the NRTI class in any patients who were treated with dolutegravir + abacavir/lamivudine in the three studies mentioned. For the comparators typical resistance was detected with TDF/FTC/EFZ (SINGLE; six with NNRTI associated resistance and one with major NRTI resistance ) and with 2 NRTIs + raltegravir (SPRING-2; four with major NRTI resistance and one with raltegravir resistance), while no de novo resistance was detected in patients treated with 2 NRTIs + DRV/RTV (FLAMINGO). Paediatric population In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravir was evaluated in combination regimens in HIV-1 infected infants, children and adolescents. At 24 weeks, 16 of 23 (69%) adolescents (12 to 17 years of age) treated with dolutegravir once daily (35 mg n=4; 50 mg n=19) plus OBR achieved viral load less than 50 copies/mL. Twenty out of 23 children and adolescents (87%) had >1 log10 c/mL decrease from Baseline in HIV-1 RNA or HIV-1 RNA <400 c/mL at Week 24.Four subjects had virologic failure none of which had INI resistance at the time of virologic failure. 5.2 Pharmacokinetic properties The Triumeq tablet has been shown to be bioequivalent to dolutegravir single entity tablet and abacavir/lamivudine fixed-dose combination tablet (ABC/3TC FDC) administered separately. This was demonstrated in a single dose, 2-way crossover bioequivalence study of Triumeq (fasted) versus 1 x 50 mg dolutegravir tablet, plus 1 x 600mg abacavir/300 mg lamivudine tablet (fasted) in healthy subjects (n=66). The effect of a high fat meal on the Triumeq tablet was evaluated in a subgroup of subjects in this study (n=12). Plasma Cmax and AUC of dolutegravir following administration of Triumeq with a high fat meal were 37% and 48% higher, respectively, than those following administration of Triumeq in the fasted state. This is not considered clinically significant (see Absorption). The effect of food on plasma exposures of abacavir and lamivudine following administration of Triumeq with a high fat meal were very similar to prior food effects observed with ABC/3TC FDC. These results indicate that Triumeq can be taken with or without food. The pharmacokinetic properties of dolutegravir, lamivudine and abacavir are described below. Absorption Dolutegravir, abacavir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 2 to 3 hours (post dose for tablet formulation), 1.5 hours and 1.0 hour for dolutegravir, abacavir and lamivudine, respectively. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1–infected subjects. In HIV-1–infected adult subjects following dolutegravir 50 mg once daily, the steady-state pharmacokinetic parameters (geometric mean [%CV]) based on population pharmacokinetic analyses were AUC(0-24) = 53.6 (27) μg.h/mL, Cmax = 3.67 (20) μg/mL, and Cmin = 1.11 (46) μg/mL. Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 µg/ml (28%) and the mean (CV) AUC∞is 11.95 µg.h/ml (21%). Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 µg/ml (26%) and the mean (CV) AUC24 is 8.87 µg.h/ml (21%). Plasma Cmax and AUC of dolutegravir following administration of Triumeq with a high fat meal were 37% and 48% higher, respectively, than those following administration of Triumeq in the fasted state). For abacavir there was a decrease in Cmax with 23% and AUC was unchanged. The exposure of lamivudine was similar with and without food. These results indicate that Triumeq can be taken with or without food. Distribution The apparent volume of distribution of dolutegravir (following oral administration of suspension formulation, Vd/F) is estimated at 12.5 L. Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively. Dolutegravir is highly bound (> 99%) to human plasma proteins based on in vitro data. Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 36%). Dolutegravir, abacavir and lamivudine are present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown. Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state. Biotransformation Dolutegravir is primarily metabolized via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose). 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. These metabolites are excreted in the urine. Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%). Elimination Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1 L/hr in HIV-infected patients based on a population pharmacokinetic analysis. The mean half-life of abacavir is about 1.5 hours. The geometric mean terminal half-life of intracellular active moiety carbovirtriphosphate (TP) at steady-state is 20.6 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces. The observed lamivudine half-life of elimination is 5 to 7 hours. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance < 50 ml/min (see section 4.2). Pharmacokinetic/pharmacodynamic relationship(s) In a randomized, dose-ranging trial, HIV-1–infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose-dependent antiviral activity with mean decline in HIV-1 RNA of 2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group. Intracellular pharmacokinetics 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 of 2.6 hours. The terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma lamivudine half-life of 5-7 hours, supporting once daily dosing of ABC and 3TC. Special patient populations Hepatic impairment Pharmacokinetic data has been obtained for dolutegravir, abacavir and lamivudine separately. Dolutegravir is primarily metabolized and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied. Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose. The results showed that there was a mean increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure. Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on data obtained for abacavir, Triumeq is not recommended in patients with moderate and severe hepatic impairment. Renal impairment Pharmacokinetic data have been obtained for dolutegravir, lamivudine and abacavir separately. Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CLcr <30 mL/min) and matching healthy subjects were observed. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected. 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. Based on the lamivudine data, Triumeq is not recommended for patients with creatinine clearance of < 50 ml/min. Elderly Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic data for dolutegravir, abacavir and lamivudine in subjects>65 years of age are limited. Paediatric population The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to 17 years) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg once daily. Limited data are available in adolescents receiving a daily dose of 600 mg of abacavir and 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults. Polymorphisms in drug metabolising enzymes There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41). Gender Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir. There is no evidence that a dose adjustment of dolutegravir, abacavir or lamivudine would be required based on the effects of gender on PK parameters. Race Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects. There is no evidence that a dose adjustment of dolutegravir, abacavir or lamivudine would be required based on the effects of race on PK parameters. Co-infection with Hepatitis B or C Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis B co-infection (see section 4.4). 5.3 Preclinical safety data There are no data available on the effects of the combination of dolutegravir, abacavir and lamivudine in animals, except a negative in vivo rat micronucleus test which tested the effects of the combination of abacavir and lamivudine. Mutagenicity and carcinogenicity Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleoside analogues, inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative. Lamivudine has not shown any genotoxic activity in the in vivo studies. Abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high tested concentrations. The carcinogenic potential of a combination of dolutegravir, abacavir and lamivudine has not been tested. Dolutegravir was not carcinogenic in long term studies in the mouse and rat. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential. Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in rats in the thyroid gland of males and in the liver, urinary bladder, lymph nodes and the subcutis of females. The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the human systemic exposure during therapy. While the clinical relevance of these findings is unknown, these data suggest that a potential carcinogenic risk to humans is outweighed by the clinical benefit. Repeat-dose toxicity The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic exposures approximately 38 and 1.5 times the 50 mg human clinical exposure based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local active substance administration, mg/kg or mg/m2 metrics are appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys occurred at 30 times the human mg/kg equivalent dose (based on 50 kg human), and 11 times the human mg/m2 equivalent dose for a total daily clinical dose of 50 mg. In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical relevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic. Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinal products hepatically metabolised has not been observed in humans. Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 21 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, dolutegravir, lamivudine and abacavir were shown to cross the placenta. Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (50 times the 50 mg human clinical exposure when administered in combination with abacavir and lamivudine based on AUC). Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity (0.74 times the 50mg human clinical exposure when administered in combination with abacavir and lamivudine based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.74 times the 50 mg human clinical exposure when administered in combination with abacavir and lamivudine based on AUC). Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure. Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. These findings included decreased foetal body weight, foetal oedema, and an increase in skeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn with regard to the teratogenic potential of abacavir because of this embryo-foetal toxicity. Fertility studies in rats have shown that dolutegravir, abacavir and lamivudine have no effect on male or female fertility. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Mannitol (E421) Microcrystalline cellulose Povidone K29/32 Sodium starch glycollate Magnesium stearate Tablet coating Opadry II Purple 85F90057 containing: Polyvinyl alcohol – part hydrolyzed titanium dioxide macrogol talc iron oxide black iron oxide red 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccant. This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container White HDPE (high density polyethylene) bottles closed with polypropylene child-resistant closures, with a polyethylene faced induction heat seal liner. Each bottle contains 30 film-coated tablets and a desiccant. Multipacks containing 90 (3 packs of 30) film-coated tablets. Each pack of 30 film-coated tablets contains a desiccant. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder ViiV Healthcare UK Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom 8. Marketing authorisation number(s) EU/1/14/940/001 EU/1/14/940/002 9. Date of first authorisation/renewal of the authorisation Date of first authorization: 2 September 2014 10. Date of revision of the text Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 三合一HIV药物Triumeq获得了欧洲批准 |
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Triumeq(dolutegravir/abacavir/lamivudine filmcoated tablets)简介:
英文药名:Triumeq(dolutegravir/abacavir/lamivudine film-coated tablets)
中文药名:复方dolutegravir和阿巴卡韦/拉米夫定片
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