DOTI Abalame Tablets Instructions

Approval date: July 26, 2017
Date of revision.
Instructions for DOTI Abalame Tablets
Please read the instructions carefully and use under the guidance of a physician
[Drug
Product
Name
Name
General
Use
Name
Name
DOTI Abalame Tablets
Commercial
Product
Name
Name: Suimekai®; TRIUMEQ ®
English
English
Name
Name：Dolutegravir Sodium, Abacavir Sulfate and Lamivudine Tablets
Chinese
Chinese
Pinyin
Pinyin
Duoti Aba Lami Pian
Composition
Ingredients】This product is a compound preparation, each tablet contains Dortilavir sodium (by Dortilavir) 50mg, Abacavir sulfate (by Abacavir) 600mg and Lamivudine 300mg.
Properties
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
【Suitability
Indications
Application
Indications
Indications]
This product is indicated for the treatment of adults and adolescents over 12 years of age (weighing at least 40 kg) who are infected with human immunodeficiency virus (HIV).
Patients infected with HIV, regardless of ethnicity, should be screened for the HLA-B*5701 allele before starting treatment with abacavir-containing products. If a patient is known to carry the HLA-B*5701 allele, products containing abacavir should not be administered.
[Regulation
Specifications
Specification
Each tablet contains dolutegravir sodium (as dolutegravir) 50mg, abacavir sulfate (as abacavir) 600mg and lamivudine 300mg.
【 【Consistency
Usage
Method
Dosage
Dosage]
This product should be taken under the supervision of a physician with experience in the treatment of HIV infection.
Dosage
Adults and adolescents (weight at least 40 kg)
For adults and adolescents, the recommended dose of this product is one tablet once a day.
If the adult or adolescent weighs less than 40 kg, this product should not be given because it is a fixed-dose tablet and the dose cannot be reduced.
This product is a fixed-dose tablet and should not be used in patients who require dose adjustment. If one of the active ingredients needs to be discontinued or a dose adjustment implemented for it, a separate formulation of dolutegravir, abacavir, or lamivudine may be used. In these cases, physicians should refer to the respective product information for these drugs.
Missed Doses
If a patient misses a dose of this product and it is more than 4 hours before the next dose, the product should be taken as soon as possible. If the next dose is less than 4 hours away, the patient should not take the missed dose but simply resume the usual dosing schedule.
Geriatric Patients
There are limited data on the dosing of dolutegravir, abacavir, and lamivudine in patients aged 65 years or older. There is no evidence that older patients require different dosing than younger adult patients (see [Pharmacokinetics]). Special caution is recommended when dosing in this age group, given age-related changes such as decreased renal function and changes in hematologic parameters.
Renal impairment
This product is not recommended for patients with creatinine clearance less than 50 mL/min (see [Pharmacokinetics]).
Hepatic impairment
Abacavir is primarily metabolized by the liver. No clinical data are available for patients with moderate or severe hepatic impairment.
Therefore, the use of this product is not recommended unless deemed necessary. In patients with mild hepatic impairment (Child-Pugh score 5-6), close monitoring, including monitoring of abacavir plasma levels if feasible, is required (see [Precautions] and [Pharmacokinetics]).
Pediatric Population
The safety and efficacy of this product for use in children under 12 years of age have not been established. No data are available.
Method of Administration
Oral administration
This product may be taken with or without food. (See [Pharmacokinetics]).
【
Adverse
Adverse
Adverse effects
Adverse effects
】
Summary of Safety Characteristics
Clinical safety data for this product are limited. The adverse reactions most frequently reported and considered to be possibly or likely associated with dolutegravir and abacavir/lamivudine (pooled data from 679 primary anti-retroviral subjects receiving this combination in phase IIb to IIIb clinical trials) were nausea (12%), insomnia (7%), dizziness (6%), and headache (6%).
Many of the adverse reactions listed in the table below (nausea, vomiting, diarrhea, fever, drowsiness, rash) occurred frequently in patients who developed abacavir hypersensitivity reactions. Therefore, if patients develop these symptoms, they should be carefully evaluated for the presence of such hypersensitivity reactions (see [Precautions]). Very rarely, a previous report of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermolysis bullosa cannot exclude an abacavir hypersensitivity reaction. In such cases, abacavir-containing drugs should be permanently discontinued.
The most serious adverse events that may be associated with dolutegravir and abacavir/lamivudine in individual patients are hypersensitivity reactions, including rash and severe hepatic effects (see [Precautions] and “Description of Specific Adverse Reactions” sections).
Adverse Reaction List
Based on clinical studies and post-marketing experience, the list of adverse reactions considered to be at least potentially related to this product component is shown in Table 1, broken down by body system organ classification and absolute frequency. Frequencies are defined as follows: very common (³1/10); common (³1/100 to <1/10); uncommon (³1/1,000 to <1/100); rare (³1/10,000 to <1/1000); very rare (<1/10,000).
An analysis of pooled data from Phase IIb through Phase IIIb clinical trials was implemented and found that the adverse reactions observed with the dotilavir + abacavir/lamivudine combination were generally consistent with the adverse reaction profile of the single components dotilavir, abacavir and lamivudine.
There was no difference between the combination and the single component in terms of the severity of the observed adverse reactions.
Table 1: Summary of adverse reactions associated with the dotilavir + abacavir/lamivudine combination in the analysis of pooled data from phase IIb to phase IIIb clinical trials and the list of adverse reactions to abacavir and lamivudine treatment when combined with other anti-retroviral agents based on clinical studies and post-marketing experience
FrequencyAdverse reactionsHematologic and lymphatic system disorders: uncommon: neutropenia2, anemia2, thrombocytopenia1 very rare: pure red blood cell aplasia1 Immune system disorders: common hypersensitivity reactions (see [Precautions])2 uncommon: immune reconstitution inflammatory syndrome (see [Precautions])2 Metabolic and nutritional disorders: common: anorexia1 uncommon: hypertriglyceridemia, Hyperglycemia very rare: lactic acidosis Psychiatric disorders: very common: insomnia common: abnormal dreaming, depression, nightmares, sleep disorders uncommon: suicidal thoughts or suicide attempts (especially in patients with a history of pre-existing depression or psychosis) Neurological disorders: very common: headache common: dizziness, drowsiness, sleepiness2 very rare: peripheral neuropathy2, sensory abnormalities2 Respiratory, thoracic and mediastinal disorders: common. Cough2, Nasal symptoms1 Gastrointestinal system disorders: very common: nausea, diarrhea common: vomiting, gastrointestinal gas, abdominal pain2, epigastric pain2, bloating, abdominal discomfort, GERD, dyspepsia rare: pancreatitis2 Hepatobiliary system disorders: uncommon: hepatitis2 Skin and subcutaneous tissue disorders: common: rash, pruritus, alopecia very rare: erythema multiforme1, Stevens-Johnson syndrome1, Toxic epidermal necrolysis1 various musculoskeletal and connective tissue disorders: common: arthralgia2, muscle disorders1 rare: rhabdomyolysis2 systemic disorders and various reactions at the site of administration: very common: fatigue common: malaise, fever2, malaise2 various tests: common: elevated CPK2, elevated ALT/AST2 rare: elevated amylase11 in TRIUMEQ ® (dolutegravir+) abacavir/lamivudine) or in phase III clinical studies of dotilaprevir, but based on clinical studies or post-marketing experience, this adverse reaction was observed when abacavir or lamivudine was used in combination with other anti-retroviral agents.
2 No reasonable basis was found in clinical trials to attribute this adverse reaction to TRIUMEQ ® (dotilavir + abacavir/lamivudine), so the highest frequency category observed in the respective component instructions was used (e.g., for dotilavir, abacavir, and/or lamivudine). Description of specific adverse reactions
Hypersensitivity reactions
Hypersensitivity reactions risk (HSR) are associated with both abacavir and dolutegravir and are more frequently observed with abacavir. The hypersensitivity reactions observed with these drugs (described below) have some common features, such as fever and/or rash, and other symptoms suggestive of multi-organ involvement. The onset of reactions associated with abacavir and dolutegravir is typically 10 to 14 days, but reactions to abacavir may occur at any time during treatment. If, based on clinical judgment, a hypersensitivity reaction cannot be ruled out, treatment with this product must be discontinued immediately without delay and treatment with this product or other products containing abacavir or dotilaprevir must never be restarted.
Hypersensitivity reactions to dotilaprevir
Symptoms include rash, systemic symptoms, and sometimes organ dysfunction, including severe hepatic reactions.
Abacavir hypersensitivity reaction
Signs and symptoms of this hypersensitivity reaction are described below. These manifestations are from clinical studies or post-marketing surveillance. Manifestations reported in at least 10% of patients with hypersensitivity reactions are shown in bold.
Fever and/or rash (usually maculopapular or urticaria) will be present as part of the syndrome in almost all patients who develop a hypersensitivity reaction, but reactions without rash or fever have also occurred. Other key symptoms include gastrointestinal, respiratory, or systemic symptoms, such as drowsiness and malaise.
Skin rash (usually maculopapular or urticaria) Gastrointestinal nausea, vomiting, diarrhea, abdominal pain, oral ulcers Respiratory dyspnea, cough, sore throat, adult-type respiratory distress syndrome, respiratory failure Other fever, drowsiness, general malaise, edema, lymphadenopathy, hypotension, conjunctivitis, allergic neurologic/psychiatric headache, sensory abnormalities Hematologic lymphopenia Elevated liver/pancreas liver function tests,. Hepatitis, liver failure musculoskeletal myalgia, rarely, muscle lysis, arthralgia, elevated creatine phosphokinase, elevated urinary creatinine, renal failure
Continued treatment can worsen symptoms associated with hypersensitivity reactions and may be life-threatening and, in rare cases, fatal.
Reintroduction of abacavir after an abacavir hypersensitivity reaction may result in a return of symptoms within a few hours. Such a recurrence of hypersensitivity reaction is generally more severe than the presentation during the initial episode and may include life-threatening hypotension and death. Similar reactions have occurred in less common cases in patients who had only one of the key symptoms of hypersensitivity reaction (see above) prior to discontinuation of abacavir, and in very rare cases, similar reactions have been observed in patients with no prior symptoms of hypersensitivity reaction (patients previously thought to be tolerant of abacavir) after restarting treatment.
Metabolic parameters
Body weight as well as lipid and blood glucose levels may be elevated during anti-retroviral therapy (see [Precautions]).
Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with recognized risk factors, advanced HIV disease, or long-term exposure to combination antiretroviral therapy (CART). The frequency of occurrence is not known (see [Caution]).
Immune reconstitution inflammatory syndrome
Inflammatory responses to asymptomatic or residual opportunistic pathogenic infections may occur at the time of initiation of combination antiretroviral drug therapy (CART) in HIV-infected patients with severe immunodeficiency. Autoimmune diseases (e.g., Graves’ disease) have also been reported; however, the timing of reported episodes is inconsistent, and these events may occur many months after treatment initiation (see [Caution]).
Laboratory chemistry changes
Elevated serum creatinine occurred during the first week of treatment with dolutegravir and remained stable over the subsequent 96-week period. In the SINGLE study, a mean change relative to baseline of 12.6 mmmol/L was observed after 96 weeks of treatment.These changes were not considered clinically significant because they did not reflect changes in glomerular filtration rate.
Asymptomatic creatine phosphokinase (CPK) elevations, primarily associated with exercise, have also been reported during dolutegravir treatment.
Chronic hepatitis B or C co-infection
Enrollment of patients co-infected with hepatitis B and/or C virus was allowed in the phase III study of dotilaprevir provided that liver function tests did not exceed 5 times the upper limit of normal (ULN) at baseline. Overall, the safety profile in patients with co-infection with hepatitis B and/or C virus was similar to that in patients without co-infection with hepatitis B or C virus, but the incidence of AST and ALT abnormalities was higher in the subgroup with co-infection with hepatitis B and/or C in all treatment groups.
Pediatric Population
There are no clinical study data on the effectiveness of this product in the pediatric population. Each single component was studied in adolescents (12 to 17 years of age).
Based on the limited available data from the treatment of adolescents (12 to 17 years of age) with dolutegravir single entity versus other anti-retroviral agents, there were no adverse reactions of any type other than those observed in the adult population.
Abacavir and lamivudine single agents were studied separately and as diphasic nucleoside based therapy in combination with ARVs for the treatment of ART primed and ART treated HIV infected pediatric patients (limited data are available on the use of abacavir and lamivudine in infants less than 3 months of age). There have been no adverse reactions of any type other than those observed in the adult population.
[Contraindications
Contraindications]
Contraindicated in patients with known hypersensitivity reactions to dolutegravir, abacavir, and lamivudine or any of the excipients.
Coadministration with dofetilide and pisciclovir is prohibited.
[Note
Caution
Caution
Note]
Transmission of HIV
Although effective suppression of the virus with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Hypersensitivity reactions (see [Adverse Reactions])
Both abacavir and dolutegravir are at risk of triggering hypersensitivity reactions (HSR) and share some common features, such as fever and/or rash and other symptoms indicating involvement of multiple organs. It is unlikely to be clinically certain whether hypersensitivity reactions occurring with this product are due to abacavir or dolutegravir. Hypersensitivity reactions with abacavir have been observed to occur more commonly, some of which can be life-threatening and, in rare cases, fatal if not managed properly. The risk of hypersensitivity reactions to abacavir is higher in patients who test positive for the HLA-B*5701 allele. However, in patients who do not carry this allele, abacavir hypersensitivity reactions are reported less frequently.
Therefore, the following measures should be followed.
– HLA-B*5701 status must be confirmed prior to initiation of treatment.
 – Treatment with this product should not be used in patients with a positive HLA-B*5701 status or in patients who have a negative HLA-B*5701 status but have had a suspected abacavir hypersensitivity reaction while previously receiving an abacavir-containing regimen.
– If a hypersensitivity reaction is suspected, the product should be discontinued without delay, even if the HLA-B*5701 allele is not present. Failure to discontinue treatment with this product immediately after the occurrence of a hypersensitivity reaction may result in an immediate life-threatening reaction. Clinical status, including hepatic aminotransferases and bilirubin, should be monitored.
– This product or any other drug containing abacavir or dolutegravir should never be reintroduced after discontinuation of this product due to a suspected hypersensitivity reaction.
 – Reintroduction of abacavir-containing medications after a suspected abacavir hypersensitivity reaction may result in a reappearance of symptoms within a few hours. Relapses are generally more severe than those seen during the initial episode and may include life-threatening hypotension and death.
– To avoid reintroduction of abacavir and dolutegravir, patients experiencing a suspected hypersensitivity reaction should be advised to discard any remaining tablets of this product.
Clinical description of hypersensitivity reactions
In clinical studies, hypersensitivity reactions were reported in <1% of patients treated with dotilaprevir and manifested as rash, systemic symptoms, and sometimes organ dysfunction, including severe hepatic reactions.
Abacavir hypersensitivity reactions have been adequately characterized during clinical studies as well as post-marketing surveillance. Symptoms generally occur within the first six weeks after initiation of abacavir treatment (median time to onset is 11 days), but these reactions may occur at any time during treatment.
Almost all hypersensitivity reactions to abacavir include fever and/or rash. Other signs and symptoms observed as part of an abacavir hypersensitivity reaction include respiratory and gastrointestinal symptoms. Importantly, these symptoms may lead to misdiagnosis of hypersensitivity reactions as respiratory disease (pneumonia, bronchitis, pharyngitis) or gastroenteritis. Continued treatment can worsen the symptoms associated with hypersensitivity reactions and may be life-threatening. These symptoms generally subside when abacavir is discontinued.
Rarely, life-threatening reactions may also occur within hours after restarting abacavir therapy after a patient has discontinued abacavir for reasons other than symptoms of hypersensitivity reactions (see [Adverse Reactions]). In such patients, restarting abacavir therapy must be done in a setting where medical assistance is immediately available. Body weight and metabolic parameters (lipids and glucose)
Weight gain and elevated lipid and glucose levels may occur during anti-retroviral therapy. These changes may be related in part to disease control and lifestyle. In some cases, there is evidence of an effect of treatment on lipids, but there is no clear evidence that weight gain is associated with any particular treatment. Monitoring of lipids and glucose should be done with reference to established HIV treatment guidelines. Dyslipidemia should be treated appropriately based on the clinical situation.
Liver disease
The safety and efficacy of this product has not been established in patients with pre-existing severe liver disease. It is not recommended for use in patients with moderate to severe hepatic impairment (see [DOSAGE AND ADMINISTRATION]).
Patients with pre-existing liver dysfunction, including those with chronic active hepatitis, have an increased frequency of liver function abnormalities during anti-retroviral drug combination therapy and should therefore be monitored according to standard norms. If, in these patients, there is evidence of worsening liver disease, suspension or discontinuation of therapy should be considered.
Patients with chronic hepatitis B or C
Patients with chronic hepatitis B or C treated with a combination of anti-retroviral drugs are at increased risk for severe and possibly fatal hepatic adverse reactions. If anti-retroviral therapy is administered concurrently for hepatitis B or C, please refer to the relevant product information for these drugs.
This product contains lamivudine, which is useful for hepatitis B. Abacavir and dolutegravir lack such an effect. Lamivudine monotherapy is generally considered to be inadequate for the treatment of hepatitis B because of the high risk of developing hepatitis B virus resistance. Thus, if this product is used to treat patients co-infected with hepatitis B, another antiviral drug is generally required. Treatment guidelines should be consulted.
If this product is discontinued in patients co-infected with hepatitis B virus, regular monitoring of liver function and HBV replication markers is recommended, as discontinuation of lamivudine may lead to acute exacerbation of hepatitis.
Immune reconstitution inflammatory syndrome
In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur upon initiation of combination anti-retroviral drug therapy (CART), resulting in severe clinical illness or exacerbation of symptoms. Such reactions are usually observed in the weeks or first few months prior to initiation of CART therapy. Relevant examples include cytomegalovirus retinitis, systemic and/or focal mycobacterial infections, and Yersinia pneumonia. Symptoms of inflammation should be evaluated and treatment instituted if necessary. Autoimmune diseases (e.g., Graves’ disease) have also been reported at the time of immune reconstitution; however, the timing of reported episodes is inconsistent, and these events may occur many months after the initiation of therapy.
Elevated liver chemistry assay values have been previously observed at the initiation of dolutegravir therapy in patients with co-infection with hepatitis B or C virus, consistent with the immune reconstitution inflammatory syndrome. Monitoring of liver chemistry test values is recommended in patients with co-infection with hepatitis B and/or C virus (see [Adverse Reactions]).
Mitochondrial dysfunction after intrauterine exposure
Nucleosides and nucleoside analogs may have varying degrees of effect on mitochondrial function, most significantly when combined with stavudine, desoxynivalenol and zidovudine. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogs in utero and/or postpartum, primarily in association with regimens containing zidovudine. The main adverse reactions reported were hematologic (anemia, neutropenia) and metabolic (hyperlactatemia, hyperlipidemia) disorders. These reactions are often transient. Some delayed neurological disorders (hypertonia, convulsions, behavioral abnormalities) have been reported sparingly. It is unclear whether neurological disorders are transient or permanent. These findings should be considered in children with severe clinical symptoms of unknown etiology, especially neurological symptoms, who were exposed to nucleosides and nucleoside analogs in utero. These results do not affect current national guidelines: use of ARVs in pregnant women to prevent vertical transmission of HIV.
Myocardial infarction
Observational studies have demonstrated an association between myocardial infarction and the use of abacavir. Patients participating in the study were primarily those who had received antiretroviral therapy. Clinical trial data showed a limited number of myocardial infarctions, and a small increase in risk could not be excluded. Overall, there is some inconsistency between the observational cohort data and the randomized trial data, so a causal relationship between abacavir treatment and the risk of myocardial infarction can neither be confirmed nor denied. To date, there is no definitive biological mechanism to explain the possible increased risk. When using this product, steps should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, and hyperlipidemia).
Osteonecrosis
Although multiple etiologies are believed (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, and high body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV disease and/or long-term exposure to CART. Patients should be advised to seek medical attention if they present with joint pain, joint stiffness, or difficulty with movement.
Opportunistic infections
Patients should be informed that this or any other anti-retroviral therapy will not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should be closely monitored clinically by a physician experienced in the treatment of HIV-related disease.
Drug Resistance
 Because the recommended dose of dolutegravir is 50 mg twice daily in patients who are resistant to integrase inhibitors, this product is not recommended for use in patients who are resistant to integrase inhibitors.
Drug Interactions
The recommended dose of dotilaprevir is 50 mg twice daily when administered concomitantly with etravirine (non-potentiating protease inhibitor), efavirenz, nevirapine, rifampin, tipranavir/ritonavir, carbamazepine, phenytoin, phenobarbital, and St. John’s wort, so TRIUMEQ ® is not recommended for patients taking the above drugs (see [Drug Interactions]).
TRIUMEQ ® should not be administered concomitantly with antacids containing multivalent cations. It is recommended that TRIUMEQ ® be administered 2 hours prior to or 6 hours after the administration of these drugs (see [Drug Interactions]).
It is recommended that TRIUMEQ ® be taken 2 hours before or 6 hours after administration of calcium or iron supplements (see [Drug Interactions]).
Dortilavir may increase the concentration of metformin. If dotilavir is administered concomitantly with metformin, metformin dose adjustment may be required at the start and stop of therapy to maintain glycemic control (see [Drug Interactions]). Metformin is eliminated by the kidneys, so renal function must be monitored when co-administered with dotilavir. Concomitant administration may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] of 45-59 mL/min) and a conservative approach is recommended. Metformin dose reduction is strongly recommended.
Lamivudine is not recommended for coadministration with cladribine (see [Drug Interactions]).
TRIUMEQ ® should not be taken with other drugs containing dolutegravir, abacavir, lamivudine, or emtricitabine.
Effects on the ability to drive and operate machinery
Patients should be informed that dizziness has been reported during treatment with dotilaprevir. When considering the patient’s ability to drive or operate machinery, the patient’s clinical status and the adverse effect profile of TRIUMEQ ® should be kept in mind.
[The
Pregnancy
Women
and
breastfeeding
Breastfeeding
during
Women
Women
Use
Medicine]
Pregnancy
In general, animal data and clinical experience in pregnant women should be considered when deciding on the use of antiretroviral drugs to treat HIV infection in pregnant women and thereby reduce the risk of vertical transmission of HIV to the newborn.
There are no data on the use of this product in pregnant women.
Data on the use of dotilavir in pregnant women are limited or not available. The effect of dotilavir on human pregnancy is not known. Regarding the combination of abacavir and lamivudine in pregnant women, there are a limited number of data indicating no teratogenic toxicity (over 400 results from pre-pregnancy exposures). With respect to lamivudine, a large number of data (more than 3000 results from pre-pregnancy exposures) suggest no teratogenic toxicity. For abacavir, a certain amount of data (more than 600 results from pre-gestational exposures) showed no teratogenic toxicity.
In animal reproductive toxicity studies, dolutegravir was found to cross the placenta. Animal studies have not demonstrated direct or indirect deleterious effects in terms of reproductive toxicity (see [Pharmacologic Toxicology]). Abacavir and lamivudine may inhibit cellular DNA replication, and abacavir has been shown to be carcinogenic in animal models (see [Pharmacologic Toxicology]). The clinical significance of these results is unclear.
This product should be used during pregnancy only if the expected benefit outweighs the risk to the fetus.
Patients co-infected with hepatitis B virus who are being treated with a lamivudine-containing drug, such as this product, and subsequently become pregnant should consider the possibility of hepatitis recurrence when discontinuing lamivudine (see [Precautions]).
Mitochondrial dysfunction
Nucleosides and nucleoside analogs have been shown to cause varying degrees of mitochondrial damage in vitro and in vivo. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogs in utero and/or postpartum (see [Precautions]).
Lactation
It is not known whether dotilaprevir is secreted into human breast milk. Available animal toxicology data indicate that dotilavir is secreted into breast milk. In lactating rats receiving 50 mg/kg dotilavir administered orally 10 days postpartum, dotilavir concentrations detected in milk were generally higher than those in blood.
Abacavir and its metabolites can be secreted into the milk of lactating rats. Abacavir is also secreted into human breast milk.
Based on data from more than 200 HIV-treated mother/child pairs, serum concentrations of lamivudine in infants breastfed by HIV-treated mothers are extremely low (less than 4% of maternal serum concentrations) and tend to decrease gradually to undetectable levels by the time the infant reaches 24 weeks of age. No safety data are available for abacavir and lamivudine administration to infants under 3 months of age.
It is recommended that HIV-infected women should not breastfeed their infants under any circumstances to avoid HIV transmission.
Fertility
No data are available on the effect of dotilavir, abacavir, or lamivudine on fertility in men or women. Animal studies have shown no effect of dolutegravir, abacavir or lamivudine on male or female fertility (see [Pharmacology and Toxicology])
【
Pediatric
Children
Use
Drug]
The safety and efficacy of this product for use in children under 12 years of age have not been established. No data are available.
【
Older
Elderly
Use
Dosage]
There are limited data on the dosing of dotilavir, abacavir and lamivudine in patients aged 65 years or older. There is no evidence that older patients require different doses than younger adult patients. Special caution is recommended when dosing in this age group, given age-related changes such as decreased renal function and changes in hematologic parameters.
[Dosage
Drug
Drug
Drug
Interactions
Interaction
Interactions]
This product contains dolutegravir, abacavir, and lamivudine, and therefore the interactions found with these drugs when administered alone are relevant to this product. No clinically significant drug interactions are expected between dotilavir, abacavir and lamivudine.
Effect of other drugs on the pharmacokinetics of dotilavir, abacavir, or lamivudine
Dortelavir is eliminated primarily through UGT1A1 metabolism. Dortilavir is also a substrate for UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP. Thus, the combination of this product with other drugs that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may increase the plasma concentration of dotilavir. Drugs that induce these enzymes or transporter proteins may decrease plasma concentrations of dotilavir, thereby decreasing the efficacy of dotilavir (see Table 2).
Certain antacids can reduce the absorption of dotilavir (see Table 2).
Abacavir is metabolized by UDP-glucuronosyltransferase (UGT) and ethanol dehydrogenase, and coadministration with UGT enzyme inducers or inhibitors or with compounds eliminated by ethanol dehydrogenase may alter abacavir exposure levels.
Lamivudine is cleared by the kidneys. Active renal secretion of lamivudine into the urine is mediated by the organic cation transporter protein (OCT2) and the multidrug and toxic compound efflux transport proteins (MATE1 and MATE-2K). Concomitant administration of lamivudine with OCT and MATE inhibitors may increase lamivudine exposure levels. Dortilavir is an OCT2 and MATE1 inhibitor, however, according to a crossover study analysis, lamivudine concentrations were similar with and without concomitant administration of lamivudine and dortilavir, indicating that in vivo, dortilavir does not affect lamivudine exposure levels.
The CYP enzyme does not significantly metabolize abacavir and lamivudine.
Effect of dotilavir, abacavir or lamivudine on the pharmacokinetics of other drugs
Dotiravir has no effect on midazolam (a CYP3A4 probe) in vitro. Based on in vivo and/in vitro data, no effect of dotilavir on the pharmacokinetics of any of the major enzymatic or transporter protein (e.g., CYP3A4, CYP2C9, and P-gp) substrate classes of drugs is expected (see [Pharmacokinetics]).
In vitro, dolutegravir inhibits the renal transporter proteins OCT2 and MATE1. In vivo, a 10% to 14% decrease in creatinine clearance was observed in patients (the proportion of excretion depended on OCT2 and MATE-1 transport). In vivo, dotilavir may increase plasma concentrations of drugs that are dependent on OCT2 or MATE-1 excretion (e.g., dofetilide, metformin) (see Table 2 and [Contraindication]).
In vitro, dotilavir inhibits renal uptake of organic anion transport protein (OAT)1 and OAT3. in vivo inhibition of OAT1 is unlikely because there is no effect on the pharmacokinetics of the OAT substrate tenofovir. in vivo inhibition of OAT3 has not been studied. Dortilavir may increase plasma concentrations of drugs that depend on OAT3 excretion.
Abacavir and lamivudine do not inhibit or induce CYP enzymes (e.g., CYP 3A4, CYP 2C9, CYP 2D6). In vitro data suggest that inhibition of P-pg and BCRP by abacavir cannot be excluded at enteric concentrations. in vitro, lamivudine inhibits OCT1 and OCT2.
The confirmed and theoretical interactions with specific anti-retroviral and non-anti-retroviral drugs are shown in Table 2.
Interaction Table
A list of interactions between dolutegravir, abacavir, and lamivudine and co-administered drugs is shown in Table 2 (increase is indicated by “↑”, decrease by “↓”, no change by “↔”, area under the concentration-time curve is indicated by “AUC”, maximum measured concentration is indicated by “Cmax”, and minimum measured concentration is indicated by “Cτ”). The table is not considered to be an exhaustive list of drugs, but rather a representative list of drugs in the category studied.
Table 2: Drug interactions
Geometric means of changes in drug-drug interactions by therapeutic area (%) Recommendations for concomitant administration of antiretroviral drugs Non-nucleoside reverse transcriptase inhibitor etravirine (non-potentiating protease inhibitor)/dotilaprevir Dotilaprevir ¯ AUC ¯ 71% Cmax
¯ 52% Cτ ¯ 88% etravirine”
(induces UGT1A1 and CYP3A enzyme classes) Etravirine (no potentiating protease inhibitor) reduces the plasma concentration of dotilaprevir. The recommended dose of dotilaprevir in patients on etravirine (non-potentiating protease inhibitor) is 50 mg twice daily, so TRIUMEQ ® is not recommended if the patient is not taking etravirine in combination with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir (see later section of the table). Lopinavir+Ritonavir+Etravirine/DotilaprevirDotilaprevir” AUC 11% Cmax
7% Ct
28% Lopinavir”
Ritonavir”
No dose adjustment is required for “etravirine”. Darunavir + ritonavir + etravirine/dotilaprevir dotilaprevir ¯ AUC ¯ 25% Cmax
¯ 12%Ct
¯ 36%
Darunavir”
Ritonavir”
No dose adjustment is required for “etravirine”. Efavirenz/dotilaprevirDotilaprev¯
AUC ¯ 57%
Cmax
¯ 39%
Cτ ¯ 75%
Efavirenz” (historical control)
(induces UGT1A1 and CYP3A enzyme class) When administered concomitantly with efavirenz, the dose of dotilaprevir is 50 mg twice daily and therefore TRIUMEQ ® should not be used concomitantly with efavirenz (see [Precautions]). Nevirapine/dotilaprevirDotilaprev¯
(not yet studied, exposure is expected to be reduced due to induction effects, similar to those observed with efavirenz) Plasma concentrations of dotilaprevir may be reduced by enzyme induction when administered concomitantly with nevirapine, which has not been studied. The effect of nevirapine on dotilaprevir exposure may be similar to or less than that of efavirenz. When administered concomitantly with nevirapine, the dose of dotilaprevir is 50 mg twice daily and therefore TRIUMEQ ® should not be used concomitantly with nevirapine. Rilpivirine/DotilaprevirDotilaprev”
AUC 12%
Cmax
13%
Cτ 22%
No dose adjustment is required for “rilpivirine”. Nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir/dotilaprevir
 
 
 
 
 Emtricitabine, desipramine, stavudine, zidovudine. Dortilavir”
AUC 1%
Cmax
¯ 3%
Cτ ¯ 8%
Tenofovir”
Interaction not studied No dose adjustment is required when TRIUMEQ ® is coadministered with nucleoside reverse transcriptase inhibitors.
 Coadministration of TRIUMEQ ® with products containing emtricitabine is not recommended because both lamivudine (a component of TRIUMEQ ®) and emtricitabine are cytidine analogues (risk of intracellular interaction exists (see [Precautions]). Protease inhibitor atazanavir/dotilaprevir dotilaprevir AUC 91% Cmax
50% Ct
180% atazanavir” (historical control)
(inhibits UGT1A1 and CYP3A enzyme class) No dose adjustment required. Atazanavir + ritonavir/dotilaprevir dotilaprevir AUC 62% Cmax
34% Ct
121% No dose adjustment required for atazanavir “ritonavir”. Tiranavir + ritonavir/dotilaprevir dotilaprevir¯ AUC ¯ 59% Cmax
¯ 47% Cτ ¯ 76% tipranavir “ritonavir”
(induction of UGT1A1 and CYP3A enzymes) When administered concomitantly with tipranavir/ritonavir, the recommended dose of dotilaprevir is 50 mg twice daily, so concomitant administration of tipranavir/ritonavir with TRIUMEQ ® is not recommended. Fusanavir
+ ritonavir/dotilaprevir dotilaprevir ¯ AUC ¯ 35% Cmax
¯ 24% Ct
¯ 49% Furoxanavir”
Ritonavir”
(induction of UGT1A1 and CYP3A enzyme classes) Furosemivir/ritonavir reduces dotilaprevir concentrations but does not result in reduced effectiveness based on limited data from phase III studies. No dose adjustment is required. Nelfinavir/dotilaprevirDotilaprev”
(not studied) No dose adjustment is required. Lopinavir + ritonavir/dotilaprevir dotilaprevir” AUC ¯ 4% Cmax
” 0% C24″ 6%
No dose adjustment required for lopinavir “ritonavir”. Darunavir + ritonavir/dotilaprevir dotilaprevir ¯ AUC ¯ 22% Cmax
¯ 11% Ct
¯ 38%
Darunavir “Ritonavir”
(induces UGT1A1 and CYP3A enzyme class) No dose adjustment is required.
Other antivirals telaprevir/dotilaprev dotilaprevir AUC 25%
Cmax
19% C
Cτ 37%
Telaprevir”
(historical control)
(CYP3A enzyme inhibition) No dose adjustment required. Poprevir/dotilaprevir dotilaprevir” AUC 7%
Cmax
Cmax 5%
Cτ 8%
Poprevir”
(historical control) No dose adjustment required. Daclatasvir/DotilaprevirDotilaprevir
AUC 33%
Cmax
29% C
Cτ 45%
Daclatasvir” Daclatasvir-induced changes in dolutegravir plasma concentrations are not clinically significant. Dotilaprevir does not change the plasma concentration of daclatasvir. No dose adjustment is required.
Anti-infective drugs methotrexate/sulfamethoxazole (cotrimoxazole)/abacavir
Methotrexate/sulfamethoxazole
(cotrimoxazole)/lamivudine
(160 mg/800 mg once daily for 5 days or 300 mg as a single dose) Interactions not studied
Lamivudine.
AUC 43%
Cmax
7%
Methotrexate.
AUC “
Sulfamethoxazole.
AUC “
(organic cationic transporter protein inhibition) No TRIUMEQ ® dose adjustment is required unless the patient has renal impairment (see [DOSAGE AND ADMINISTRATION]).
Anti-Mycobacterial Rifampin/Dotilaprevir Dotilaprevir ¯ AUC ¯ 54% Cmax
¯ 43%Ct
¯ 72%
(induces UGT1A1 and CYP3A enzyme class) When administered concomitantly with rifampin, dotilavir is administered at a dose of 50 mg twice daily, so concomitant administration of rifampin with TRIUMEQ ® is not recommended. Rifabutin/dotilaprevir dotilaprevir” AUC ¯ 5% Cmax
16% Cτ ¯ 30%
(induces UGT1A1 and CYP3A enzyme class) No dose adjustment is required. Anticonvulsant carbamazepine/dotilaprevir dotilaprevir” AUC ¯ 49% Cmax
33% Cτ ¯ 73% When administered concomitantly with carbamazepine, the dose of dotilavir is 50 mg twice daily, so concomitant administration of carbamazepine with DTG/ABC/3TC FDC is not recommended. Phenobarbital/Dotilavir
Phenytoin/Dotilavir
Oxcarbazepine/Dotilaprevir
Dortilavir¯
(not studied, exposure is expected to be reduced due to induction of UGT1A1 and CYP3A enzyme classes, similar to observations with carbamazepine) When administered concomitantly with these metabolic inducers, the dose of dotilavir is 50 mg twice daily, so concomitant administration of DTG/ABC/3TC FDC with these metabolic inducers should be avoided.
Interactions have not been studied with the anti-blocking amine (histamine H2 receptor antagonist) ranitidine.
Clinically meaningful interactions are unlikely to occur. No dose adjustment is required. Cimetidine was not studied for interaction.
Clinically significant interactions are unlikely to occur. No dose adjustment required. The cytotoxic drug cladribine/lamivudine has not been studied for interaction.
In in vitro assays, lamivudine inhibited intracellular cladribine phosphorylation, which may lead to cladribine failure when co-administered under clinical conditions. Some clinical results also confirm a possible interaction between lamivudine and cladribine. Concomitant use of TRIUMEQ ® with cladribine is not recommended (see [Precautions]). Opioids Methadone/Abacavir
(40 to 90 mg once daily for 14 days or 600 mg as a single dose followed by 600 mg twice daily for 14 days) Abacavir.
AUC “
Cmax
¯ 35%
Methadone.
CL/F 22% Most patients may not require methadone dose adjustment, but may occasionally require methadone dose readjustment. Retinoids Retinoids (e.g., isotretinoin) Interactions not studied
Considering that both are metabolized and eliminated by ethanol dehydrogenase, interactions may occur (abacavir component). Insufficient data to recommend dose adjustment. Other ethanol ethanol/dotilaprevir
Ethanol/lamivudine
 Ethanol/Abacavir
(0.7 g/kg single dose, or 600 mg single dose) Interaction not studied (inhibition of ethanol dehydrogenase)
Abacavir.
AUC 41%
Ethanol.
AUC” No dose adjustment required. Antiarrhythmic drug dofetilide/dotilavir dofetilide
(not studied, may increase dofetilide concentrations by inhibiting OCT2 transporter protein) Concomitant administration of TRIUMEQ ® with dofetilide is contraindicated due to the potential for life-threatening toxicity at high levels of dofetilide (see [Contraindications]). Antacids and supplements containing magnesium/aluminum antacids/dotilaprevirDotilaprevir ¯ AUC ¯ 74% Cmax
¯ 72% (complex bound to multivalent ions) Magnesium/Aluminum-containing antacids should be administered at a time separate from TRIUMEQ ® (at least 2 hours after administration or 6 hours before administration). Calcium Supplementation/Dotilaprevir Dotilaprevir ¯ AUC ¯ 39% Cmax
¯ 37% C24
¯ 39%
(complexes bound to multivalent ions) Calcium supplements, iron supplements, or multivitamins should be administered at a time separate from TRIUMEQ ® (at least 2 hours after administration or 6 hours before administration). Iron supplements/DotilaprevirDotilaprevir ¯ AUC ¯ 54% Cmax
¯ 57% C24
¯ 56%
(complexes bound to multivalent ions) Multivitamin/DotilaprevirDotilaprevir¯
AUC ¯ 33%
Cmax
¯ 35%
C24
¯ 32% Corticosteroid prednisone/dotilaprevir dotilaprevir”
AUC 11%
Cmax
6%
Cτ 17% No dose adjustment required. Diabetes medication Metformin/Dotilavir Metformin
Dortilavir”
When administered concomitantly with dotilavir 50 mg QD.
Metformin
AUC 79%
Cmax
66%
When administered concomitantly with dotilaprevir 50 mg BID.
Metformin
AUC 145%
Cmax
111% When initiating and discontinuing dotilavir in combination with metformin, dose adjustment of metformin should be considered to maintain glycemic control. In patients with moderate renal impairment, dose adjustment of metformin should be considered when administered concomitantly with dotilavir because elevated metformin concentrations increase the risk of lactic acidosis in patients with moderate renal impairment (see [Precautions]). Herbal preparations St. John’s Wort/Dotilaprevir
Dotilaprevir¯
(not studied, exposure is expected to be reduced due to induction of UGT1A1 and CYP3A enzymes, similar to observations with carbamazepine) The recommended dose of dotilavir is 50 mg twice daily when administered concomitantly with St. John’s wort; therefore, concomitant administration of DTG/ABC/3TC FDC with St. John’s wort is not recommended. Effects of oral contraceptives ethinyl estradiol (EE) and Norgestromin (NGMN)/dotilaprevir dotilaprevir.
EE” AUC 3% Cmax
¯ 1% Effect of dotilaprevir.
NGMN ” AUC ¯ 2% Cmax
¯ 11% no pharmacodynamic effect of dotilavir on luteinizing hormone (LH), follicle stimulating hormone (FSH) and progesterone. No dose adjustment of oral contraceptives is required when administered concomitantly with TRIUMEQ ®. Pediatric Population
Interaction studies have only been conducted in adults.
[Dosage
Drug
Drug
Excess
Overdose]
No specific signs or symptoms other than those listed as adverse reactions have been identified after the occurrence of an acute overdose of dolutegravir, abacavir or lamivudine.
There is no specific treatment for overdose of this product. If an overdose occurs, the patient should receive supportive therapy and appropriate monitoring, if necessary. Because lamivudine can be dialyzed, continuous hemodialysis may be used in the treatment of overdose, but this has not been studied. It is not clear whether abacavir can be cleared by peritoneal dialysis or hemodialysis. Dortilavir has a high binding rate to plasma proteins, so it is unlikely to be significantly cleared by dialysis.
[Clinical Trials].
The effectiveness of this product in treatment-naïve HIV-infected subjects is based on analysis of data from two randomized, international, double-blind, positive-controlled trials, SINGLE (ING114467) and SPRING-2 (ING113086), and one international, open, positive-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, patients had a median age of 35 years, 16% were female, 32% were non-white, 7% were co-infected with hepatitis C virus, and 4% were CDC category C. These characteristics were similar between the two treatment groups. The results at week 48 (including results according to key covariates at baseline) are shown in Table 3.
Table 3: Virological results of SINGLE randomized treatment at week 48 (snapshot approach)
 Week 48 DTG 50 mg + ABC/3TC
Once daily
N = 414 EFV/TDF/FTC
Once daily
N = 419 HIV-1 RNA <50 copies/mL88% 81% Treatment difference* 7.4% (95% CI: 2.5%, 12.3%) Virologic non-response† 5% 6% No virologic data at week 48 time window 7% 13% Reason Termination of study/study drug due to adverse event or death‡ 2% 10% Termination of study/study drug for other reasons§ 5% 3% Missing data during the window but continued to participate in the study0 <1% HIV-1 RNA according to baseline period covariates <50 copies/mL Subjects baseline period plasma viral load (copies/mL) n/N (%) n/N (%) 100,000 253/280 (90%) 238/288 (83%) >100,000  111/134 (83%) 100/131 (76%) CD4+ at baseline (cells/mm3) <200 45/57 (79%) 48/62 (77%) 200 to <350 143/163 (88%) 126/159 (79%)
³350176/194 (91%) 164/198 (83%) Sex Male 307/347 (88%) 291/356 (82%) Female 57/67 (85%) 47/63 (75%) Ethnicity White 255/284 (90%) 238/285 (84%) African American/African
/Other 109/130 (84%) 99/133 (74%) Age (years) <50 319/361 (88%) 302/375 (81%) 
³50 45/53 (85%) 36/44 (82%) *Adjusted for baseline period stratification factors.
† Includes subjects who discontinued prior to Week 48 due to lack or loss of effectiveness and subjects with ³50 copies at the Week 48 time window.
‡ Includes subjects whose dosing was discontinued at any time point between Day 1 and the Week 48 analysis time window due to adverse events or death, provided that the discontinuation resulted in the absence of on-treatment virologic data during the analysis time window.
§ Includes the following reasons: withdrawal of consent, missed visits, migration, and deviation from the protocol.
Note: ABC/3TC = abacavir 600 mg, lamivudine 300 mg administered as a Kivexa®/Epzicom® fixed-dose combination (FDC).
EFV/TDF/FTC = efavirenz 600 mg, tenofovir 300 mg, emtricitabine 200 mg, administered as Atripla FDC.
 In the 48-week primary analysis, the proportion of patients achieving virologic suppression was better in the dolutegravir + ABC/3TC group than in the FTC/TDF/ETC group, p = 0.003, with the same treatment differences observed in subjects defined according to baseline phase HIV RNA levels (<or>100,000 copies/mL). The median time to obtain virologic suppression was shorter in the ABC/3TC + DTG group (28 vs. 84 days, respectively; p < 0.0001). The adjusted mean change in CD4+ T cell count relative to the baseline period was 267 versus 208 cells/mm3, respectively (p<0.001). The time to obtain virological suppression and the analysis of change relative to the baseline period were pre-specified and adjusted for multiplicity. At week 96, responses were 80% and 72%, respectively. The endpoint difference remained statistically significant (p = 0.006). response was statistically higher in the DTG + ABC/3TC group, primarily due to a higher proportion of withdrawals due to adverse events in the FTC/TDF/FTC group, independent of viral load stratification. The overall treatment difference at week 96 applied to patients with higher and lower viral loads at baseline. Patients maintained virologic suppression for 144 weeks of the SINGLE open phase, with the DTG+ABC/3TC group (71%) outperforming the EFV/TDF/FTC group (63%) with a treatment difference of 8.3% (2.0, 14.6).
In SPRING-2, 822 patients were treated with dolutegravir 50 mg once daily or raltegravir 400 mg twice daily (blinded), all in combination with fixed-dose ABC/3TC (approximately 40%) or TDF/FTC (approximately 60%), administered in an open fashion. Baseline period demographics and outcomes are summarized in Table 4. dortelavir was non-inferior to raltegravir, including in the subset of patients treated with the abacavir/lamivudine base regimen.
Table 4: Demographic data and virologic outcomes for SPRING-2 randomized treatment (snapshot approach)
 DTG 50 mg
Once daily
+ 2 NRTI
N = 411 RAL 400 mg
Twice daily
+ 2 NRTI
N = 411 Demographics Median age (years)37 35 Female 15% 14% Non-white 16% 14% Hepatitis B and/or C 13% 11% CDC Class C 2% 2% ABC/3TC Basal medication 41% 40% Week 48 effectiveness results HIV-1 RNA <50 copies/mL 88% 85% Treatment difference* 2.5% (95% CI: – (2.2%, 7.1%) Virologic non-response† 5% 8% No virologic data at week 48 time window 7% 7% 
Reason Termination of study/investigational drug due to adverse event or death‡ 2% 1% Termination of study/investigational drug for other reasons§ 5% 6% HIV-1 RNA <50 copies/mL in patients receiving ABC/3TC 86% 87% Week 96 effectiveness results HIV-1 RNA <50 copies/mL 81% 76% Treatment difference* 4.5% (95% CI: -1.1%, 10.0%)
HIV-1 RNA <50 copies/mL74% 76% in patients receiving ABC/3TC *Adjusted for baseline period stratification factors.
† Includes subjects who discontinued prior to week 48 due to lack or loss of effectiveness and subjects with ≥50 copies in the 48-week time window.
‡ Includes subjects whose dosing was discontinued at any time point between Day 1 and the Week 48 analysis time window due to adverse events or death, provided that the discontinuation resulted in the absence of on-treatment virologic data during the analysis time window.
§ The following reasons were included: deviation from the regimen, missed visits, and withdrawal of consent.
Note: DTG = dotilaprevir; RAL = raltegravir.
 In FLAMINGO, 485 patients received dotilaprevir 50 mg once daily or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily, all in combination with ABC/3TC (approximately 33%) or TDF/FTC (approximately 67%). All treatments were administered in an open fashion. Key demographics and outcomes are summarized in Table 5.
Table 5: Demographic data and virological outcomes of FLAMINGO randomized treatment (snapshot approach)
 DTG 50 mg
Once daily
+ 2 NRTI
 N = 242 DRV + RTV
800 mg + 100 mg
Once a day
+2 NRTI
N = 242 Demographics Median age (years) 34 34 Female 13% 17% Non-white 28% 27% Hepatitis B and/or C 11% 8% CDC Class C 4% 2% ABC/3TC basal medication 33% 33% Week 48 effectiveness results HIV-1 RNA <50 copies/mL 90% 83% Treatment difference* 7.1% (95% CI. 0.9%, 13.2%) Virologic non-response† 6% 7% No virologic data at week 48 time window 4% 10% Reason Termination of study/study drug due to adverse event or death‡ 1% 4% Termination of study/study drug for other reasons§ 2% 5% Missing data during window but continued in study<1% 2% Among patients receiving ABC/3TC, HIV-1 RNA <50 copies/mL 90% 85% Median time to achieve viral suppression** 28 days 85 days *Adjusted for baseline period stratification factors, p=0.025.
† Includes subjects who discontinued prior to week 48 due to lack or loss of effectiveness and subjects with ≥50 copies in the 48-week time window.
‡ Includes subjects whose dosing was discontinued at any time point between Day 1 and the Week 48 analysis time window due to adverse events or death, provided that the discontinuation resulted in the absence of on-treatment virologic data during the analysis time window.
§ Includes the following reasons: withdrawal of consent, missed visits, and deviation from the protocol.
** p<0.001.
Note: DRV + RTV = darunavir + ritonavir, DTG = dotilaprevir.
 Virologic suppression was better in the dotilaprevir group (80%) than in the DRV/r group (68%) at week 96 (adjusted treatment difference [DTG – (DRV + RTV)]: 12.4%; 95% CI: [4.7, 20.2]). Response rates at week 96 were 82% (DTG+ABC/3TC) and 75% (DRV/r+ABC/3TC).
New-onset drug resistance in treatment-naïve patients in the SINGLE, SPRING-2 and FLAMINGO studies
No new-onset resistance to integrase analogues or NRTIs was detected in patients treated with dolutegravir + abacavir/lamivudine in any of these three studies.
Regarding control agents, typical resistance was detected in the TDF/FTC/EFV group (SINGLE; 6 cases with NNRTI-related resistance and one severe NRTI resistance) and 2 NRTI + raltegravir (SPRING-2; 4 severe NRTI resistance and one raltegravir resistance), while in patients receiving 2 NRTI + DRV/RTV (FLAMINGO ), no new resistance was detected in patients treated with 2 NRTI + DRV/RTV (FLAMINGO).
Pediatric population
 In a phase I/II 48-week multicenter, open study (P1093/ING112578) of HIV-1-infected infants, children and adolescents receiving a co-administration regimen, the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravir were evaluated.
At week 24, 16 of 23 adolescents (aged 12 to 17 years) treated with dotilaprevir once daily (35 mg n=4; 50 mg n=19) plus OBR achieved a viral load of <50 copies/mL.
In 20 of 23 children and adolescents (87%), the reduction in HIV-1 RNA relative to baseline was greater than 1 log10 copies/mL or HIV-1 RNA <400 copies/mL at week 24. 4 subjects experienced virologic failure, but none had INI resistance at the time of virologic failure.
[Drug
Rationale
Toxicology
Pharmacology]
Pharmacological action
Mechanism of action
Dortilavir: It inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of reverse transcription deoxyribonucleic acid (DNA) integration (a key step in the HIV replication cycle).
Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by intracellular enzymes to the active metabolite carbasvir triphosphate (CBVTP), a deoxyguanosine 5′-triphosphate (dGTP) analogue. CBVTP inhibits HIV1 reverse transcriptase (RT) activity by competing with the natural substrate dGTP and inserting into viral DNA.
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Lamivudine undergoes intracellular phosphorylation to produce the active 5′-triphosphate metabolite, lamivudine triphosph. The main mode of action of 3TCTP is the termination of DNA strand synthesis by insertion of a nucleotide analogue, thereby inhibiting RT activity.
In vitro antiviral effects
Dortilavir: Dortilavir exhibited antiviral activity against laboratory isolates of wild-type HIV-1 in peripheral blood mononuclear cells (PBMC) and MT-4 cells, with an average drug concentration (EC50) of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) required to inhibit 50% of viral replication. In a viral susceptibility assay using the integrase codon region of clinical isolates, dotilaprevir showed antiviral activity against 13 subtype B clinical isolates with a median EC50 value of 0.54 nM (range: 0.41 – 0.60 nM). In cell cultures, dotilaprevir showed antiviral activity against a group of HIV-1 clinical isolates with median EC50 values of 0.18 nM (n = 3, range: 0.09 – 0.5 nM), 0.08 nM (n = 5, range: 0.05 – 2.14 nM), 0.12 nM (n = 4), and 0.12 nM (n = 4) for subtypes A, B, C, D, E, F, and G and group O viruses, respectively. (range: 0.05~0.51 nM), 0.17 nM (n = 3, range: 0.16~0.35 nM), 0.24 nM (n = 3, range: 0.09~0.32 nM), 0.17 nM (range: 0.07~0.44 nM), 0.2 nM (n = 3, range: 0.02~0.87 nM), and 0.42 nM (n = 3) , range: 0.41~1.79 nM). In the PBMC trial, the EC50 of dotilaprevir against the three HIV-1 clinical isolates
values ranged from 0.09 to 0.61 nM.
Abacavir: The antiviral activity of abacavir against HIV1 was evaluated in multiple cell lines including primary monocytes/macrophages and PBMC. The EC50 of abacavir against HIV1IIIB and HIV1BaL
values ranged from 3.7 to 5.8 μM (1 μM = 0.28 μg/mL) and 0.07 to 1.0 μM, respectively, and the mean EC50 values for the eight clinical isolates were
The median EC50 values for abacavir against HIV1 subtypes A-G and group O viruses (n = 3; except subtype B: n = 2) were 344 nM (range: 14.8-676 nM), 16.9 nM (n = 5, range: 5.9-27.9 nM), 8.1 nM (n = 5, range: 1.5-16.7 nM), 356 nM (n = 5, range: 1.5-16.7 nM) , 356 nM (n = 5, range: 35.7 ~ 396 nM), 105 nM (n = 5, range: 28.1 ~ 168 nM), 47.6 nM (n = 5, range: 5.2 ~ 200 nM), 51.4 nM (n = 5, range: 7.1 ~ 177 nM), and 282 nM (n = 5, range: 22.4 ~ 598 nM). The EC50 values for HIV2 isolates (n = 4) ranged from 0.024 to 0.49 μM.
Lamivudine: Several cell lines were used to evaluate the antiviral activity of lamivudine against HIV-1 in a standard susceptibility assay. EC50 values ranged from 0.003 to 15 μM (1 μM = 0.23 μg/mL). The median EC50 values of lamivudine against HIV1 subtypes A-G and group O viruses (n = 3; except subtype B: n = 2) were 60 nM (range: 20-70 nM), 35 nM (range: 30-40 nM), 30 nM (range: 20-90 nM), 20 nM (range: 3-40 nM), 30 nM (range: 1-60 nM), 30 nM (range: 20~70 nM), 30 nM (range: 3~70 nM), and 30 nM (range: 20~90 nM). In PBMC, the EC50 of lamivudine against HIV2 isolates (n = 4)
values ranged from 0.003 to 0.120 μM. The use of ribavirin (50 μM) in the treatment of chronic HCV infection resulted in a 3.5-fold decrease in the anti-HIV1 activity of lamivudine in MT4 cells.
Antiviral activity in combination with other antivirals
In vitro, no antagonistic effects were seen with the combination of dotilaprevir and other anti-retroviral drugs (drugs tested: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir, raltegravir). In addition, no significant effect of ribavirin on dortilavir activity was observed.
In vitro, the antiviral activity of abacavir was not antagonized when abacavir was co-administered with the nucleoside reverse transcriptase inhibitors (NRTI) desoxymethyldeoxyinosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amiprenavir.
In vitro, no antagonistic effects were observed when lamivudine was co-administered with other anti-retroviral drugs (drugs tested: abacavir, desoxycarbamol, zalcitabine, nevirapine, zidovudine).
In vitro drug resistance
Dortilavir: Using different wild-type HIV-1 strains and different subtypes, dortilavir-resistant viruses were obtained from cell culture selection, and amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K were detected in different generations, causing a decrease in susceptibility of the strains to dortilavir up to 4-fold.
Abacavir and lamivudine: HIV-1 isolates selected from cell cultures in which amino acid substitutions K65R, L74V, Y115F and M184V/I occurred in HIV-1 RT showed reduced susceptibility to combination therapy with abacavir and lamivudine. When K65R, L74M or Y115F substitution was accompanied by M184V or I substitution, the susceptibility of the strain to abacavir was reduced 7-8-fold, and triple substitution reduced susceptibility by more than 8-fold.
Cross-resistance
Dortelavir: A single INSTI-resistant strain with substitutions T66K, I151L and S153Y reduces susceptibility to dortelavir by more than 2-fold (range: 2.3 to 3.6-fold). The susceptibility of the strains to dotilaprevir was reduced more than 2-fold (range: 2.5 to 21-fold). In HIV-2 mutants, the combination of A153G/N155H/S163G and E92Q/T97A/N155H/S163D substitutions reduced the susceptibility of the strains to dotilaprevir by 4-fold, and E92Q/N155H and G140S/Q148R substitutions resulted in an 8.5-fold and 17-fold reduction in the susceptibility of the strains to dotilaprevir, respectively.
Abacavir and lamivudine: cross-resistance had been observed in NRTI treatment. Studies have demonstrated that co-administration of abacavir/lamivudine reduces the susceptibility of K65R substituted (with or without M184V/I substitution) virus, L74V+M184V/I substituted virus and thymidine analog mutation (TAM) substituted (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/ N)+ M184V virus. The higher the number of TAM, the lower the susceptibility of the strain to abacavir.
Toxicological studies
Genotoxicity
Dortilavir: negative results in Ames test, mouse lymphoma test, and rodent in vivo micronucleus test.
Abacavir: In in vitro cytogenetic studies of human lymphocytes, abacavir induced chromosomal aberrations with or without metabolic activation. In the L5178Y mouse lymphoma assay, abacavir was mutagenic without metabolic activation, but not after metabolic activation. In the mouse bone marrow micronucleus test, abacavir was positive in male mice and negative in female mice. In the Ames test, results were negative with and without metabolic activation.
Lamivudine: Lamivudine showed mutagenicity in the L5178Y mouse lymphoma test and chromosome breakage activity in the human lymphocyte genetics test. Lamivudine did not show mutagenicity in the microbial mutagenicity assay, in vitro cell transformation assay, rat micronucleus assay, rat bone marrow cytogenetics assay, or rat liver non-programmed DNA synthesis assay.
Reproductive toxicity
Dortilavir, abacavir and lamivudine had no effect on fertility in male or female rats when exposed to approximately 44, 9 and 112 times the human exposure (doses of 50 mg, 600 mg and 300 mg, respectively) in rats.
Dortilavir: Reproduction studies in rats and rabbits at doses up to 50 times the human dose (50 mg/day) showed no evidence that dortilavir impaired fertility or harmed fetuses.
Oral administration of dotilavir at doses up to 1000 mg/kg/day (approximately 50 times the human dose of 50 mg/day in terms of AUC) from day 6 to day 17 of gestation in pregnant rats did not cause maternal toxicity, developmental toxicity, or teratogenicity.
Oral administration of dotilaprevir at doses up to 1000 mg/kg/day (approximately 0.74 times the human dose of 50 mg/day in terms of AUC) from day 6 to day 18 of gestation in pregnant rabbits did not show developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food intake, little or no stool/urine, slowed body weight gain) was observed at doses of 1000 mg/kg.
Abacavir: Studies in pregnant rats have shown that abacavir can be transferred to the fetus via the placenta. Fetal malformations (increased incidence of generalized edema and skeletal malformations in fetuses) and developmental toxicity (reduced fetal body weight and parietal-rump length) were observed in rats at doses that produced exposures (in terms of AUC) equivalent to 28 times the human clinical exposure at a dose of 600 mg. In separate fertility studies in rats, embryo/fetus toxicity (increased fetal resorption and decreased fetal body weight) and offspring toxicity (increased incidence of stillbirths and decreased body weight) occurred at half the dose described above. In rabbits, no developmental toxicity or increased fetal malformations were observed when the dose administered produced an exposure (in terms of AUC) equivalent to 7 times the human exposure at the recommended dose.
Lamivudine: Studies in pregnant rats have shown that lamivudine can be transferred to the fetus via the placenta. Reproductive toxicity studies of lamivudine administered orally were conducted in rats and rabbits. Plasma levels at the study dose were up to approximately 32 times the human exposure at the 300 mg dose. No evidence of teratogenicity of lamivudine was seen. Early embryonic death was observed in rabbits at exposure levels similar to human exposure, but this effect was not observed in rats when plasma levels were up to 32 times the human exposure.
Carcinogenicity
Dortilavir: Results of 2-year carcinogenicity studies in mice and rats showed that the highest doses administered were 500 mg/kg and 50 mg/kg, respectively. no significant increase in the incidence of drug-associated tumors was observed in mice, and the exposure (AUC) to dortilavir at the highest dose was approximately 26 times the human exposure at the recommended dose (50 mg once daily). No significant increase in the incidence of drug-associated tumors was observed in rats at the highest dose tested, and dotilavir exposure (AUC) in male and female rats at this dose was 17 and 30 times higher than the recommended human exposure (50 mg once daily), respectively.
Abacavir: Increased incidence of malignant and non-malignant tumors was observed in a 2-year oral administration carcinogenicity study in mice and rats. Malignant tumors were seen in the prepuce gland in males and the clitoral gland in females of both species and in the liver of female rats. Non-malignant tumors were seen in the liver and thyroid gland of female rats, where the systemic exposure in animals was 7-28 times the human exposure at the recommended dose of 600 mg.
Lamivudine: Carcinogenicity studies in mice and rats showed no potential carcinogenicity at doses up to 12 times (mice) and 57 times (rats) the recommended human dose of 300 mg.
Repeated Dosing Toxicity
Myocardial degeneration was seen in mice and rats given abacavir for 2 consecutive years, with systemic exposures in animals equivalent to 7-21 times the expected systemic exposure in humans at a dose of 600 mg; the clinical significance of this finding is unclear.
 [Drug
Generation
Kinetic
Pharmacokinetic
Pharmacokinetic]
Bioequivalence has been demonstrated with dotilavir single tablets and abacavir/lamivudine fixed-dose combination tablets (ABC/3TC FDC) administered alone. This was demonstrated in a single-administration, 2-factor crossover, bioequivalence study of this product (fasting) versus 1 x 50 mg dotilavir tablet plus 1 x 600 mg abacavir/300 mg lamivudine tablet (fasting) in healthy subjects (n=66). In a subgroup of subjects in this study (n=12), the effect of a high-fat meal on this product was evaluated. The plasma Cmax and AUC of dolutegravir were 37% and 48% higher, respectively, after high-fat meal administration than fasting administration of this product. Abacavir Cmax was reduced by 23% and AUC was unchanged. This was not considered clinically significant (see Absorption). The effect of food on plasma exposure levels of abacavir and lamivudine after administration of this product with a high-fat meal was similar to the food effect previously observed with ABC/3TC FDC. These results suggest that the timing of food intake need not be considered when administering this product.
Exposure levels to dotilavir were essentially similar between healthy subjects and HIV-1-infected subjects. In adult subjects infected with HIV-1, dotilavir 50 mg administered once daily, the steady-state pharmacokinetic parameters (geometric mean [CV%]) based on population pharmacokinetic analysis were AUC(0-24) = 53.6 mg.h/mL (27%), Cmax = 3.67 mg/mL (20%), and Cmin = 1.11 mg/mL (46%) ). After a single dose of abacavir 600 mg, the mean (CV) Cmax was 4.26 µg/ml (28%) and the mean (CV) AUC¥ was 11.95 µg.h/ml (21%). After multiple oral administration of lamivudine 300 mg once daily for 7 days, the steady-state mean (CV) Cmax was 2.04 µg/ml (26%) and the mean (CV) AUC24 was 8.87 µg.h/ml (21%).
The pharmacokinetic properties of dotilavir, lamivudine and abacavir are described below.
Absorption
Dortilavir, abacavir and lamivudine are rapidly absorbed after oral administration. The absolute bioavailability of dotilavir has not been determined. In adults, the absolute bioavailability is approximately 83% versus 80% to 85% for oral abacavir and lamivudine, respectively. The time to maximum serum concentration (tmax) is approximately 2 to 3 hours (after tablet administration), 1.5 hours, and 1.0 hour for dotilavir, abacavir, and lamivudine, respectively.
 Distribution
The apparent volume of distribution (Vd/F after oral administration of the suspension formulation) of dotilavir was estimated to be 12.5 L. Intravenous administration studies of abacavir and lamivudine showed mean apparent volumes of distribution of 0.8 and 1.3 L/kg, respectively.
Based on in vitro data, the binding of dotilavir to human plasma proteins was high (>99%). The binding rate of dotilavir to plasma proteins was independent of the dotilavir concentration. The mean values of the ratio of whole blood and plasma drug-related radioactivity concentrations ranged from 0.441 to 0.535, indicating a minimal association of radioactivity with blood cell composition. When serum albumin levels were low (<35 g/L), the proportion of unbound dotilavir in plasma increased, similar to that observed in subjects with moderate liver damage. In vitro plasma protein binding studies have demonstrated only low to moderate (approximately 49%) binding of abacavir to human plasma proteins at therapeutic concentrations. In the therapeutic dose range, the pharmacokinetics of lamivudine were linear with limited in vitro plasma protein binding (<36%).
Dotilaprevir, abacavir and lamivudine can be present in cerebrospinal fluid (CSF).
The mean dotilavir concentration in cerebrospinal fluid was 18 mg/mL (similar to unbound plasma concentrations and above the IC50) in 13 untreated subjects receiving a stable dotilavir + abacavir/lamivudine regimen. Abacavir studies demonstrated CSF to plasma AUC ratios ranging from 30% to 44%. Measured values of peak concentrations were 9 times higher than the abacavir IC50 (0.08 µg/mL or 0.26 µM) when abacavir 600 mg was administered twice daily. The mean lamivudine cerebrospinal fluid/plasma concentration ratio was approximately 12% 2 to 4 hours after oral administration. The true extent to which lamivudine penetrates the blood-brain barrier and its relationship to clinical effectiveness is unclear.
Dortilavir can be found in both the female and male reproductive tracts. At steady state, the AUC in cervicovaginal fluid, cervical tissue, and vaginal tissue is 6% to 10% of the corresponding plasma AUC. At steady state, the AUC in semen and in rectal tissue is 7% and 17% of the corresponding plasma AUC, respectively.
 Biotransformation
Dortilavir is primarily metabolized by UGT1A1, with CYP3A accounting for a small proportion (9.7% of the total administered dose in a human mass balance study). Dortilavir is the major circulating compound in plasma; renal clearance of the unchanged active substance is low (<1% of the dose). Fifty-three percent of the total oral dose was excreted in the fecal form as a prototype. It is unclear whether all or part of this is due to biliary excretion of the unabsorbed active substance or glucuronide conjugate, which can be further degraded to the parent compound in the intestinal lumen. Thirty-two percent of the total oral dose is excreted in the urine, in the form of dolutegravir ether glucuronide (18.9% of the total dose), N-dealkylated metabolites (3.6% of the total dose), and metabolites formed by benzyl carbon oxidation (3.0% of the total dose).
Abacavir is primarily metabolized by the liver, with approximately 2% of the administered dose excreted by the kidneys as a prototype compound. The major metabolic pathway in humans is via ethanol dehydrogenase and glucuronidation to yield 5′-carboxylic acid and 5′-glucuronide, which account for approximately 66% of the administered dose. These metabolites are excreted through the urine.
The metabolism of lamivudine is a secondary elimination pathway. Lamivudine is primarily cleared from prototype lamivudine by renal excretion. The potential for metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5% to 10%).
Drug Interactions
In in vitro assays, dolutegravir did not directly inhibit or weakly inhibited (IC50>50 μM) the following enzymes: cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A; uridine diphosphate glucuronosyltransferase (UGT) Based on these data, dotilaprevir is not expected to affect the pharmacokinetics of the major enzyme or transporter protein substrate classes (CYP1A2, CYP2B6, CYP3A4, CYP2-K, MRP2, or MRP4). The pharmacokinetics of the class of drugs (see [Drug Interactions]).
In in vitro assays, dotilavir is not a substrate for human OATP 1B1, OATP 1B3, or OCT 1.
Elimination
The terminal half-life of dotilaprevir is approximately 14 hours. Based on a population pharmacokinetic analysis, the apparent oral clearance (CL/F) in HIV-infected patients is approximately 1 L/hr.
The mean half-life of abacavir is approximately 1.5 hours. The geometric mean terminal half-life of the intracellular active moiety triphosphorylated carbovir (TP) at steady state was 20.6 hours. There was no significant accumulation of abacavir after repeated oral administration of abacavir 300 mg twice daily. Abacavir elimination was via hepatic metabolism, with subsequent excretion of metabolites primarily in the urine. In the urine, unchanged abacavir and metabolites accounted for approximately 83% of the abacavir administered dose. The remainder is eliminated through the feces.
The observed elimination half-life of lamivudine is 5 to 7 hours. The intracellular terminal half-life of lamivudine was 16 to 19 hours in patients receiving lamivudine 300 mg administered once daily. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg and is primarily cleared by the kidneys (> 70%) via the organic cation transport system. Studies in patients with renal impairment suggest that lamivudine elimination is affected by renal dysfunction. Patients with creatinine clearance less than 50 mL/min require dose reduction (see [Dosage]).
Pharmacokinetic/Pharmacodynamic Relationships
In a randomized, dose-ranging exploratory trial, subjects infected with HIV-1 received dolutegravir monotherapy (ING111521), which demonstrated rapid, dose-dependent antiviral activity with a mean HIV-1 RNA decline of 2.5 log10 on day 11 using a 50 mg dose. in the 50 mg group, 3 to 4 days after the last dose remained The antiviral response was maintained.
Intracellular pharmacokinetics
At steady state, the geometric mean intracellular terminal half-life of carbovir-TP was 20.6 hours, while the geometric mean plasma half-life of abacavir was 2.6 hours. The intracellular terminal half-life of lamivudine-TP was extended to 16 to 19 hours compared to a plasma half-life of 5 to 7 hours for lamivudine, which supports once-daily dosing of ABC and 3TC.
 Special Patient Populations
Liver damage
Separate pharmacokinetic data were obtained for dotilavir, abacavir and lamivudine.
Dortilavir was primarily metabolized and eliminated by the liver. 8 subjects with moderate liver impairment (Child-pugh class B) and 8 matched healthy adult control subjects received a single dose of dortilavir 50 mg. Although total plasma dotilavir concentrations were similar, free dotilavir exposure levels were 1.5-2 times higher in subjects with moderate liver impairment than in healthy control subjects. No dose adjustment was required in patients with mild to moderate liver impairment. The effect of severe liver impairment on the pharmacokinetics of dotilavir was not studied.
Abacavir is metabolized primarily by the liver. The pharmacokinetics of abacavir was studied in patients with mild liver impairment (Child-pugh score 5 to 6) who received a single dose of 600 mg. The results showed a mean increase in abacavir AUC to 1.89 [1.32; 2.70] times and an increase in elimination half-life to 1.58 [1.22; 2.04] times. Due to the significant variability in abacavir exposure levels, dose reduction is not recommended in patients with mild liver impairment.
Data collected in patients with moderate to severe liver impairment showed no significant effect of liver dysfunction on the pharmacokinetics of lamivudine.
Based on the abacavir data collected, the use of this product in patients with moderate and severe hepatic impairment is not recommended.
Renal impairment
Separate pharmacokinetic data were obtained for dolutegravir, lamivudine, and abacavir.
For dotilavir, renal clearance of the prototypically active substance is a minor elimination pathway. A dotilavir pharmacokinetic study was conducted in subjects with severe renal impairment (CLcr <30 mL/min). No clinically meaningful pharmacokinetic differences were observed between subjects with severe renal impairment (CLcr <30 mL/min) and matched healthy subjects. Dortilavir has not been studied in patients receiving dialysis therapy, but no differences in exposure levels are expected.
Abacavir is primarily metabolized by the liver, with approximately 2% of abacavir excreted in the urine as a prototype compound. In patients with end-stage renal disease, the pharmacokinetics of abacavir are similar to those of patients with normal renal function.
Lamivudine studies have shown increased plasma concentrations (AUC) in patients with renal dysfunction due to reduced clearance.
Based on data from lamivudine, it is not recommended for use in patients with creatinine clearance <50 mL/min.
Geriatric Patients
A dolutegravir population pharmacokinetic analysis using data from HIV-1-infected adults showed no clinically meaningful effect of age on dolutegravir exposure levels.
Pharmacokinetic data for dotilavir, abacavir and lamivudine were limited in subjects aged >65 years.
Pediatric population
In 10 HIV-1-infected adolescents (12 to 17 years of age) who had received antiretroviral therapy, the pharmacokinetics of dotilavir showed that exposure levels following dotilavir 50 mg once-daily dosing were similar to those observed in adults receiving dotilavir 50 mg once-daily dosing.
Limited data were available in adolescents receiving abacavir 600 mg and lamivudine 300 mg administered daily. Pharmacokinetic parameters were similar to those reported in adults.
Polymorphisms of drug-metabolizing enzymes
 There is no evidence that common drug-metabolizing enzyme polymorphisms have a clinically meaningful effect on the extent of altered dolutegravir pharmacokinetics. A meta-analysis using pharmacogenomic samples collected in clinical studies in healthy subjects showed that in subjects carrying the UGT1A1 genotype, which causes poor metabolism of dotilavir (n=7), dotilavir clearance was 32% lower and AUC 46% higher than in subjects carrying the UGT1A1 genotype, which causes normal metabolism (n=41).
Gender
Population pharmacokinetic analyses using pooled pharmacokinetic data from phase IIb and phase III adult trials showed no clinically meaningful effect of gender on dotilavir exposure levels. There was no evidence of the need to adjust the dose of dotilavir, abacavir or lamivudine based on the effect of gender on pharmacokinetic parameters.
Ethnicity
Population pharmacokinetic analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials showed no clinically meaningful effect of ethnicity on dotilavir exposure levels. The pharmacokinetics of dotilavir in Japanese subjects following a single oral dose were similar to the parameters observed in Western (US) subjects. There is no evidence that the dose of dotilavir, abacavir, or lamivudine needs to be adjusted based on the effect of ethnicity on pharmacokinetic parameters.
Chronic hepatitis B or C co-infection
Population pharmacokinetic analysis showed no clinically meaningful effect of hepatitis C virus co-infection on dotilavir exposure levels. Pharmacokinetic data are limited in subjects co-infected with hepatitis B virus (see [Precautions]).
【
Storage
Storage
Store under seal at 30°C.
This product should be stored in its original packaging to avoid moisture absorption of the tablet. Seal the bottle strictly and do not remove the desiccant.
Package
Packaging
High-density polyethylene bottle, 30 tablets/bottle.
[Available
Efficacy
Period
24 months.
[Enforcement
Execution
Standard
Standard
Imported drug registration standards: JX20160192
Approval
Approval
Document
No.]
Imported drug registration certificate number: H20170345
[approval number
Production
Production
Enterprise
Company
Company
Production facility] Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations)
Location
Address】Priory Street, Ware, Hertfordshire, SG12 0DJ, UK
Packing House】Glaxo Wellcome S.A.
Address】Avenida Extremadura 3, Pol. Ind. Allendeduero, Aranda de Duero, Burgos 09400, Spain
 China Office.
6F, Metropolitan Headquarters Building, No. 168 Xizang Middle Road, Shanghai, China
Postal Code: 200001
Tel: (86 21) 23019800
Fax: (86 21) 23019801
24-hour service hotline: 800-820-3383/400-183-3383
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