Tivicay PD (Page 6 of 9)

8.5 Geriatric Use

Clinical trials of TIVICAY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TIVICAY in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY and TIVICAY PD are not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY, TIVICAY PD, or other coadministered antiretroviral agents [see Clinical Pharmacology (12.3)]. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

10 OVERDOSAGE

There is no known specific treatment for overdose with TIVICAY or TIVICAY PD. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

11 DESCRIPTION

TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. The chemical name of dolutegravir sodium is sodium (4R ,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H -pyrido[1′,2′:4,5]pyrazino[2,1-b ][1,3]oxazin-7-olate. The empirical formula is C20 H18 F2 N3 NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula:

dolutegravir chemical structure

Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.

Each film-coated tablet of TIVICAY for oral administration contains 10.5, 26.3, or 52.6 mg of dolutegravir sodium, which is equivalent to 10, 25, or 50 mg dolutegravir free acid, respectively, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film‑coating contains the inactive ingredients iron oxide yellow (25-mg and 50-mg tablets only), macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

Each TIVICAY PD tablet for oral suspension contains 5.26 mg of dolutegravir sodium, which is equivalent to 5 mg dolutegravir free acid, and the following inactive ingredients: calcium sulfate dihydrate, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, strawberry cream flavor, sucralose, and sodium stearyl fumarate. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dolutegravir is an HIV-1 antiretroviral agent [see Microbiology (12.4)].

12.2 Pharmacodynamics

Effects on Electrocardiogram

In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose.

Effects on Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3‑arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

12.3 Pharmacokinetics

The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects (Table 9) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials.

Table 9. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1–Infected Adults
a Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2.b Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3.

Parameter

50 mg Once Daily

Geometric Meana (%CV)

50 mg Twice Daily

Geometric Meanb (%CV)

AUC(0-24) (mcg h/mL)

53.6 (27)

75.1 (35)

Cmax (mcg/mL)

3.67 (20)

4.15 (29)

Cmin (mcg/mL)

1.11 (46)

2.12 (47)

TIVICAY tablets and TIVICAY PD tablets for oral suspension are not bioequivalent. The relative bioavailability of TIVICAY PD is approximately 1.6-fold higher than TIVICAY; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis [see Dosage and Administration (2.3)].

Absorption

Following oral administration of dolutegravir, peak plasma concentrations were observed 1 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax , and C24 h ranging from 1.2 to 1.5.

Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.

Effect of Food: TIVICAY or TIVICAY PD may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir following a 50-mg dose of TIVICAY. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.

Distribution

Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.

Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.

Elimination

Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses.

Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A.

Polymorphisms in DrugMetabolizing Enzymes: In a meta-analysis of healthy subject trials, 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).

Excretion: After a single oral dose of [14 C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose).

Specific Populations

Pediatric Patients: The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in 2 weight-band-based pharmacokinetic substudies from the ODYSSEY trial. Steady-state plasma exposure at doses by weight band are summarized in Table 10 [see Clinical Studies (14.3)].

Mean dolutegravir AUC0-24h and C24h in HIV-1–infected pediatric subjects were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean Cmax is higher in pediatrics, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see Use in Specific Populations (8.4)].

Table 10. Summary of Pharmacokinetic Parameters in Pediatric HIV-1–Infected Subjects (Pooled Analyses for IMPAACT P1093 and ODYSSEYa Trials)
a Data from 2 weight-band-based pharmacokinetic substudies in the ODYSSEY trial.b The bioavailability of TIVICAY PD tablets for oral suspension is ~1.6-fold that of TIVICAY tablets.

Weight Band

Doseb of TIVICAY or TIVICAY PD

n

Pharmacokinetic Parameter Geometric Mean (%CV)

Cmax (mcg/mL)

AUC0-24h (mcg∙h/mL)

C24h (ng/mL)

3 kg to <6 kg

TIVICAY PD5 mg once daily

8

3.80 (34)

49.37 (49)

962 (98)

6 kg to <10 kg

TIVICAY PD15 mg once daily

17

5.27 (50)

57.17 (76)

706 (177)

10 kg to <14 kg

TIVICAY PD20 mg once daily

13

5.99 (33)

68.75 (48)

977 (100)

14 kg to <20 kg

TIVICAY PD25 mg once daily

19

5.97 (42)

58.97 (44)

725 (75)

20 kg to <25 kg

TIVICAY PD30 mg once daily

9

7.16 (26)

71.53 (26)

759 (73)

≥20 kg

TIVICAY50 mg once daily

49

4.92 (40)

54.98 (43)

778 (62)

Geriatric Patients: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.

Patients with Hepatic Impairment: In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.

Patients with Renal Impairment: In a trial evaluating the pharmacokinetics of a single 50-mg tablet of dolutegravir comparing 8 subjects with severe renal impairment (CrCl less than 30 mL per min) with 8 matched healthy controls, AUC, Cmax , and C24 of dolutegravir were lower by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

HBV or HCV Co-infected Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection.

Gender and Race: Population analyses using pooled pharmacokinetic data from adult trials indicated gender and race had no clinically relevant effect on the exposure of dolutegravir.

Drug Interaction Studies

Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered drugs are summarized in Table 11 and the effects of coadministered drugs on the exposure of dolutegravir are summarized in Table 12.

Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 8[see Dosage and Administration (2.2), Drug Interactions (7.3)].

Table 11. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs
a The number of subjects represents the maximum number of subjects that were evaluated.

Coadministered Drug(s)

and Dose(s)

Dose of TIVICAY

n

Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00

Cmax

AUC

Cτ or C24

Daclatasvir 60 mg once daily

50 mgonce daily

12

1.03(0.84 to 1.25)

0.98(0.83 to 1.15)

1.06(0.88 to 1.29)

Elbasvir

50 mg once daily

50 mg

single dose

12

0.97

(0.89, 1.05)

0.98

(0.93, 1.04)

0.98

(0.93, 1.03)

Ethinyl estradiol 0.035 mg

50 mgtwice daily

15

0.99(0.91 to 1.08)

1.03(0.96 to 1.11)

1.02(0.93 to 1.11)

Grazoprevir

200 mg once daily

50 mg

single dose

12

0.64

(0.44, 0.93)

0.81

(0.67, 0.97)

0.86

(0.79, 0.93)

Metformin 500 mg twice daily

50 mgonce daily

15a

1.66(1.53 to 1.81)

1.79(1.65 to 1.93)

_

Metformin 500 mg twice daily

50 mgtwice daily

15a

2.11(1.91 to 2.33)

2.45(2.25 to 2.66)

_

Methadone 16 to 150 mg

50 mgtwice daily

11

1.00(0.94 to 1.06)

0.98(0.91 to 1.06)

0.99(0.91 to 1.07)

Midazolam 3 mg

25 mgonce daily

10

_

0.95(0.79 to 1.15)

_

Norelgestromin 0.25 mg

50 mgtwice daily

15

0.89(0.82 to 0.97)

0.98(0.91 to 1.04)

0.93(0.85 to 1.03)

Rilpivirine 25 mg once daily

50 mgonce daily

16

1.10(0.99 to 1.22)

1.06(0.98 to 1.16)

1.21(1.07 to 1.38)

Sofosbuvir

400 mg once daily

Metabolite (GS-331007)

50 mg

once daily

24

0.88

(0.80, 0.98)

0.92

(0.85, 0.99)

NA

1.01

(0.93, 1.10)

0.99

(0.97, 1.01)

0.99

(0.97, 1.01)

Tenofovir disoproxil fumarate 300 mg once daily

50 mgonce daily

15

1.09(0.97 to 1.23)

1.12(1.01 to 1.24)

1.19(1.04 to 1.35)

Velpatasvir

100 mg once daily

50 mg

once daily

24

0.94

(0.86, 1.02)

0.91

(0.84, 0.98)

0.88

(0.82, 0.94)

Table 12. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir
a The number of subjects represents the maximum number of subjects that were evaluated.b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.c Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.

Coadministered Drug(s)

and Dose(s)

Dose of TIVICAY

n

Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00

Cmax

AUC

Cτ or C24

Atazanavir 400 mg once daily

30 mg once daily

12

1.50(1.40 to 1.59)

1.91(1.80 to 2.03)

2.80(2.52 to 3.11)

Atazanavir/ritonavir 300/100 mg once daily

30 mg once daily

12

1.34(1.25 to 1.42)

1.62(1.50 to 1.74)

2.21(1.97 to 2.47)

Darunavir/ritonavir 600/100 mg twice daily

30 mg once daily

15

0.89(0.83 to 0.97)

0.78(0.72 to 0.85)

0.62(0.56 to 0.69)

Efavirenz 600 mg once daily

50 mgonce daily

12

0.61(0.51 to 0.73)

0.43(0.35 to 0.54)

0.25(0.18 to 0.34)

Elbasvir/grazoprevir

50/200 mg once daily

50 mg

single dose

12

1.22

(1.05, 1.40)

1.16

(1.00, 1.34)

1.14

(0.95, 1.36)

Etravirine 200 mg twice daily

50 mgonce daily

16

0.48(0.43 to 0.54)

0.29(0.26 to 0.34)

0.12(0.09 to 0.16)

Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily

50 mgonce daily

9

0.88(0.78 to 1.00)

0.75(0.69 to 0.81)

0.63(0.52 to 0.76)

Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily

50 mg once daily

8

1.07(1.02 to 1.13)

1.11(1.02 to 1.20)

1.28(1.13 to 1.45)

Fosamprenavir/ritonavir 700 mg/100 mg twice daily

50 mg once daily

12

0.76(0.63 to 0.92)

0.65(0.54 to 0.78)

0.51(0.41 to 0.63)

Lopinavir/ritonavir 400/100 mg twice daily

30 mg once daily

15

1.00(0.94 to 1.07)

0.97(0.91 to 1.04)

0.94(0.85 to 1.05)

Rilpivirine 25 mg once daily

50 mg once daily

16

1.13 (1.06 to 1.21)

1.12 (1.05 to 1.19)

1.22 (1.15 to 1.30)

Tenofovir 300 mg once daily

50 mg once daily

15

0.97(0.87 to 1.08)

1.01(0.91 to 1.11)

0.92

(0.82 to 1.04)

Tipranavir/ritonavir 500/200 mg twice daily

50 mg once daily

14

0.54(0.50 to 0.57)

0.41(0.38 to 0.44)

0.24(0.21 to 0.27)

Antacid (MAALOX) simultaneous administration

50 mg single dose

16

0.28(0.23 to 0.33)

0.26(0.22 to 0.32)

0.26(0.21 to 0.31)

Antacid (MAALOX) 2 h after dolutegravir

50 mg single dose

16

0.82(0.69 to 0.98)

0.74(0.62 to 0.90)

0.70(0.58 to 0.85)

Calcium carbonate 1,200 mg simultaneous administration (fasted)

50 mgsingle dose

12

0.63(0.50 to 0.81)

0.61(0.47 to 0.80)

0.61(0.47 to 0.80)

Calcium carbonate 1,200 mg simultaneous administration (fed)

50 mgsingle dose

11

1.07(0.83 to 1.38)

1.09(0.84 to 1.43)

1.08(0.81 to 1.42)

Calcium carbonate 1,200 mg 2 h after dolutegravir

50 mgsingle dose

11

1.00(0.78 to 1.29)

0.94(0.72 to 1.23)

0.90(0.68 to 1.19)

Carbamazepine 300 mg twice daily

50 mg once daily

16a

0.67(0.61 to 0.73)

0.51(0.48 to 0.55)

0.27(0.24 to 0.31)

Daclatasvir 60 mg once daily

50 mg once daily

12

1.29(1.07 to 1.57)

1.33(1.11 to 1.59)

1.45(1.25 to 1.68)

Ferrous fumarate 324 mg simultaneous administration (fasted)

50 mgsingle dose

11

0.43(0.35 to 0.52)

0.46(0.38 to 0.56)

0.44(0.36 to 0.54)

Ferrous fumarate 324 mg simultaneous administration (fed)

50 mgsingle dose

11

1.03(0.84 to 1.26)

0.98(0.81 to 1.20)

1.00(0.81 to 1.23)

Ferrous fumarate 324 mg 2 h after dolutegravir

50 mgsingle dose

10

0.99(0.81 to 1.21)

0.95(0.77 to 1.15)

0.92(0.74 to 1.13)

Multivitamin (One-A-Day) simultaneous administration

50 mgsingle dose

16

0.65(0.54 to 0.77)

0.67(0.55 to 0.81)

0.68(0.56 to 0.82)

Omeprazole 40 mg once daily

50 mg single dose

12

0.92(0.75 to 1.11)

0.97(0.78 to 1.20)

0.95(0.75 to 1.21)

Prednisone 60 mg once daily with taper

50 mg once daily

12

1.06(0.99 to 1.14)

1.11(1.03 to 1.20)

1.17(1.06 to 1.28)

Rifampinb 600 mg once daily

50 mg twice daily

11

0.57(0.49 to 0.65)

0.46(0.38 to 0.55)

0.28(0.23 to 0.34)

Rifampinc 600 mg once daily

50 mg twice daily

11

1.18(1.03 to 1.37)

1.33(1.15 to 1.53)

1.22(1.01 to 1.48)

Rifabutin 300 mg once daily

50 mg once daily

9

1.16(0.98 to 1.37)

0.95(0.82 to 1.10)

0.70(0.57 to 0.87)

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