DRUG INTERACTIONS- summary

 x See full prescribing information for complete list of significant drug interactions. 

x Doses of oral contraceptives should not contain more than 30 mcg of ethinyl estradiol per day. 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  27

 ADVERSE REACTIONS

 The most common adverse reaction (all grades) observed in ?5% of subjects was nausea. 

x QTc prolongation: Use RUKOBIA with caution in patients with a history of QTc prolongation or with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. 

x Elevations in hepatic transaminases in patients with hepatitis B or C virus co-infection: Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. 

 INDICATIONS AND USAGE

 RUKOBIA, a human immunodeficiency virus type 1 (HIV-1) gp120-directed attachment inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. 

DOSAGE AND ADMINISTRATION                                                                                  One tablet taken twice daily with or without food. 

 DOSAGE FORMS AND STRENGTHS                                                                           - Extended-release tablets: 600 mg 

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions-

Inform patients that if they have had a hypersensitivity reaction to RUKOBIA or any of its components, they should not take RUKOBIA [see Contraindications (4)].

Immune Reconstitution Syndrome-

Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection, as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when RUKOBIA is started.

QTc Interval Prolongation -

Advise patients that RUKOBIA may produce changes in their electrocardiogram (i.e., QT prolongation).

Instruct patients to consult their healthcare provider if they experience symptoms  such as dizziness, lightheadedness, abnormal heart rhythm, or loss of consciousness .

Patients with Hepatitis B or C Virus- Co-infection-

Advise patients that it is recommended to have laboratory testing and to take medications for HBV or HCV as prescribed .

Drug Interactions-

RUKOBIA may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort ].

Pregnancy Registry -

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to RUKOBIA during pregnancy..

Lactation Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk .

 Potential Odor of Tablets-                                                                                         RUKOBIA tablets may have a slight vinegar-like odor .

Missed Dosage

Advise patients to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss a dose of RUKOBIA, to take it as soon as they remember.

Advise patients not to double their next dose or take more than the prescribed dose 

Trademark is owned by or licensed to the ViiV Healthcare group of companies

Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709 by: GlaxoSmithKline Research Triangle Park, NC 27709 28 Reference ID: 4635448 ©2020 ViiV Healthcare group of companies or its licensor. RK

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action RUKOBIA is an HIV-1 antiretroviral agent [see Microbiology (12.4)].

12.2 Pharmacodynamics Cardiac Electrophysiology At therapeutic doses, RUKOBIA does not prolong the QT interval to any clinically relevant extent. At 4 times the recommended dose, the mean (upper 90% confidence interval) QTcF increase was 11.2 milliseconds (13.3 milliseconds). The observed increase in QTcF was temsavir concentration-dependent [see Warnings and Precautions (5.2)].

Exposure-Response Relationship In the Phase 3 trial evaluating the recommended dosing regimen of RUKOBIA (600 mg twice daily) in subjects with multidrug resistant HIV-1 infection on their failing regimen, no relationship was observed between plasma temsavir Ctrough and change in plasma HIV-1 RNA from Day 1 to Day 8.

12.3 Pharmacokinetics Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed (Table 4). Following oral administration, increases in plasma temsavir exposure (Cmax and AUCtau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV-1–infected subjects.

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of temsavir following administration of RUKOBIA are provided in Table 4. The multiple-dose pharmacokinetic parameters are provided in Table 5. 12 Reference ID: 4635448 Table 4. Pharmacokinetic Properties of Temsavir

Absorption % Absolute bioavailabilitya 26.9 Tmax (h) 2.0 Effect of standard meal (relative to fasting) b AUC ratio =1.10 (0.95, 1.26) Effect of high-fat meal (relative to fasting) b AUC ratio =1.81 (1.54, 2.12)

Distribution % Plasma protein binding 88.4 (primarily to HSA) Blood-to-plasma ratio 0.74 Steady-state volume of distribution (Vss, L)c 29.5

Elimination Major route of elimination Metabolism Clearance (CL and CL/F d , L/h) 17.9 and 66.4 Half-life (h) 11

Metabolism Metabolic pathwayse Hydrolysis (esterases) [36.1% of oral dose] Oxidation (CYP3A4) [21.2% of oral dose] UGT [<1% of oral dose]

Excretion % of dose excreted in urine (unchanged drug) f 51 (<2) % of dose excreted in feces (unchanged drug) f 33 (1.1) HSA = Human Serum Albumin; UGT = Uridine diphosphate glucuronosyl transferases.

a Dosing in absolute bioavailability study: single-dose administration of fostemsavir extendedrelease tablet 600 mg followed by single IV infusion of [13C] temsavir 100 mcg. b Geometric mean ratio (fed/fasted) in pharmacokinetic parameters and (90% confidence interval). Standard meal = ~423 kcal, 36% fat, 47% carbohydrates, and 17% protein. Highcalorie/high-fat meal = ~985 kcal, 60% fat, 28% carbohydrates, and 12% protein. c Volume of distribution at steady state (Vss) following IV administration. d Apparent clearance. e In vitro studies have shown that temsavir is biotransformed into 2 predominant circulating inactive metabolites: BMS-646915 (hydrolysis metabolite) and BMS-930644 (N-dealkylated metabolite). f Dosing in mass balance study: single-dose administration of [14C] fostemsavir oral solution 300 mg containing 100 microCi (3.7 MBq) of total radioactivity. 13 Reference ID: 4635448 Table 5. Multiple-Dose Pharmacokinetic Parameters of Temsavir Parameter Mean (CV%) Temsavira Cmax (ng/mL) 1,770 (39.9) AUCtau (ng.h/mL) 12,900 (46.4) Ctrough or C12 (ng/mL) 478 (81.5) CV = Coefficient of Variation; Cmax = Maximum concentration; AUC = Area under the time concentration curve; C12 = Concentration at 12 hours. a Based on population pharmacokinetic analyses in heavily treatment-experienced adult subjects with HIV-1 infection receiving 600 mg of RUKOBIA twice daily with or without food in combination with other antiretroviral drugs.

Specific Populations No clinically significant differences in the pharmacokinetics of temsavir were observed based on age, sex, race/ethnicity (white, black/African American, Asian, or other). The effect of hepatitis B and/or C virus co-infection on the pharmacokinetics of temsavir is unknown. The pharmacokinetics of temsavir has not been studied in pediatric subjects and data are limited in subjects aged 65 years or older. Population pharmacokinetic analyses of subjects with HIV-1 infection aged up to 73 years from studies with RUKOBIA indicated age had no clinically relevant effect on the pharmacokinetics of temsavir [see Use in Specific Populations (8.4, 8.5)].

Patients with Renal Impairment: No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe renal impairment. No clinically relevant differences in temsavir pharmacokinetics were observed in patients with end-stage renal disease (ESRD) on hemodialysis compared with the same patients with ESRD off hemodialysis. Temsavir was not readily cleared by hemodialysis with approximately 12.3% of the administered dose removed during the 4-hour hemodialysis session [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: No clinically relevant differences in total and unbound temsavir pharmacokinetics were observed in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C) [see Use in Specific Populations (8.7)].

Drug Interaction Studies Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Drugs that induce or inhibit CYP3A, P-gp, and BCRP may affect temsavir plasma concentrations. Coadministration of fostemsavir with drugs that are strong CYP3A inducers result in decreased concentrations of temsavir. Coadministration of fostemsavir with drugs that are moderate CYP3A inducers and/or strong CYP3A, P-gp and/or BCRP inhibitors are not likely to have a clinically relevant effect on the plasma concentrations of temsavir. 14 Reference ID: 4635448 Temsavir is an inhibitor of OATP1B1 and OATP1B3. Additionally, temsavir and 2 metabolites (Table 4) are inhibitors of BCRP. Thus, temsavir is expected to affect the pharmacokinetics of drugs that are substrates of OATP1B1/3 and/or BCRP [see Drug Interactions (7.3)]. At clinically relevant concentrations, significant interactions are not expected when RUKOBIA is coadministered with substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 2D6, and 3A4; UGT1A1, 1A4, 1A6, 1A9, 2B7; P-gp; multidrug resistance protein (MRP)2; bile salt export pump (BSEP); sodium taurocholate co-transporting polypeptide (NTCP); multidrug and toxin extrusion protein (MATE)1/2K; organic anion transporters (OAT)1 and OAT3; organic cation transporters (OCT)1 and OCT2 based on in vitro and clinical drug interaction results (Table 6). Drug interaction studies were performed with RUKOBIA and other drugs likely to be coadministered for pharmacokinetic interactions. The effects of temsavir on the pharmacokinetics of coadministered drugs are summarized in Table 6 and the effects of coadministration of other drugs on the pharmacokinetics of temsavir are summarized in Table 7. Dosing recommendations as a result of established and other potentially significant drug-drug interactions with RUKOBIA are provided in Table 3 [see Drug Interactions (7.3)]. Table 6. Effect of Fostemsavira on the Pharmacokinetics of Coadministered Drugs Coadministered Drug(s) and Dose(s) Dose of RUKOBIA n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drugs with/without RUKOBIA No Effect = 1.00 Cmax AUC Ctau Atazanavir + Ritonavir 300 mg once daily/ 100 mg once daily 600 mg twice daily 18 1.03 (0.96, 1.10) 1.02 (0.96, 1.09) 1.09 (1.03, 1.15) 1.07 (1.03, 1.10) 1.19 (1.10, 1.30) 1.22 (1.12, 1.32) Darunavir + Ritonavir 600 mg twice daily/ 100 mg twice daily 600 mg twice daily 13 0.98 (0.93, 1.04) 1.00 (0.86, 1.16) 0.94 (0.89, 1.00) 1.15 (0.99, 1.33) 0.95 (0.87, 1.04) 1.19 (1.06, 1.35) Darunavir + Ritonavir + Etravirine 600 mg twice daily/ 100 mg twice daily/ 200 mg twice daily 600 mg twice daily 13 0.95 (0.90, 1.01) 1.14 (0.96, 1.35) 1.18 (1.10, 1.27) 0.94 (0.89, 0.99) 1.09 (0.98, 1.22) 1.28 (1.20, 1.36) 0.88 (0.77, 1.01) 1.07 (0.97, 1.17) 1.28 (1.18, 1.39) Etravirine 200 mg twice daily 600 mg twice daily 14 1.11 (1.04, 1.19) 1.11 (1.05, 1.17) 1.14 (1.08, 1.21) Tenofovir disoproxil fumarate 300 mg once daily 600 mg twice daily 18 1.18 (1.12, 1.25) 1.19 (1.12, 1.25) 1.28 (1.20, 1.38) 15 Reference ID: 4635448 Rosuvastatin 10-mg single dose 600 mg twice daily 18 1.78 (1.52, 2.09) 1.69 (1.44, 1.99) NA Ethinyl estradiol/ Norethindrone 0.030 mg once daily/ 1.5 mg once daily 600 mg twice daily 26 1.39 (1.28, 1.51) 1.08 (1.01, 1.16) 1.40 (1.29, 1.51) 1.08 (1.03, 1.14) NA NA Maravir

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of RUKOBIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures (see Data). The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. Data Animal Data: Fostemsavir was administered orally to pregnant rats (50, 200, 600 mg/kg/day) and rabbits (25, 50, or 100 mg/kg/day) during Gestation Days 6 to 15 (rat) and 7 to 19 (rabbit). No fetal abnormalities were observed at temsavir exposures of approximately 180 (rat) and 30 (rabbit) times those in humans at the maximum recommended human dose (MRHD). In rabbits, increased embryonic death associated with maternal toxicity was observed at temsavir exposures approximately 60 times those in humans at the MRHD. In a separate rat study conducted at drug exposures approximately 200 times those in humans at the MRHD, fetal abnormalities (cleft 9 Reference ID: 4635448 palate, open eyes, shortened snout, microstomia, misaligned mouth/jaw, and protruding tongue) and reductions in fetal body weights occurred in the presence of maternal toxicity. In a rat pre- and postnatal development study, fostemsavir was administered orally at doses of 10, 50, or 300 mg/kg/day from Gestation Day 6 through Lactation Day 20. Reduced neonatal survival (7 to 14 days after birth) in the absence of other adverse fetal or neonatal effects was observed at maternal temsavir exposures approximately 130 times those in humans at the MRHD. No adverse fetal or neonatal effects were observed at maternal temsavir exposures approximately 35 times those in humans at the MRHD. In a distribution study in pregnant rats, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) crossed the placenta and were detectable in fetal tissue. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether RUKOBIA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk (see Data). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving RUKOBIA. Data In a distribution study, fostemsavir-related drug materials (i.e., temsavir and/or temsavir-derived metabolites) were excreted in rat milk following a single dose of fostemsavir administered to lactating rats 7 to 9 days postpartum. In the pre- and postnatal development study in rats, temsavir was present in milk at concentrations similar to those measured in maternal plasma, as determined 11 days postpartum. In addition, lactational exposure was associated with reduced offspring survival at maternal temsavir exposures not thought to be clinically relevant. 8.4 Pediatric Use The safety and effectiveness of RUKOBIA have not been established in pediatric patients. 8.5 Geriatric Use Clinical trials of RUKOBIA 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 administration of RUKOBIA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy 10 Reference ID: 4635448 [see Clinical Pharmacology (12.3)]. Elderly patients may be more susceptible to drug-induced QT interval prolongation [see Warnings and Precautions (5.2)]. 8.6 Renal Impairment No dosage adjustment is required for patients with renal impairment or those on hemodialysis [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment is required in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C) [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no known specific treatment for overdose with RUKOBIA. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 11 DESCRIPTION Fostemsavir tromethamine