Dosage & Administration
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Delstrigo Prescribing Information
Severe acute exacerbations of hepatitis B (HBV) have been reported in people with concomitant HIV-1 and HBV who have discontinued lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue DELSTRIGO. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].
DELSTRIGO® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:
- with no prior antiretroviral treatment history, OR
- to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO [see Clinical Studies (14)].
Testing When Initiating and During Treatment with DELSTRIGO
Prior to or when initiating DELSTRIGO, test patients for HBV infection [see Warnings and Precautions (5.2)].
Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.3)].
Recommended Dosage
DELSTRIGO is a fixed-dose combination product containing 100 mg of doravirine (DOR), 300 mg of lamivudine (3TC), and 300 mg of TDF. The recommended dosage of DELSTRIGO in adults and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)].
Renal Impairment
Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
Dosage Adjustment with Rifabutin
If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine 100 mg (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO for the duration of rifabutin co-administration [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
DELSTRIGO film-coated tablets are yellow, oval-shaped tablets, debossed with the corporate logo and 776 on one side and plain on the other side. Each tablet contains 100 mg doravirine, 300 mg lamivudine, and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
There is insufficient prospective pregnancy data from the APR to adequately assess the risk of birth defects and miscarriage. Doravirine use in individuals during pregnancy has not been evaluated; however, lamivudine and TDF use during pregnancy has been evaluated in a limited number of individuals reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for lamivudine and TDF compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.
In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose.
No adverse developmental effects were observed when doravirine and TDF were administered separately at doses/exposures ≥8 (doravirine) and ≥14 (TDF) times those of the recommended human dose (RHD) of DELSTRIGO (see Data).
Data
Human Data
Lamivudine: The APR has received a total of over 13,000 prospective reports with follow-up data of possible exposure to lamivudine-containing regimens; over 5,900 reports in the first trimester; over 5,600 reports in the second trimester; and over 1,800 reports in the third trimester. Birth defects occurred in 170 of 5,472 (3.1%, 95% CI: 2.7% to 3.6%) live births for lamivudine-containing regimens (first trimester exposure); and 218 of 7,513 (2.9%, 95% CI: 2.5% to 3.3%) live births for lamivudine-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between lamivudine and overall birth defects observed in the APR.
TDF: The APR has received a total of over 7,000 prospective reports with follow-up data of possible exposure to tenofovir disoproxil-containing regimens; over 5,100 reports in the first trimester; over 1,300 reports in the second trimester; and over 600 reports in the third trimester. Birth defects occurred in 113 of 4,576 (2.5%, 95% CI: 2.0% to 3.0%) live births for TDF-containing regimens (first trimester exposure); and 51 of 1,965 (2.6%, 95% CI: 1.9% to 3.4%) live births for TDF-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between tenofovir and overall birth defects observed in the APR.
Animal Data
Doravirine: Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20.
Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on GD 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at system exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.
TDF: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of harm to the fetus.
Lactation
Risk Summary
Based on limited published data, both lamivudine and tenofovir are present in human milk. It is unknown whether doravirine is present in human milk, but doravirine is present in the milk of lactating rats (see Data). It is not known whether DELSTRIGO or the components of DELSTRIGO affects human milk production, or has effects on the breastfed infant. Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults.
Data
Doravirine: Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from GD 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14.
Pediatric Use
The safety and efficacy of DELSTRIGO for the treatment of HIV-1 infection have been established in pediatric patients weighing at least 35 kg [see Indications and Usage (1) and Dosage and Administration (2.2)].
Use of DELSTRIGO in this group is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, safety, and efficacy data from an open-label trial in virologically-suppressed or treatment-naïve pediatric participants 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric participants were similar to that in adults, and there was no clinically significant difference in exposure for the components of DELSTRIGO. [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].
Safety and efficacy of DELSTRIGO in pediatric patients weighing less than 35 kg have not been established.
Geriatric Use
Clinical trials of doravirine, lamivudine, or TDF did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants. In general, caution should be exercised in the administration of DELSTRIGO 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)].
Renal Impairment
Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF, both components of DELSTRIGO, cannot be altered, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
Hepatic Impairment
No dosage adjustment of DELSTRIGO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. DELSTRIGO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].
- DELSTRIGO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO [see Warnings and Precautions (5.4), Drug Interactions (7.2), and Clinical Pharmacology (12.3)]. These drugs include, but are not limited to, the following:
- -
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- -
- the androgen receptor inhibitor enzalutamide
- -
- the antimycobacterials rifampin, rifapentine
- -
- the cytotoxic agent mitotane
- -
- St. John's wort (Hypericum perforatum)
- DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.