ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1)] New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2)] Bone Loss and Mineralization Defects [see Warnings and Precautions (5.4)] Immune Reconstitution Syndrome [see Warnings and Precautions (5.5)] Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1)] New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2)] Bone Loss and Mineralization Defects [see Warnings and Precautions (5.4)] Immune Reconstitution Syndrome [see Warnings and Precautions (5.5)] Most common adverse reactions (incidence greater than or equal to 5%, all grades) are dizziness, nausea, and abnormal dreams. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions in Adults with No Antiretroviral Treatment HistoryThe safety assessment of DELSTRIGO is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials. total of 747 subjects received doravirine either as the single entity in combination with other antiretroviral drugs as background regimens (n=383) or as the fixed-dose DELSTRIGO (n=364), and total of 747 subjects were randomized to control arms.In DRIVE-AHEAD (Protocol 021), 728 adult subjects received either DELSTRIGO (n=364) or EFV/FTC/TDF once daily (n=364). By Week 96, 3% in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication.Adverse reactions reported in greater than or equal to 5% of subjects in any treatment group in DRIVE-AHEAD are presented in Table 1.Table 1: Adverse ReactionsFrequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. (All Grades) Reported in >=5%No adverse reactions of Grade or higher (moderate or severe) occurred in >=2% of subjects treated with DELSTRIGO. of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 96)DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364Dizziness7%32%Nausea5%7%Abnormal Dreams5%10%Headache4%5%Insomnia4%5%Diarrhea4%6%Somnolence3%7%RashRash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic. 2%12%The majority (66%) of adverse reactions associated with DELSTRIGO occurred at severity Grade (mild).. Neuropsychiatric Adverse EventsFor DRIVE-AHEAD, the analysis of subjects with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of subjects who reported one or more neuropsychiatric adverse events was 24% and 57% in the DELSTRIGO and EFV/FTC/TDF groups, respectively.A statistically significantly lower proportion of DELSTRIGO-treated subjects compared to EFV/FTC/TDF-treated subjects reported neuropsychiatric adverse events by Week 48 in the three pre-specified categories of dizziness, sleep disorders and disturbances, and altered sensorium.Table 2: DRIVE-AHEAD Analysis of Subjects with Neuropsychiatric Adverse EventsAll causality and all grade events were included in the analysis. (Week 48)DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364Treatment Difference(DELSTRIGO EFV/FTC/TDF)Estimate (95% CI)The 95% CIs were calculated using Miettinen and Nurminens method. Categories pre-specified for statistical testing were dizziness (p <0.001), sleep disorders and disturbances (p <0.001), and altered sensorium (p=0.033). Sleep disorders and disturbancesPredefined using MedDRA preferred terms including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism. 12%26%-13.5 (-19.1, -7.9)Dizziness9%37%-28.3 (-34.0, -22.5)Altered sensoriumPredefined using MedDRA preferred terms including: altered state of consciousness, lethargy, somnolence, syncope. 4%8%-3.8 (-7.6, -0.3)Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of subjects, in the DELSTRIGO and EFV/FTC/TDF groups, respectively.In DRIVE-AHEAD through 48 weeks of treatment, the majority of subjects who reported neuropsychiatric adverse events reported events that were mild to moderate in severity (97% [83/86] and 96% [198/207], in the DELSTRIGO and EFV/FTC/TDF groups, respectively) and the majority of subjects reported these events in the first weeks of treatment (72% [62/86] in the DELSTRIGO group and 86% [177/207] in the EFV/FTC/TDF group).Neuropsychiatric adverse events led to treatment discontinuation in 1% (2/364) and 1% (5/364) of subjects in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of subjects who reported neuropsychiatric adverse events through Week was 17% (62/364) in the DELSTRIGO group and 49% (177/364) in the EFV/FTC/TDF group. At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. At Week 96, the prevalence of neuropsychiatric adverse events was 13% (47/364) in the DELSTRIGO group and 23% (82/364) in the EFV/FTC/TDF group.. Laboratory AbnormalitiesThe percentages of subjects with selected laboratory abnormalities (that represent worsening from baseline) who were treated with DELSTRIGO or EFV/FTC/TDF in DRIVE-AHEAD are presented in Table 3.Table 3: Selected Laboratory Abnormalities Reported in Adult Subjects with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 96)Laboratory Parameter Preferred Term (Unit)/LimitDELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364Blood ChemistryEach subject is only counted once per parameter at the highest toxicity grade. Only subjects with baseline value and at least one on-treatment value for given laboratory parameter are included.ULN Upper limit of normal range.Total bilirubin1.1 <1.6 ULN5%0%1.6 <2.6 ULN2%0%>=2.6 ULN1%<1%Creatinine (mg/dL)>1.3 1.8 ULN or Increase of >0.3 mg/dL above baseline3%2%>1.8 ULN or Increase of >=1.5 above baseline3%2%Aspartate aminotransferase (IU/L)2.5 <5.0 ULN3%3%>=5.0 ULN1%4%Alanine aminotransferase (IU/L)2.5 <5.0 ULN4%4%>=5.0 ULN1%3%Alkaline phosphatase (IU/L)2.5 <5.0 ULN<1%1%>=5.0 ULN0%<1%Lipase1.5 <3.0 ULN6%4%>=3.0 ULN2%3%Creatine kinase (IU/L)6.0 <10.0 ULN3%3%>=10.0 ULN4%6%Cholesterol, fasted (mg/dL)>=300 mg/dL1%<1%LDL cholesterol, fasted (mg/dL)>=190 mg/dL<1%2%Triglycerides, fasted (mg/dL)>500 mg/dL1%3%. Change in Lipids from BaselineFor DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. Changes from baseline at Week 96 were similar to findings at Week 48.The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority of DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated.Table 4: Mean Change from Baseline in Fasting Lipids in Adult Subjects with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 48)Laboratory Parameter Preferred TermDELSTRIGOOnce DailyN=320EFV/FTC/TDFOnce DailyN=307Difference Estimates(DELSTRIGO EFV/FTC/TDF)BaselineChangeBaselineChangeDifference (95% CI)Subjects on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=15 and EFV/FTC/TDF n=10).Subjects initiating lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=3 and EFV/FTC/TDF n=8).LDL-Cholesterol (mg/dL)P-value for the pre-specified hypothesis testing for treatment difference was <0.0001. 91.7-2.191.38.3-10.2 (-13.8, -6.7)Non-HDL Cholesterol (mg/dL) 114.7-4.1115.312.7-16.9 (-20.8, -13.0)Total Cholesterol (mg/dL)Not pre-specified for hypothesis testing. 156.8-2.2156.821.1-Triglycerides (mg/dL) 118.7-12.0122.621.6-HDL-Cholesterol (mg/dL) 42.11.841.68.4-. Adverse Reactions in Virologically-Suppressed AdultsThe safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from 670 subjects in the DRIVE-SHIFT trial (Protocol 024), randomized, international, multicenter, open-label trial in which virologically-suppressed subjects were switched from baseline regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with protease inhibitor (PI) plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no antiretroviral treatment history.. Laboratory Abnormalities. Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of subjects in the immediate switch group experienced ALT and AST elevations of greater than 1.25 ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent time patterns with regard to time to onset relative to switch were observed. One percent of subjects had ALT or AST elevations greater than x ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic, and not associated with bilirubin elevations. In comparison, 4% and 4% of subjects in the delayed switch group experienced ALT and AST elevations of greater than 1.25 ULN through 24 weeks on their baseline regimen.. Change in Lipids from BaselineChanges from baseline at Week 24 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol in subjects on PI plus ritonavir-based regimen at baseline are shown in Table 5. The LDL and non-HDL comparisons were pre-specified, and the differences were statistically significant, showing superiority for an immediate switch to DELSTRIGO for both parameters. The clinical benefit of these findings has not been demonstrated.Table 5: Mean Change from Baseline in Fasting Lipids in Adult Virologically-Suppressed Subjects on PI plus Ritonavir-based Regimen at Baseline in DRIVE-SHIFT (Week 24)Laboratory Parameter Preferred TermDELSTRIGO(Week 0-24)Once DailyN=244PI+ritonavir(Week 0-24)Once DailyN=124Difference EstimatesBaselineChangeBaselineChangeDifference (95% CI)Subjects on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=26 and PI+ritonavir n=13). Subjects initiating lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (DELSTRIGO n=4 and PI+ritonavir n=2).LDL-Cholesterol (mg/dL)P-value for the pre-specified hypothesis testing for treatment difference was <0.0001. 108.7-16.3110.5-2.6-14.5 (-18.9, -10.1)Non-HDL Cholesterol (mg/dL) 138.6-24.8138.8-2.1-22.8 (-27.9, -17.7)Total Cholesterol (mg/dL)Not pre-specified for hypothesis testing. 188.5-26.1187.4-0.2-Triglycerides (mg/dL) 153.1-44.4151.4-0.4-HDL-Cholesterol (mg/dL) 50.0-1.348.51.9-Adverse Reactions in Pediatric PatientsThe safety of DELSTRIGO was evaluated in 45 HIV-1-infected virologically-suppressed or treatment-naive pediatric patients 12 to less than 18 years of age through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) [see Clinical Studies (14.3)]. The safety profile in pediatric subjects was similar to that in adults. There were no serious or Grade or adverse reactions. No subjects discontinued due to an adverse event.. 6.2Postmarketing Experience. The following adverse reactions have been identified during postmarketing experience in patients receiving lamivudine- or TDF-containing regimens. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Lamivudine:Body as Whole: redistribution/accumulation of body fatEndocrine and Metabolic: hyperglycemiaGeneral: WeaknessHemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy)Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbations of hepatitis BHypersensitivity: anaphylaxis, urticariaMusculoskeletal: muscle weakness, CPK elevation, rhabdomyolysisSkin: alopecia, pruritus. TDF:Immune System Disorders: allergic reaction, including angioedemaMetabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemiaRespiratory, Thoracic, and Mediastinal Disorders: dyspneaGastrointestinal Disorders: pancreatitis, increased amylase, abdominal painHepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)Skin and Subcutaneous Tissue Disorders: rashMusculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathyRenal and Urinary Disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuriaGeneral Disorders and Administration Site Conditions: astheniaThe following adverse reactions, listed under the body system headings above, may occur as consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

BOXED WARNING SECTION.

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and 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 therapy may be warranted [see Warnings and Precautions (5.1)].. WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning.Severe acute exacerbations of hepatitis (HBV) have been reported in patients coinfected with HIV-1 and HBV who have discontinued lamivudine or tenofovir disoproxil fumarate (TDF), two of the components of DELSTRIGO. Closely monitor hepatic function in these patients. If appropriate, initiation of anti-hepatitis therapy may be warranted. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Doravirine: Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to and times, respectively, the human exposures at the RHD. statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls.. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the RHD.. TDF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and times (rats) those observed in humans at the RHD. At the high dose in female mice, liver adenomas were increased at exposures 16 times of that in humans. In rats, the study was negative for carcinogenic findings at exposures up to times that observed in humans at the RHD.. Mutagenesis. Doravirine: Doravirine was not genotoxic in battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays.. Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection.. TDF: TDF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.. Impairment of Fertility. Doravirine: There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to the highest dose tested. Systemic exposures (AUC) to doravirine were approximately times the exposure in humans at the RHD.. Lamivudine: In study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.. TDF: There were no effects on fertility, mating performance or early embryonic development when TDF was administered to male rats at dose equivalent to 10 times the RHD based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day of gestation. There was, however, an alteration of the estrous cycle in female rats.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. DELSTRIGO is fixed-dose combination of the antiretroviral drugs doravirine, lamivudine, and TDF [see Microbiology (12.4)]. 12.2 Pharmacodynamics. In Phase trial evaluating doravirine over dose range of 0.25 to times the recommended dose of doravirine in DELSTRIGO (in combination with FTC/TDF) in HIV-1-infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine.. Cardiac ElectrophysiologyAt doravirine dose of 1200 mg, which provides approximately times the peak concentration observed following the recommended dose of doravirine in DELSTRIGO does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. Single-dose administration of one DELSTRIGO tablet to healthy subjects provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus TDF tablets (300 mg). Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Pharmacokinetic properties of the components of DELSTRIGO are provided in Table 7.Table 7: Pharmacokinetic Properties of the Components of DELSTRIGOParameterDoravirineLamivudineTenofovirAbbreviations: NA=not available; AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax=time to Cmax; Vdss=apparent volume of distribution at steady state; t1/2=elimination half-life; CL/F=apparent clearance; CLrenal renal clearanceGeneral Steady State ExposurePresented as geometric mean (%CV: geometric coefficient of variation) or mean +- SD. AUC0-24 (mcgh/mL)16.1 (29)Doravirine 100 mg once daily to HIV-1-infected subjects. 8.87 +- 1.83Lamivudine 300 mg once daily for days to 60 healthy subjects. 2.29 +- 0.69Single 300 mg dose of TDF to HIV-1-infected subjects in the fasted state. Cmax (mcg/mL)0.962 (19) 2.04 +- 0.54 0.30 +- 0.09 C24 (mcg/mL)0.396 (63) NANAAbsorptionAbsolute Bioavailability64%86%25%Tmax (h)2NA1 Effect of FoodGeometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1000 kcal, 50% fat. The effect of food is not clinically relevant. AUC Ratio1.10 (1.01, 1.20)0.93 (0.84, 1.03)1.27 (1.17, 1.37)Cmax Ratio0.95 (0.80, 1.12)0.81 (0.65, 1.01)0.88 (0.74, 1.04)C24 Ratio1.26 (1.13, 1.41)NANADistribution Vdss Based on IV dose. 60.5 L1.3 L/kg1.3 L/kgPlasma Protein Binding76%< 36%<0.7%Eliminationt1/2 (h)155-717CL/F (mL/ min) 106 (35.2)398.5 +- 69.11,043.7 +- 115.4CLrenal (mL/ min) 9.3 (18.6)199.7 +- 56.9243.5 +- 33.3 MetabolismPrimary Pathway(s)CYP3AMinorNo CYP Metabolism ExcretionMajor route of eliminationMetabolismGlomerular filtration and active tubular secretionGlomerular filtration and active tubular secretionUrine (unchanged)6%71%70-80%Biliary/Fecal (unchanged)MinorNANA. Specific PopulationsIn adults, no clinically significant differences in the pharmacokinetics of certain DELSTRIGO components were observed based on age >=65 years (for doravirine), sex (for doravirine, lamivudine, tenofovir), and race/ethnicity (for doravirine, lamivudine). The effects of age (>=65 years) on the pharmacokinetics of lamivudine and tenofovir, and the effect of race on the pharmacokinetics of tenofovir are unknown.. Patients with Renal Impairment. Doravirine: No clinically significant difference in the pharmacokinetics of doravirine were observed in subjects with mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault). Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.. Lamivudine: The AUCinf, Cmax, and half-life of lamivudine increased and CL/F decreased to clinically significant extent with diminishing renal function (CLcr 111 to 10 mL/min).. TDF: clinically significant increase in the Cmax and AUC of tenofovir was observed in subjects with CLcr 50 mL/min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].. Patients with Hepatic Impairment. Doravirine: No clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).. Lamivudine: No clinically significant differences in lamivudine pharmacokinetics were observed with diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.. TDF: No clinically significant differences in tenofovir pharmacokinetics were observed between subjects with any degree of hepatic impairment and healthy subjects.. Pediatric PatientsMean doravirine exposures were similar in 54 pediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO. Exposures of lamivudine and tenofovir in pediatric patients following the administration of DELSTRIGO were similar to those in adults following administration of lamivudine and tenofovir (Table 8). For pediatric patients weighing >= 35 kg and 45 kg who receive doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0-24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0-24 and Cmax increases are not considered clinically significant.Table 8: Steady State Pharmacokinetics for Doravirine, Lamivudine, and Tenofovir Following Administration of Doravirine or DELSTRIGO in HIV-1-Infected Pediatric Patients Aged 12 to Less than 18 Years and Weighing at Least 35 kgParameterPresented as geometric mean (%CV: geometric coefficient of variation) DoravirineFrom population PK analysis (n=53 weighing >=45 kg, n=1 weighing >=35 kg to <45 kg) LamivudineFrom intensive PK analysis (n=10) Tenofovir Abbreviations: NA=not applicable; AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hoursAUC0-24 (mcgoh/mL)16.4 (24)11.3 (28)2.55 (14)Cmax (mcg/mL)1.03 (16)2.1 (24)0.293 (37)C24 (mcg/mL)0.379 (42)NANA. Drug Interaction StudiesDELSTRIGO is complete regimen for the treatment of HIV-1 infection; therefore, DELSTRIGO is not recommended to be administered with other HIV-1 antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided.The drug interaction trials described were conducted with doravirine, lamivudine and/or TDF, as single entities; no drug interaction trials have been conducted using the combination of doravirine, lamivudine, and TDF. No clinically relevant drug interactions were observed between doravirine, lamivudine, and TDF.. Doravirine: Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine.Doravirine is not likely to have clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (Cmax, AUC, and C24) of doravirine are summarized in Table 9. single doravirine 100 mg dose was administered in these studies unless otherwise noted.Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered DrugCo-administered DrugRegimen of Co-administered DrugNGeometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00)AUCAUC0- for single-dose, AUC0-24 for once daily. Cmax C24 CI confidence interval; QD once daily; BID twice dailyAzole Antifungal AgentsketoconazoleChanges in doravirine pharmacokinetic values are not clinically relevant. 400 mg QD103.06 (2.85, 3.29)1.25 (1.05, 1.49)2.75 (2.54, 2.98)Antimycobacterialsrifampin600 mg QD100.12 (0.10, 0.15)0.43 (0.35, 0.52)0.03 (0.02, 0.04)rifabutin300 mg QD120.50 (0.45, 0.55)0.99 (0.85, 1.15)0.32 (0.28, 0.35)300 mg QDDoravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. 151.03 (0.94, 1.14)0.97 (0.87, 1.08)0.98 (0.88, 1.10)HIV Antiviral Agentsritonavir A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. 100 mg BID83.54 (3.04, 4.11)1.31 (1.17, 1.46)2.91 (2.33, 3.62)efavirenz600 mg QDThe first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 170.38 (0.33, 0.45)0.65 (0.58, 0.73)0.15 (0.10, 0.23)600 mg QD14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 170.68 (0.58, 0.80)0.86 (0.77, 0.97)0.50 (0.39, 0.64)Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, ritonavir, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. Lamivudine:. Trimethoprim/Sulfamethoxazole: Co-administration of TMP/SMX with lamivudine resulted in an increase of 43% +-23% (mean +-SD) in lamivudine AUC, decrease of 29% +-13% in lamivudine oral clearance, and decrease of 30% +-36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by co-administration with lamivudine.. Sorbitol (Excipient): Co-administration of lamivudine with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol resulted in dose-dependent decreases of 14%, 32%, and 36% in the AUC; and 28%, 52%, and 55% in the Cmax of lamivudine, respectively.. TDF:No clinically significant changes in exposure were observed for tenofovir when co-administered with tacrolimus or entecavir.No clinically significant changes in exposure were observed for the following drugs when co-administered with tenofovir: tacrolimus, entecavir, methadone, or ethinyl estradiol/norgestimate.. 12.4Microbiology. Mechanism of Action. Doravirine: Doravirine is pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC50) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in biochemical assay was 12.2+-2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases , and mitochondrial DNA polymerase .. Lamivudine: Lamivudine is synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Lamivudine triphosphate (3TC-TP) is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. TDF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity in Cell Culture. Doravirine: Doravirine exhibited an EC50 value of 12.0+-4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells and median EC50 value for HIV-1 subtype primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM. The antiviral activity of doravirine was not antagonistic when combined with lamivudine and TDF.. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and peripheral blood mononuclear cells (PBMCs) using standard susceptibility assays. EC50 values were in the range of to 15,000 nM (1,000 nM 230 ng per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.. TDF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 40-8,500 nM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 500-2,200 nM).. Resistance. In Cell Culture. Doravirine: Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred 10-fold reduction in susceptibility to doravirine.. Lamivudine: Lamivudine-resistant variants of HIV-1 have been selected in cell culture and in subjects treated with lamivudine. Genotypic analysis showed that substitutions M184I or cause resistance to lamivudine.. TDF: HIV-1 isolates selected by tenofovir in cell culture expressed K65R substitution in HIV-1 RT and showed 2-4 -fold reduction in susceptibility to tenofovir. In addition, K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.. In Clinical Trials. Clinical Trial Results in Adults with No Antiretroviral Treatment History. Doravirine: In the doravirine treatment arm of the DRIVE-AHEAD trial (n=364) through 96 weeks, 10 subjects showed the emergence of doravirine resistance-associated substitutions among 24 (42%) subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: V90V/G, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F, and Y318Y/S. Six of the 10 subjects with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and all of them had greater than 100-fold reduction in doravirine susceptibility (range >103 to >211). The other virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold.In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364) through Week 96, 15 subjects showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) subjects in the resistance analysis subset.. Lamivudine and TDF: In pooled analysis of antiretroviral-naive subjects who received doravirine, lamivudine, and TDF, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure or at time of early study drug discontinuation. Genotypic resistance developed in evaluable subjects who received DOR/3TC/TDF through Week 96. The resistance-associated substitutions that emerged were RT M41L (n=1), A62A/V (n=1), K65R (n=2), T69T/A (n=1), V75V/I (n=1), and M184V (n=5). In comparison, genotypic resistance to emtricitabine or tenofovir developed in evaluable subjects who received EFV/FTC/TDF in DRIVE-AHEAD; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or (n=5), and K219K/E (n=1).. Clinical Trial Results in Virologically-Suppressed AdultsIn the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2)], there were subjects in the immediate switch group (n=447) and subjects in the delayed switch group (n=209) who met the protocol-defined virologic failure criteria (confirmed HIV-1 RNA >= 50 copies/mL). Two of the virologic failure subjects in the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir during treatment with DELSTRIGO. One of the two virologic failure subjects in the delayed switch group who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen.. Cross-ResistanceNo significant cross-resistance has been demonstrated between doravirine-resistant HIV-1 variants and lamivudine/emtricitabine or tenofovir or between lamivudine or tenofovir-resistant variants and doravirine.. Doravirine: Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the virologic failure subjects who developed doravirine phenotypic resistance, all had phenotypic resistance to efavirenz and nevirapine, had phenotypic resistance to rilpivirine, and had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure subjects phenotypically resistant to efavirenz, (18%) had decreased susceptibility to doravirine (18- and 36-fold).The treatment-emergent doravirine resistance-associated substitution Y318F did not confer reduced susceptibility to efavirenz, etravirine, or rilpivirine.A panel of 96 diverse clinical isolates containing NNRTI resistance-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine.. Lamivudine: Cross-resistance has been observed among NRTIs. The M184I/V lamivudine resistance-associated substitution confers resistance to abacavir, didanosine and emtricitabine. Lamivudine also has reduced susceptibility against the K65R substitution.. TDF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. The K70E substitution selected clinically by TDF results in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 isolates from patients (n=20) whose HIV-1 expressed mean of zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an RT L74V substitution without zidovudine resistance-associated substitutions (n=8) had reduced response to TDF. Limited data are available for patients whose virus expressed Y115F substitution (n=3), Q151M substitution (n=2), or T69 insertion (n=4) in HIV-1 RT, all of whom had reduced response in clinical trials.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Clinical Trial Results in Adults with No Antiretroviral Treatment History. The efficacy of DELSTRIGO is based on the analyses of 96-week data from randomized, multicenter, double-blind, active controlled Phase trial (DRIVE-AHEAD, NCT02403674) in HIV-1-infected subjects with no antiretroviral treatment history (n=728).Subjects were randomized and received at least dose of either DELSTRIGO or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of subjects was 31 years, 15% were female, 52% were non-white, 3% had hepatitis or coinfection, 14% had history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm3; these characteristics were similar between treatment groups. Week 96 outcomes for DRIVE-AHEAD are provided in Table 10.Mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 238 and 223 cells/mm3, respectively.Table 10: Virologic Outcome in DRIVE-AHEAD at Week 96 in HIV-1 Adult Subjects with No Antiretroviral Treatment HistoryOutcomeDELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364HIV-1 RNA <50 copies/mL77%74% Treatment Difference (95% CI) The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. 3.8% (-2.4%, 10.0%)HIV-1 RNA >= 50 copies/mLIncludes subjects who discontinued study drug or study before Week 96 for lack or loss of efficacy and subjects with HIV-1 RNA equal to or above 50 copies/mL in the Week 96 window.15%12%No Virologic Data at Week 96 Window 7%14% Discontinued study due to AE or DeathIncludes subjects who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 96 window. 3%8% Discontinued study for Other ReasonsOther reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by subject. 4%5% On study but missing data in window 1%1%Proportion (%) of Subjects With HIV-1 RNA <50 copies/mL at Week 96 by Baseline and Demographic CategoryGender Male78% (N 305)73% (N 311) Female75% (N 59)75% (N 53)Race White80% (N 176)74% (N 170) Non-White76% (N 188)74% (N 194)EthnicityDoes not include subjects whose ethnicity or viral subtypes were unknown. Hispanic or Latino81% (N 126)77% (N 119) Not Hispanic or Latino76% (N 238)72% (N 239)Baseline HIV-1 RNA (copies/mL) <=100,000 copies/mL80% (N 291)77% (N 282) >100,000 copies/mL67% (N 73)62% (N 82)CD4+ T-cell Count (cells/mm3) <=200 cells/mm3 59% (N 44)70% (N 46) >200 cells/mm3 80% (N 320)74% (N 318)Viral Subtype Subtype B80% (N 232)72% (N 253) Subtype Non-B73% (N 130)77% (N 111). 14.2Clinical Trial Results in Virologically-Suppressed Adults. The efficacy of switching from baseline regimen consisting of two NRTIs in combination with PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI to DELSTRIGO was evaluated in randomized, open-label trial (DRIVE-SHIFT, NCT02397096), in virologically-suppressed HIV-1-infected adults. Subjects must have been virologically-suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen for at least months prior to trial entry, with no history of virologic failure. Subjects were randomized to either switch to DELSTRIGO at baseline [n 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to DELSTRIGO [n 223, Delayed Switch Group (DSG)].At baseline, the median age of subjects was 43 years, 16% were female, and 24% were Non-White, 21% were of Hispanic or Latino ethnicity, 3% had hepatitis and/or virus co-infection, 17% had history of AIDS, 96% had CD4+ T-cell count greater than or equal to 200 cells/mm3, 70% were on regimen containing PI plus ritonavir, 24% were on regimen containing an NNRTI, 6% were on regimen containing elvitegravir plus cobicistat, and 1% were on regimen containing PI plus cobicistat; these characteristics were similar between treatment groups.Virologic outcome results are shown in Table 11.Table 11: Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Subjects Who Switched to DELSTRIGOOutcomeDELSTRIGOOnce Daily ISG Week 48N=447Baseline Regimen DSG Week 24N=223HIV-1 RNA >= 50 copies/mLIncludes subjects who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and subjects with HIV-1 RNA >=50 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG2%1%ISG-DSG, Difference (95% CI)The 95% CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. Assessed using non-inferiority margin of 4%. 0.7% (-1.3%, 2.6%)HIV-1 RNA <50 copies/mL91%95%No Virologic Data Within the Time Window8%4% Discontinued study due to AE or DeathIncludes subjects who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window. 3%<1% Discontinued study for Other ReasonsOther reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by subject. 4%4% On study but missing data in window00Proportion (%) of Subjects With HIV-1 RNA <50 copies/mL by Baseline and Demographic CategoryAge (years) <5090% (N 320)95% (N 157) >=5094% (N 127)94% (N 66)Gender Male91% (N 372)94% (N 194) Female91% (N 75)100% (N 29)Race White90% (N 344)95% (N 168) Non-White93% (N 103)93% (N 55)Ethnicity Hispanic or Latino88% (N 99)91% (N 45) Not Hispanic or Latino91% (N 341)95% (N 175)CD4+ T-cell Count (cells/mm3) <200 cells/mm3 85% (N 13)75% (N 4) >=200 cells/mm3 91% (N 426)95% (N 216)Baseline RegimenBaseline Regimen PI plus either ritonavir or cobicistat (specifically atazanavir, darunavir, or lopinavir), or elvitegravir plus cobicistat, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs. PI plus either ritonavir or cobicistat90% (N 316)94% (N 156) elvitegravir plus cobicistat or NNRTI93% (N 131)96% (N 67). 14.3 Clinical Trial Results in Pediatric Patients. The efficacy of DELSTRIGO was evaluated in cohort of an open-label, single-arm 2-cohort trial in HIV-1-infected pediatric patients 12 to less than 18 years of age (IMPAACT 2014 (Protocol 027), NCT03332095). In cohort 1, virologically-suppressed subjects (n=9) received single 100 mg dose of doravirine followed by intensive PK sampling. In cohort 2, virologically-suppressed subjects (n=43) were switched to DELSTRIGO and treatment-naive subjects (n=2) were started on DELSTRIGO.In cohort 2, at baseline the median age of subjects was 15 years (range: 12 to 17), the median weight was 52 kg (range: 45 to 80), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm3 (range 84 to 1397). After switching to DELSTRIGO, 95% (41/43) of virologically-suppressed subjects remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naive subjects achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naive subject met the protocol-defined virologic failure criteria (defined as consecutive plasma HIV-1 RNA test results >=200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir was detected.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. 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 (5.3), 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. Johns wort (Hypericum perforatum) DELSTRIGO is contraindicated in patients with previous hypersensitivity reaction to lamivudine.. 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 (5.3), 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. Johns wort (Hypericum perforatum) -the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin. -the androgen receptor inhibitor enzalutamide. -the antimycobacterials rifampin, rifapentine. -the cytotoxic agent mitotane. -St. Johns wort (Hypericum perforatum). DELSTRIGO is contraindicated in patients with previous hypersensitivity reaction to lamivudine.. 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. (4)DELSTRIGO is contraindicated in patients with previous hypersensitivity reaction to lamivudine.. 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. (4). DELSTRIGO is contraindicated in patients with previous hypersensitivity reaction to lamivudine.

DESCRIPTION SECTION.

11 DESCRIPTION. DELSTRIGO is fixed-dose combination, film-coated tablet, containing doravirine, lamivudine, and TDF for oral administration.Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).Lamivudine is the (-)enantiomer of dideoxy analogue of cytidine and is an HIV-1 nucleoside analogue reverse transcriptase inhibitor.TDF (a prodrug of tenofovir) is fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo TDF is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5-monophosphate. Tenofovir is an HIV-1 reverse transcriptase inhibitor.Each tablet contains 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium stearyl fumarate. The tablets are film coated with coating material containing the following inactive ingredients: hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax.. Doravirine:The chemical name for doravirine is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile.It has molecular formula of C17H11ClF3N5O3 and molecular weight of 425.75.It has the following structural formula:Doravirine is practically insoluble in water.. Chemical Structure. Lamivudine:The chemical name for lamivudine is (-)-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cytosine.It has molecular formula of C8H11N3O3S and molecular weight of 229.26.It has the following structural formula:Lamivudine is soluble in water.. Chemical Structure. TDF:The chemical name for TDF is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy] phosphinyl]- methoxy]propyl]adenine fumarate (1:1).It has molecular formula of C19H30N5O10 PC4H4O4 and molecular weight of 635.52.It has the following structural formula:TDF is slightly soluble in water.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Testing: Prior to or when initiating DELSTRIGO, test for HBV infection. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on 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. (2.1)Recommended dosage: One tablet taken orally once daily with or without food in adults and pediatric patients weighing at least 35 kg. (2.2)Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (2.3)Dosage adjustment 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. (2.4). Testing: Prior to or when initiating DELSTRIGO, test for HBV infection. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on 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. (2.1). Recommended dosage: One tablet taken orally once daily with or without food in adults and pediatric patients weighing at least 35 kg. (2.2). Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (2.3). Dosage adjustment 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. (2.4). 2.1Testing When Initiating and During Treatment with DELSTRIGO. Prior to or when initiating DELSTRIGO, test patients for HBV infection [see Warnings and Precautions (5.1)]. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on 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 (5.2)]. 2.2Recommended Dosage. DELSTRIGO is 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)].. 2.3Renal Impairment. Because DELSTRIGO is 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 (5.2) and Use in Specific Populations (8.6)].. 2.4Dosage 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 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).. Tablets: 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate. (3). Tablets: 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Because DELSTRIGO is complete regimen, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. (7.1)Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. (4, 5.3, 7). Because DELSTRIGO is complete regimen, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. (7.1). Consult the full prescribing information prior to and during treatment for important potential drug-drug interactions. (4, 5.3, 7). 7.1Concomitant Use with Other Antiretroviral Medications. Because DELSTRIGO is complete regimen for the treatment of HIV-1 infection, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided.. 7.2Effect of Other Drugs on DELSTRIGO. Co-administration of DELSTRIGO with CYP3A inducer decreases doravirine plasma concentrations, which may reduce DELSTRIGO efficacy [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].Co-administration of DELSTRIGO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.Table shows the significant drug interactions with the components of DELSTRIGO. The drug interactions described are based on studies conducted with either DELSTRIGO or the components of DELSTRIGO as individual agents.Table 6: Drug Interactions with DELSTRIGOThis table is not all-inclusive Concomitant Drug Class: Drug NameEffect on Concentration Clinical Comment increase, decreaseAll other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways.Androgen Receptorsenzalutamide doravirineCo-administration is contraindicated with enzalutamide.At least 4-week cessation period is recommended prior to initiation of DELSTRIGO.Anticonvulsantscarbamazepineoxcarbazepinephenobarbitalphenytoin doravirineCo-administration is contraindicated with these anticonvulsants. At least 4-week cessation period is recommended prior to initiation of DELSTRIGO.AntimycobacterialsrifampinThe interaction between doravirine and the concomitant drug was evaluated in clinical study. rifapentine doravirineCo-administration is contraindicated with rifampin or rifapentine. At least 4-week cessation period is recommended prior to initiation of DELSTRIGO.rifabutin doravirineIf DELSTRIGO is co-administered with rifabutin, one tablet of doravirine (PIFELTRO) should be taken approximately 12 hours after the dose of DELSTRIGO [see Dosage and Administration (2.4)].Cytotoxic Agentsmitotane doravirineCo-administration is contraindicated with mitotane. At least 4-week cessation period is recommended prior to initiation of DELSTRIGO.Hepatitis Antiviral Agentsledipasvir/sofosbuvirsofosbuvir/velpatasvir tenofovirMonitor for adverse reactions associated with TDF.Herbal ProductsSt. Johns wort doravirineCo-administration is contraindicated with St. Johns wort. At least 4-week cessation period is recommended prior to initiation of DELSTRIGO.Other Agentssorbitol lamivudineCo-administration of single doses of lamivudine and sorbitol resulted in sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines.Co-administration of DELSTRIGO with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, or methadone [see Clinical Pharmacology (12.3)].No clinically significant changes in concentration were observed for tenofovir when co-administered with tacrolimus or entecavir [see Clinical Pharmacology (12.3)].. 7.3Effect of DELSTRIGO on Other Drugs. No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, or midazolam.No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, sofosbuvir, or tacrolimus in studies conducted in healthy subjects.Lamivudine is not significantly metabolized by CYP enzymes nor does it inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur through these pathways [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical trials of doravirine, lamivudine, or TDF did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7Hepatic 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Each DELSTRIGO tablet contains 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil), is yellow, oval-shaped, film-coated, and is debossed with the corporate logo and 776 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-5007-01) and silica gel desiccants, and is closed with child-resistant closure.. Store DELSTRIGO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccants.Store DELSTRIGO at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DELSTRIGO(TM) is indicated as 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 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)].. 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 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)].. DELSTRIGO is three-drug combination of doravirine (a non-nucleoside reverse transcriptase inhibitor [NNRTI]), lamivudine, and tenofovir disoproxil fumarate (both nucleoside analogue reverse transcriptase inhibitors) and is indicated as complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:with no 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 stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. (1). with no 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 stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBVInform patients that severe acute exacerbations of hepatitis have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued lamivudine or TDF and may occur with discontinuation of DELSTRIGO [see Warnings and Precautions (5.1)]. Advise patients not to discontinue DELSTRIGO without first informing their healthcare provider.. Drug InteractionsInform patients that DELSTRIGO may interact with certain 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. Johns wort [see Contraindications (4), Warnings and Precautions (5.3), and Drug Interactions (7)].For patients concomitantly receiving rifabutin, take one tablet of doravirine (PIFELTRO) 100 mg approximately 12 hours after the dose of DELSTRIGO [see Dosage and Administration (2.4)].. New Onset or Worsening Renal ImpairmentInform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF. Advise patients to avoid DELSTRIGO with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple NSAIDS) [see Warnings and Precautions (5.2)]. Bone Loss and Mineralization DefectsInform patients that decreases in bone mineral density have been observed with the use of TDF, component of DELSTRIGO. Assessment of bone mineral density (BMD) should be considered in patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.4)].. Immune Reconstitution SyndromeInform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the bodys immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.5)].. Dosing InstructionsAdvise patients to take DELSTRIGO every day at regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance. If patient forgets to take DELSTRIGO, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take doses at one time and to take the next dose at the regularly scheduled time.. Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to DELSTRIGO [see Use in Specific Populations (8.1)]. LactationInstruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection.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. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving DELSTRIGO.. Data. Doravirine: Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed hours post dose on lactation day 14.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. DELSTRIGO is fixed-dose combination of the antiretroviral drugs doravirine, lamivudine, and TDF [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4Microbiology. Mechanism of Action. Doravirine: Doravirine is pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC50) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in biochemical assay was 12.2+-2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases , and mitochondrial DNA polymerase .. Lamivudine: Lamivudine is synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Lamivudine triphosphate (3TC-TP) is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. TDF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity in Cell Culture. Doravirine: Doravirine exhibited an EC50 value of 12.0+-4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells and median EC50 value for HIV-1 subtype primary isolates (n=118) of 4.1 nM (range: 1.0 nM-16.0 nM). Doravirine demonstrated antiviral activity against broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 1.2 nM to 10.0 nM. The antiviral activity of doravirine was not antagonistic when combined with lamivudine and TDF.. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and peripheral blood mononuclear cells (PBMCs) using standard susceptibility assays. EC50 values were in the range of to 15,000 nM (1,000 nM 230 ng per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.. TDF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 40-8,500 nM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 500-2,200 nM).. Resistance. In Cell Culture. Doravirine: Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred 10-fold reduction in susceptibility to doravirine.. Lamivudine: Lamivudine-resistant variants of HIV-1 have been selected in cell culture and in subjects treated with lamivudine. Genotypic analysis showed that substitutions M184I or cause resistance to lamivudine.. TDF: HIV-1 isolates selected by tenofovir in cell culture expressed K65R substitution in HIV-1 RT and showed 2-4 -fold reduction in susceptibility to tenofovir. In addition, K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.. In Clinical Trials. Clinical Trial Results in Adults with No Antiretroviral Treatment History. Doravirine: In the doravirine treatment arm of the DRIVE-AHEAD trial (n=364) through 96 weeks, 10 subjects showed the emergence of doravirine resistance-associated substitutions among 24 (42%) subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having post-baseline resistance samples). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: V90V/G, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F, and Y318Y/S. Six of the 10 subjects with emergent doravirine resistance-associated substitutions showed doravirine phenotypic resistance and all of them had greater than 100-fold reduction in doravirine susceptibility (range >103 to >211). The other virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold.In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364) through Week 96, 15 subjects showed the emergence of efavirenz resistance-associated substitutions among 25 (60%) subjects in the resistance analysis subset.. Lamivudine and TDF: In pooled analysis of antiretroviral-naive subjects who received doravirine, lamivudine, and TDF, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-1 RNA greater than 400 copies per mL at confirmed virologic failure or at time of early study drug discontinuation. Genotypic resistance developed in evaluable subjects who received DOR/3TC/TDF through Week 96. The resistance-associated substitutions that emerged were RT M41L (n=1), A62A/V (n=1), K65R (n=2), T69T/A (n=1), V75V/I (n=1), and M184V (n=5). In comparison, genotypic resistance to emtricitabine or tenofovir developed in evaluable subjects who received EFV/FTC/TDF in DRIVE-AHEAD; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), M184I or (n=5), and K219K/E (n=1).. Clinical Trial Results in Virologically-Suppressed AdultsIn the DRIVE-SHIFT clinical trial [see Clinical Studies (14.2)], there were subjects in the immediate switch group (n=447) and subjects in the delayed switch group (n=209) who met the protocol-defined virologic failure criteria (confirmed HIV-1 RNA >= 50 copies/mL). Two of the virologic failure subjects in the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir during treatment with DELSTRIGO. One of the two virologic failure subjects in the delayed switch group who had available resistance data developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen.. Cross-ResistanceNo significant cross-resistance has been demonstrated between doravirine-resistant HIV-1 variants and lamivudine/emtricitabine or tenofovir or between lamivudine or tenofovir-resistant variants and doravirine.. Doravirine: Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the virologic failure subjects who developed doravirine phenotypic resistance, all had phenotypic resistance to efavirenz and nevirapine, had phenotypic resistance to rilpivirine, and had resistance to etravirine in the Monogram PhenoSense assay. Of the 11 virologic failure subjects phenotypically resistant to efavirenz, (18%) had decreased susceptibility to doravirine (18- and 36-fold).The treatment-emergent doravirine resistance-associated substitution Y318F did not confer reduced susceptibility to efavirenz, etravirine, or rilpivirine.A panel of 96 diverse clinical isolates containing NNRTI resistance-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine.. Lamivudine: Cross-resistance has been observed among NRTIs. The M184I/V lamivudine resistance-associated substitution confers resistance to abacavir, didanosine and emtricitabine. Lamivudine also has reduced susceptibility against the K65R substitution.. TDF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. The K70E substitution selected clinically by TDF results in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 isolates from patients (n=20) whose HIV-1 expressed mean of zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an RT L74V substitution without zidovudine resistance-associated substitutions (n=8) had reduced response to TDF. Limited data are available for patients whose virus expressed Y115F substitution (n=3), Q151M substitution (n=2), or T69 insertion (n=4) in HIV-1 RT, all of whom had reduced response in clinical trials.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Doravirine: Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to and times, respectively, the human exposures at the RHD. statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls.. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the RHD.. TDF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and times (rats) those observed in humans at the RHD. At the high dose in female mice, liver adenomas were increased at exposures 16 times of that in humans. In rats, the study was negative for carcinogenic findings at exposures up to times that observed in humans at the RHD.. Mutagenesis. Doravirine: Doravirine was not genotoxic in battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays.. Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection.. TDF: TDF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.. Impairment of Fertility. Doravirine: There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to the highest dose tested. Systemic exposures (AUC) to doravirine were approximately times the exposure in humans at the RHD.. Lamivudine: In study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.. TDF: There were no effects on fertility, mating performance or early embryonic development when TDF was administered to male rats at dose equivalent to 10 times the RHD based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day of gestation. There was, however, an alteration of the estrous cycle in female rats.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No data are available on overdose of DELSTRIGO in patients and there is no known specific treatment for overdose with DELSTRIGO. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.. Doravirine: There is no known specific treatment for overdose with doravirine.. Lamivudine: Because negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in lamivudine overdose event.. TDF: TDF is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following single 300 mg dose of TDF, 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 Tablet Bottle Label. NDC 0006-5007-01Delstrigo(TM)(doravirine, lamivudine, andtenofovir disoproxil fumarate) tablets100mg/300mg/300mgEach tablet contains 100 mg doravirine, 300 mglamivudine, and 300 mg tenofovir disoproxil fumarate(equivalent to 245 mg tenofovir disoproxil).ALERT: Find out about medicines thatshould NOT be taken with Delstrigo(TM).Rx only30 Tablets. PRINCIPAL DISPLAY PANEL 30 Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 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-naive pediatric subjects 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric subjects 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In Phase trial evaluating doravirine over dose range of 0.25 to times the recommended dose of doravirine in DELSTRIGO (in combination with FTC/TDF) in HIV-1-infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine.. Cardiac ElectrophysiologyAt doravirine dose of 1200 mg, which provides approximately times the peak concentration observed following the recommended dose of doravirine in DELSTRIGO does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Single-dose administration of one DELSTRIGO tablet to healthy subjects provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus TDF tablets (300 mg). Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Pharmacokinetic properties of the components of DELSTRIGO are provided in Table 7.Table 7: Pharmacokinetic Properties of the Components of DELSTRIGOParameterDoravirineLamivudineTenofovirAbbreviations: NA=not available; AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax=time to Cmax; Vdss=apparent volume of distribution at steady state; t1/2=elimination half-life; CL/F=apparent clearance; CLrenal renal clearanceGeneral Steady State ExposurePresented as geometric mean (%CV: geometric coefficient of variation) or mean +- SD. AUC0-24 (mcgh/mL)16.1 (29)Doravirine 100 mg once daily to HIV-1-infected subjects. 8.87 +- 1.83Lamivudine 300 mg once daily for days to 60 healthy subjects. 2.29 +- 0.69Single 300 mg dose of TDF to HIV-1-infected subjects in the fasted state. Cmax (mcg/mL)0.962 (19) 2.04 +- 0.54 0.30 +- 0.09 C24 (mcg/mL)0.396 (63) NANAAbsorptionAbsolute Bioavailability64%86%25%Tmax (h)2NA1 Effect of FoodGeometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1000 kcal, 50% fat. The effect of food is not clinically relevant. AUC Ratio1.10 (1.01, 1.20)0.93 (0.84, 1.03)1.27 (1.17, 1.37)Cmax Ratio0.95 (0.80, 1.12)0.81 (0.65, 1.01)0.88 (0.74, 1.04)C24 Ratio1.26 (1.13, 1.41)NANADistribution Vdss Based on IV dose. 60.5 L1.3 L/kg1.3 L/kgPlasma Protein Binding76%< 36%<0.7%Eliminationt1/2 (h)155-717CL/F (mL/ min) 106 (35.2)398.5 +- 69.11,043.7 +- 115.4CLrenal (mL/ min) 9.3 (18.6)199.7 +- 56.9243.5 +- 33.3 MetabolismPrimary Pathway(s)CYP3AMinorNo CYP Metabolism ExcretionMajor route of eliminationMetabolismGlomerular filtration and active tubular secretionGlomerular filtration and active tubular secretionUrine (unchanged)6%71%70-80%Biliary/Fecal (unchanged)MinorNANA. Specific PopulationsIn adults, no clinically significant differences in the pharmacokinetics of certain DELSTRIGO components were observed based on age >=65 years (for doravirine), sex (for doravirine, lamivudine, tenofovir), and race/ethnicity (for doravirine, lamivudine). The effects of age (>=65 years) on the pharmacokinetics of lamivudine and tenofovir, and the effect of race on the pharmacokinetics of tenofovir are unknown.. Patients with Renal Impairment. Doravirine: No clinically significant difference in the pharmacokinetics of doravirine were observed in subjects with mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault). Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.. Lamivudine: The AUCinf, Cmax, and half-life of lamivudine increased and CL/F decreased to clinically significant extent with diminishing renal function (CLcr 111 to 10 mL/min).. TDF: clinically significant increase in the Cmax and AUC of tenofovir was observed in subjects with CLcr 50 mL/min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].. Patients with Hepatic Impairment. Doravirine: No clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).. Lamivudine: No clinically significant differences in lamivudine pharmacokinetics were observed with diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.. TDF: No clinically significant differences in tenofovir pharmacokinetics were observed between subjects with any degree of hepatic impairment and healthy subjects.. Pediatric PatientsMean doravirine exposures were similar in 54 pediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or DELSTRIGO in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or DELSTRIGO. Exposures of lamivudine and tenofovir in pediatric patients following the administration of DELSTRIGO were similar to those in adults following administration of lamivudine and tenofovir (Table 8). For pediatric patients weighing >= 35 kg and 45 kg who receive doravirine 100 mg or DELSTRIGO, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0-24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0-24 and Cmax increases are not considered clinically significant.Table 8: Steady State Pharmacokinetics for Doravirine, Lamivudine, and Tenofovir Following Administration of Doravirine or DELSTRIGO in HIV-1-Infected Pediatric Patients Aged 12 to Less than 18 Years and Weighing at Least 35 kgParameterPresented as geometric mean (%CV: geometric coefficient of variation) DoravirineFrom population PK analysis (n=53 weighing >=45 kg, n=1 weighing >=35 kg to <45 kg) LamivudineFrom intensive PK analysis (n=10) Tenofovir Abbreviations: NA=not applicable; AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hoursAUC0-24 (mcgoh/mL)16.4 (24)11.3 (28)2.55 (14)Cmax (mcg/mL)1.03 (16)2.1 (24)0.293 (37)C24 (mcg/mL)0.379 (42)NANA. Drug Interaction StudiesDELSTRIGO is complete regimen for the treatment of HIV-1 infection; therefore, DELSTRIGO is not recommended to be administered with other HIV-1 antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided.The drug interaction trials described were conducted with doravirine, lamivudine and/or TDF, as single entities; no drug interaction trials have been conducted using the combination of doravirine, lamivudine, and TDF. No clinically relevant drug interactions were observed between doravirine, lamivudine, and TDF.. Doravirine: Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine.Doravirine is not likely to have clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (Cmax, AUC, and C24) of doravirine are summarized in Table 9. single doravirine 100 mg dose was administered in these studies unless otherwise noted.Table 9: Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered DrugCo-administered DrugRegimen of Co-administered DrugNGeometric Mean Ratio (90% CI) of Doravirine Pharmacokinetics with/without Co-administered Drug (No Effect=1.00)AUCAUC0- for single-dose, AUC0-24 for once daily. Cmax C24 CI confidence interval; QD once daily; BID twice dailyAzole Antifungal AgentsketoconazoleChanges in doravirine pharmacokinetic values are not clinically relevant. 400 mg QD103.06 (2.85, 3.29)1.25 (1.05, 1.49)2.75 (2.54, 2.98)Antimycobacterialsrifampin600 mg QD100.12 (0.10, 0.15)0.43 (0.35, 0.52)0.03 (0.02, 0.04)rifabutin300 mg QD120.50 (0.45, 0.55)0.99 (0.85, 1.15)0.32 (0.28, 0.35)300 mg QDDoravirine 100 mg BID resulted in similar pharmacokinetic values when compared to 100 mg QD without rifabutin. 151.03 (0.94, 1.14)0.97 (0.87, 1.08)0.98 (0.88, 1.10)HIV Antiviral Agentsritonavir A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered. 100 mg BID83.54 (3.04, 4.11)1.31 (1.17, 1.46)2.91 (2.33, 3.62)efavirenz600 mg QDThe first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 170.38 (0.33, 0.45)0.65 (0.58, 0.73)0.15 (0.10, 0.23)600 mg QD14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD. 170.68 (0.58, 0.80)0.86 (0.77, 0.97)0.50 (0.39, 0.64)Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, ritonavir, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. Lamivudine:. Trimethoprim/Sulfamethoxazole: Co-administration of TMP/SMX with lamivudine resulted in an increase of 43% +-23% (mean +-SD) in lamivudine AUC, decrease of 29% +-13% in lamivudine oral clearance, and decrease of 30% +-36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by co-administration with lamivudine.. Sorbitol (Excipient): Co-administration of lamivudine with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol resulted in dose-dependent decreases of 14%, 32%, and 36% in the AUC; and 28%, 52%, and 55% in the Cmax of lamivudine, respectively.. TDF:No clinically significant changes in exposure were observed for tenofovir when co-administered with tacrolimus or entecavir.No clinically significant changes in exposure were observed for the following drugs when co-administered with tenofovir: tacrolimus, entecavir, methadone, or ethinyl estradiol/norgestimate.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryThere 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 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 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 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) to 20) and rats (up to 450 mg/kg/day on GD to 20 and separately from GD 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 times (rats) and 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 gestation day 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 gestation Days through 16 [rat] and 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.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)01/2022Dosage and Administration (2), Recommended Dosage (2.2)01/2022.

RENAL IMPAIRMENT SUBSECTION.

8.6Renal Impairment. Because DELSTRIGO is 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 (5.2) and Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationDELSTRIGO(TM) (del-STREE-go)(doravirine, lamivudine, and tenofovir disoproxil fumarate)tabletsThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 01/2022What is the most important information should know about DELSTRIGODELSTRIGO can cause serious side effects, including:Worsening of hepatitis virus infection (HBV). If you have Human Immunodeficiency Virus-1 (HIV-1) and HBV infection, your HBV infection may get worse (flare-up) if you stop taking DELSTRIGO. flare-up is when your HBV infection suddenly returns in worse way than before. Your healthcare provider will test you for HBV infection before you start treatment with DELSTRIGO.Do not run out of DELSTRIGO. Refill your prescription or talk to your healthcare provider before your DELSTRIGO is all gone.Do not stop taking DELSTRIGO without first talking to your healthcare provider. If you stop taking DELSTRIGO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking DELSTRIGO. For more information about side effects, see What are the possible side effects of DELSTRIGO What is DELSTRIGODELSTRIGO is prescription medicine that is used without other HIV-1 medicines to treat HIV-1 infection in adults and children who weigh at least 77 pounds (35 kg):who have not received HIV-1 medicines in the past, orto replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).DELSTRIGO contains the prescription medicines doravirine, lamivudine and tenofovir disoproxil fumarate.It is not known if DELSTRIGO is safe and effective in children who weigh less than 77 pounds (35 kg).Who should not take DELSTRIGODo not take DELSTRIGO if you take any of the following medicines:carbamazepineoxcarbazepinephenobarbitalphenytoinenzalutamiderifampinrifapentinemitotaneSt. Johns wortAsk your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above. If you have taken any of the medicines in the past weeks, talk to your healthcare provider or pharmacist before starting treatment with DELSTRIGO. Do not take DELSTRIGO if you have ever had an allergic reaction to lamivudine.What should tell my healthcare provider before treatment with DELSTRIGOBefore treatment with DELSTRIGO, tell your healthcare provider about all of your medical conditions, including if you:have hepatitis virus infectionhave kidney problemshave bone problems, including history of bone fracturesare pregnant or plan to become pregnant. It is not known if DELSTRIGO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with DELSTRIGO. Pregnancy Registry: There is pregnancy registry for people who take DELSTRIGO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you take DELSTRIGO. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.Two of the medicines in DELSTRIGO (lamivudine and tenofovir) can pass into your breast milk. It is not known if doravirine can pass into your breast milk.Talk with your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with DELSTRIGO. Keep list of your medicines to show your healthcare provider and pharmacist.Tell your healthcare provider if you have taken rifabutin in the past weeks.You can ask your healthcare provider or pharmacist for list of medicines that interact with DELSTRIGO.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DELSTRIGO with other medicines. How should take DELSTRIGOTake DELSTRIGO every day exactly as your healthcare provider tells you to take it.Take DELSTRIGO time each day, at about the same time every day.DELSTRIGO is usually taken by itself (without other HIV-1 medicines).If you take the medicine rifabutin during treatment with DELSTRIGO, your healthcare provider will also prescribe an additional dose of doravirine for you. You may not have enough doravirine in your blood if you take rifabutin during treatment with DELSTRIGO. Carefully follow your healthcare providers instructions about when to take doravirine and how much to take. This is usually tablet of doravirine about 12 hours after your last dose of DELSTRIGO.Take DELSTRIGO with or without food.Do not change your dose or stop taking DELSTRIGO without talking to your healthcare provider. Stay under healthcare providers care when taking DELSTRIGO.It is important that you do not miss or skip doses of DELSTRIGO.If you miss dose of DELSTRIGO, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take doses of DELSTRIGO at the same time.If you have any questions, call your healthcare provider or pharmacist.If you take too much DELSTRIGO, call your healthcare provider or go to the nearest hospital emergency room right away.When your DELSTRIGO supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to DELSTRIGO and become harder to treat.What are the possible side effects of DELSTRIGODELSTRIGO may cause serious side effects, including:See What is the most important information should know about DELSTRIGONew or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with DELSTRIGO. Your healthcare provider may tell you to stop taking DELSTRIGO if you develop new or worse kidney problems.Bone problems can happen in some people who take DELSTRIGO. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones.Tell your healthcare provider if you have any of the following symptoms during treatment with DELSTRIGO: bone pain that does not go away or worsening bone pain, pain in your arms, legs, hands or feet, broken (fractured) bones or muscle pain or weakness. These may be symptoms of bone or kidney problem.Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.The most common side effects of DELSTRIGO include dizziness, nausea, and abnormal dreams.These are not all the possible side effects of DELSTRIGO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store DELSTRIGOStore DELSTRIGO tablets at room temperature between 68F to 77F (20C to 25C).Keep DELSTRIGO in the original bottle.Do not take the tablets out of the bottle to store in another container, such as pill box.Keep the bottle tightly closed to protect DELSTRIGO from moisture.The DELSTRIGO bottle contains desiccants to help keep your medicine dry (protect it from moisture). Keep the desiccants in the bottle. Do not eat the desiccants. Keep DELSTRIGO and all medicines out of the reach of children.General information about the safe and effective use of DELSTRIGO.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use DELSTRIGO for condition for which it was not prescribed. Do not give DELSTRIGO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DELSTRIGO that is written for healthcare professionals.What are the ingredients in DELSTRIGOActive ingredients: doravirine, lamivudine, and tenofovir disoproxil fumarate.Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating contains hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax.Manufactured by: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USAU.S. License No. 0002For patent information: www.merck.com/product/patent/home.htmlThe trademarks depicted herein are owned by their respective companies.Copyright (C) 2018-2022 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved.usppi-mk1439a-t-2201r002For more information, go to www.DELSTRIGO.com or call 1-877-888-4231.. Do not run out of DELSTRIGO. Refill your prescription or talk to your healthcare provider before your DELSTRIGO is all gone.. Do not stop taking DELSTRIGO without first talking to your healthcare provider. If you stop taking DELSTRIGO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking DELSTRIGO.. who have not received HIV-1 medicines in the past, or. to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.. carbamazepine. oxcarbazepine. phenobarbital. phenytoin. enzalutamide. rifampin. rifapentine. mitotane. St. Johns wort. have hepatitis virus infection. have kidney problems. have bone problems, including history of bone fractures. are pregnant or plan to become pregnant. It is not known if DELSTRIGO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with DELSTRIGO. Pregnancy Registry: There is pregnancy registry for people who take DELSTRIGO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.. are breastfeeding or plan to breastfeed. Do not breastfeed if you take DELSTRIGO. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.Two of the medicines in DELSTRIGO (lamivudine and tenofovir) can pass into your breast milk. It is not known if doravirine can pass into your breast milk.Talk with your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. Two of the medicines in DELSTRIGO (lamivudine and tenofovir) can pass into your breast milk. It is not known if doravirine can pass into your breast milk.. Talk with your healthcare provider about the best way to feed your baby.. Some medicines interact with DELSTRIGO. Keep list of your medicines to show your healthcare provider and pharmacist.. Tell your healthcare provider if you have taken rifabutin in the past weeks.. You can ask your healthcare provider or pharmacist for list of medicines that interact with DELSTRIGO.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take DELSTRIGO with other medicines.. Take DELSTRIGO every day exactly as your healthcare provider tells you to take it.. Take DELSTRIGO time each day, at about the same time every day.. DELSTRIGO is usually taken by itself (without other HIV-1 medicines).. If you take the medicine rifabutin during treatment with DELSTRIGO, your healthcare provider will also prescribe an additional dose of doravirine for you. You may not have enough doravirine in your blood if you take rifabutin during treatment with DELSTRIGO. Carefully follow your healthcare providers instructions about when to take doravirine and how much to take. This is usually tablet of doravirine about 12 hours after your last dose of DELSTRIGO.. Take DELSTRIGO with or without food.. Do not change your dose or stop taking DELSTRIGO without talking to your healthcare provider. Stay under healthcare providers care when taking DELSTRIGO.. It is important that you do not miss or skip doses of DELSTRIGO.. If you miss dose of DELSTRIGO, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take doses of DELSTRIGO at the same time.. If you have any questions, call your healthcare provider or pharmacist.. If you take too much DELSTRIGO, call your healthcare provider or go to the nearest hospital emergency room right away.. When your DELSTRIGO supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even short time. The virus may develop resistance to DELSTRIGO and become harder to treat.. See What is the most important information should know about DELSTRIGO. New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with DELSTRIGO. Your healthcare provider may tell you to stop taking DELSTRIGO if you develop new or worse kidney problems.. Bone problems can happen in some people who take DELSTRIGO. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones.. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine.. Store DELSTRIGO tablets at room temperature between 68F to 77F (20C to 25C).. Keep DELSTRIGO in the original bottle.. Do not take the tablets out of the bottle to store in another container, such as pill box.. Keep the bottle tightly closed to protect DELSTRIGO from moisture.. The DELSTRIGO bottle contains desiccants to help keep your medicine dry (protect it from moisture). Keep the desiccants in the bottle. Do not eat the desiccants.

SPL UNCLASSIFIED SECTION.

2.1Testing When Initiating and During Treatment with DELSTRIGO. Prior to or when initiating DELSTRIGO, test patients for HBV infection [see Warnings and Precautions (5.1)]. Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on 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 (5.2)].

STORAGE AND HANDLING SECTION.

Store DELSTRIGO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccants.Store DELSTRIGO at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2)Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4). Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2). Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is 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 SummaryThere 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 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 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 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) to 20) and rats (up to 450 mg/kg/day on GD to 20 and separately from GD 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 times (rats) and 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 gestation day 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 gestation Days through 16 [rat] and 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.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection.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. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving DELSTRIGO.. Data. Doravirine: Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed hours post dose on lactation day 14.. 8.4 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-naive pediatric subjects 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric subjects 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.. 8.5 Geriatric Use. Clinical trials of doravirine, lamivudine, or TDF did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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)]. 8.6Renal Impairment. Because DELSTRIGO is 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 (5.2) and Clinical Pharmacology (12.3)].. 8.7Hepatic 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. New onset or worsening renal impairment: Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. Avoid administering DELSTRIGO with concurrent or recent use of nephrotoxic drugs. (5.2)Bone loss and mineralization defects: Consider monitoring BMD in patients with history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.4)Monitor for Immune Reconstitution Syndrome. (5.5). New onset or worsening renal impairment: Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. Avoid administering DELSTRIGO with concurrent or recent use of nephrotoxic drugs. (5.2). Bone loss and mineralization defects: Consider monitoring BMD in patients with history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.4). Monitor for Immune Reconstitution Syndrome. (5.5). 5.1Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV. All patients with HIV-1 should be tested for the presence of HBV before initiating antiretroviral therapy.Severe acute exacerbations of hepatitis (e.g., liver decompensated and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine and/or TDF, and may occur with discontinuation of DELSTRIGO. Patients who are coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DELSTRIGO. If appropriate, initiation of anti-hepatitis therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.. 5.2New Onset or Worsening Renal Impairment. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, component of DELSTRIGO.DELSTRIGO should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on 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. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.The lamivudine and TDF components of DELSTRIGO are primarily excreted by the kidney. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min as dose interval adjustment required for lamivudine and TDF cannot be achieved with the fixed-dose combination tablet [see Use in Specific Populations (8.6)].. 5.3Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of DELSTRIGO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7.2)]: Loss of therapeutic effect of DELSTRIGO and possible development of resistance.Possible clinically significant adverse reactions from greater exposures of component of DELSTRIGO.See Table for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during DELSTRIGO therapy, review concomitant medications during DELSTRIGO therapy, and monitor for adverse reactions.. Loss of therapeutic effect of DELSTRIGO and possible development of resistance.. Possible clinically significant adverse reactions from greater exposures of component of DELSTRIGO.. 5.4Bone Loss and Mineralization Defects. Bone Mineral DensityIn clinical trials in HIV-1-infected adults, TDF (a component of DELSTRIGO) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin levels were also higher in subjects receiving TDF.Clinical trials evaluating TDF in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials.The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1-infected adult and pediatric patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.. Mineralization DefectsCases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF [see Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [see Warnings and Precautions (5.2)].. 5.5Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.