Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate

DELSTRIGO ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: with no prior antiretroviral treatment history, OR to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO [see Clinical Studies (14) ] . DELSTRIGO is a 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 a 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 a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. ( 1 )

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 )

DELSTRIGO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO [see Warnings and Precautions (5.4) , Drug Interactions (7.2) , and Clinical Pharmacology (12.3) ] . These drugs include, but are not limited to, the following: – the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin – the androgen receptor inhibitor enzalutamide – the antimycobacterials rifampin, rifapentine – the cytotoxic agent mitotane – St. John's wort ( Hypericum perforatum) DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. 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 a previous hypersensitivity reaction to lamivudine.

Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), have been reported. Discontinue DELSTRIGO immediately if signs or symptoms of severe skin reactions develop. ( 5.1 ) New onset or worsening renal impairment: Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. Avoid administering DELSTRIGO with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.5 ) Monitor for Immune Reconstitution Syndrome. ( 5.6 )

5.1 Skin and Hypersensitivity Reactions Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens [see Adverse Reactions (6.2) ] . In addition, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) was reported in a clinical trial with a two-drug regimen containing doravirine. Discontinue DELSTRIGO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement, a progressive severe rash, or a rash with constitutional symptoms, eosinophilia, lymphadenopathy, or other organ involvement develops. Clinical status should be closely monitored, and appropriate therapy should be initiated.

5.2 Severe Acute Exacerbation of Hepatitis B in People with Concomitant 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 B (e.g., liver decompensated and liver failure) have been reported in people with concomitant HIV-1 and HBV who 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 B 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.

5.3 New 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, a component of DELSTRIGO. DELSTRIGO should be avoided with concurrent or recent use of a 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 patients living with HIV 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 a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. 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) ] .

5.4 Risk 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 a component of DELSTRIGO. See Table 6 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.

5.5 Bone Loss and Mineralization Defects Bone Mineral Density In clinical trials in adults living with HIV, 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 D levels were also higher in participants receiving TDF. Clinical trials evaluating TDF in pediatric participants were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In participants 2 years to less than 18 years of age living with HIV, bone effects were similar to those observed in adult participants and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated pediatric participants living with HIV as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric participants 2 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 in adults and pediatric participants 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children are unknown. Assessment of BMD should be considered for adult and pediatric patients living with HIV who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Mineralization Defects Cases 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 (5.3) ] .

5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. […]

The following adverse reactions are discussed in other sections of the labeling: Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Severe Acute Exacerbation of Hepatitis B in people with concomitant HIV-1 and HBV [see Warnings and Precautions (5.2) ] New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.6) ] 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 LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 History The safety assessment of DELSTRIGO is based on Week 96 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials. A total of 747 participants 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 a total of 747 participants were randomized to control arms. In DRIVE-AHEAD (Protocol 021), 728 adult participants 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 participants in any treatment group in DRIVE-AHEAD are presented in Table 1. Table 1: Adverse Reactions Frequencies 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 2 or higher (moderate or severe) occurred in ≥2% of participants treated with DELSTRIGO. of Participants in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 96) DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Dizziness 7% 32% Nausea 5% 7% Abnormal Dreams 5% 10% Headache 4% 5% Insomnia 4% 5% Diarrhea 4% 6% Somnolence 3% 7% Rash Rash: 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 1 (mild). Neuropsychiatric Adverse Events For DRIVE-AHEAD, the analysis of participants with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of participants 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 participants compared to EFV/FTC/TDF-treated participants 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 Participants with Neuropsychiatric Adverse Events All causality and all grade events were included in the analysis. (Week 48) DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Treatment Difference (DELSTRIGO – EFV/FTC/TDF) Estimate (95% CI) The 95% CIs were calculated using Miettinen and Nurminen's 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 disturbances Predefined using MedDRA preferred terms including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism. 12% 26% -13.5 (-19.1, -7.9) Dizziness 9% 37% -28.3 (-34.0, -22.5) Altered sensorium Predefined 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 participants, in the DELSTRIGO and EFV/FTC/TDF groups, respectively. In DRIVE-AHEAD through 48 weeks of treatment, the majority of participants 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 participants reported these events in the first 4 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 participants in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of participants who reported neuropsychiatric adverse events through Week 4 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 Abnormalities The percentages of participants with selected laboratory abnormalities (that represent a 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 Participants with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 96) Laboratory Parameter Preferred Term (Unit)/Limit DELSTRIGO Once Daily N=364 EFV/FTC/TDF Once Daily N=364 Blood Chemistry Each participant is only counted once per parameter at the highest toxicity grade. Only participants with a baseline value and at least one on-treatment value for a given laboratory parameter are included. ULN = Upper limit of normal range. Total bilirubin (mg/dL) 1.1 – <1.6 × ULN 5% 0% 1.6 – <2.6 × ULN 2% 0% ≥2.6 × ULN 1% <1% Creatinine (mg/dL) >1.3 – 1.8 × ULN or Increase of >0.3 mg/dL above baseline 3% 2% >1.8 × ULN or Increase of ≥1.5 × above baseline 3% 2% Aspartate aminotransferase (IU/L) 2.5 – <5.0 × ULN 3% 3% ≥5.0 × ULN 1% 4% Alanine aminotransferase (IU/L) 2.5 – <5.0 × ULN 4% 4% ≥5.0 × ULN 1% 3% Alkaline phosphatase (IU/L) 2.5 – <5.0 × ULN <1% 1% ≥5.0 × ULN 0% <1% Lipase 1.5 – <3.0 × ULN 6% 4% ≥3.0 × ULN 2% 3% Creatine kinase (IU/L) 6.0 – <10.0 × ULN 3% 3% ≥10.0 × ULN 4% 6% Cholesterol, fasted (mg/dL) ≥300 mg/dL 1% <1% LDL cholesterol, fasted (mg/dL) ≥190 mg/dL <1% 2% Triglycerides, fasted (mg/dL) >500 mg/dL 1% 3% Change in Lipids from Baseline For 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 Participants with No Antiretroviral Treatment History in DRIVE-AHEAD (Week 48) Laboratory Parameter Preferred Term DELSTRIGO Once Daily N=320 EFV/FTC/TDF Once Daily N=307 Difference Estimates (DELSTRIGO – EFV/FTC/TDF) Baseline Change Baseline Change Difference (95% CI) Participants on lipid-lowering agents at baseline were excluded from these analyses (DELSTRIGO n=15 and EFV/FTC/TDF n=10). […]

Because DELSTRIGO is a 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 , 5.4 , 7 )

7.1 Concomitant Use with Other Antiretroviral Medications Because DELSTRIGO is a 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.

7.2 Effect of Other Drugs on DELSTRIGO Co-administration of DELSTRIGO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce DELSTRIGO efficacy [see Contraindications (4) , Warnings and Precautions (5.4) , 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 6 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 DELSTRIGO This table is not all-inclusive Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment ↑ = increase, ↓ = decrease All other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways. Androgen Receptors enzalutamide ↓ doravirine Co-administration is contraindicated with enzalutamide. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin ↓ doravirine Co-administration is contraindicated with these anticonvulsants. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Antimycobacterials rifampin The interaction between doravirine and the concomitant drug was evaluated in a clinical study. rifapentine ↓ doravirine Co-administration is contraindicated with rifampin or rifapentine. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. rifabutin ↓ doravirine If 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 Agents mitotane ↓ doravirine Co-administration is contraindicated with mitotane. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Hepatitis C Antiviral Agents ledipasvir/sofosbuvir sofosbuvir/velpatasvir ↑ tenofovir Monitor for adverse reactions associated with TDF. Herbal Products St. John's wort ↓ doravirine Co-administration is contraindicated with St. John's wort. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. Other Agents sorbitol ↓ lamivudine Co-administration of single doses of lamivudine and sorbitol resulted in a 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 (5.3) 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) ] .

7.3 Effect 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 participants. 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) ] .

Pediatrics: Not recommended for patients weighing less than 35 kg. ( 8.4 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There is insufficient prospective pregnancy data from the APR to adequately assess the risk of birth defects and miscarriage. Doravirine use in individuals during pregnancy has not been evaluated; however, lamivudine and TDF use during pregnancy has been evaluated in a limited number of individuals reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for lamivudine and TDF compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) ( see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the recommended clinical dose. No adverse developmental effects were observed when doravirine and TDF were administered separately at doses/exposures ≥8 (doravirine) and ≥14 (TDF) times those of the recommended human dose (RHD) of DELSTRIGO ( see Data ). Data Human Data Lamivudine : The APR has received a total of over 13,000 prospective reports with follow-up data of possible exposure to lamivudine-containing regimens; over 5,900 reports in the first trimester; over 5,600 reports in the second trimester; and over 1,800 reports in the third trimester. Birth defects occurred in 170 of 5,472 (3.1%, 95% CI: 2.7% to 3.6%) live births for lamivudine-containing regimens (first trimester exposure); and 218 of 7,513 (2.9%, 95% CI: 2.5% to 3.3%) live births for lamivudine-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between lamivudine and overall birth defects observed in the APR. TDF : The APR has received a total of over 7,000 prospective reports with follow-up data of possible exposure to tenofovir disoproxil-containing regimens; over 5,100 reports in the first trimester; over 1,300 reports in the second trimester; and over 600 reports in the third trimester. Birth defects occurred in 113 of 4,576 (2.5%, 95% CI: 2.0% to 3.0%) live births for TDF-containing regimens (first trimester exposure); and 51 of 1,965 (2.6%, 95% CI: 1.9% to 3.4%) live births for TDF-containing regimens (second/third trimester exposure). Among pregnant mothers in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between tenofovir and overall birth defects observed in the APR. Animal Data Doravirine : Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on GD 20. Lamivudine : Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on GD 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) 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 (C max ) 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 Summary Based on limited published data, both lamivudine and tenofovir are present in human milk. It is unknown whether doravirine is present in human milk, but doravirine is present in the milk of lactating rats ( see Data ). It is not known whether DELSTRIGO or the components of DELSTRIGO affects human milk production, or has effects on the breastfed infant. Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1-negative infants), (2) developing viral resistance (in HIV-1-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults. Data Doravirine : Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from GD 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14.

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-naïve pediatric participants 12 to less than 18 years of age. The safety and efficacy of DELSTRIGO in these pediatric participants were similar to that in adults, and there was no clinically significant difference in exposure for the components of DELSTRIGO. [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ]. Safety and efficacy of DELSTRIGO in pediatric patients weighing less than 35 kg have not been established.

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

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