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1 Indications And Usage
PIFELTRO™ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history.
2.1 Recommended Dosage
The recommended dosage regimen of PIFELTRO in adults is one 100 mg tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)].
2.2 Dosage Adjustment With Rifabutin
If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart) for the duration of rifabutin co-administration [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
3 Dosage Forms And Strengths
PIFELTRO film-coated tablets are white, oval-shaped tablets, debossed with the corporate logo and 700 on one side and plain on the other side. Each tablet contains 100 mg doravirine.
- PIFELTRO 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 PIFELTRO [see Warnings and Precautions (5.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. These drugs include, but are not limited to, the following:the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytointhe androgen receptor inhibitor enzalutamidethe antimycobacterials rifampin, rifapentinethe cytotoxic agent mitotaneSt. John's wort (Hypericum perforatum)
5.1 Risk Of Adverse Reactions Or Loss Of Virologic Response Due To Drug Interactions
The concomitant use of PIFELTRO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of PIFELTRO and possible development of resistance [see Dosage and Administration (2.2), Contraindications (4) and Drug Interactions (7.1)].See Table 5 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 PIFELTRO therapy, review concomitant medications during PIFELTRO therapy, and monitor for adverse reactions.
5.2 Immune 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, and Guillain-Barré syndrome) 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.
6 Adverse Reactions
- The following adverse reactions are discussed in other sections of the labeling:Immune Reconstitution Syndrome [see Warnings and Precautions (5.2)]
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.
The safety assessment of PIFELTRO used in combination with other antiretroviral agents is based on Week 48 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)).In DRIVE-FORWARD, 766 adult subjects received either PIFELTRO 100 mg (n=383) or darunavir 800 mg + ritonavir 100 mg (DRV+r) (n=383) once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC). By Week 48, 2% in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.In DRIVE-AHEAD, 728 adult subjects received either DELSTRIGO [doravirine (DOR)/3TC/TDF] (n=364) or efavirenz (EFV)/FTC/TDF once daily (n=364). By Week 48, 3% in the DELSTRIGO group and 6% 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-FORWARD and 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 2 or higher (moderate or severe) occurred in ≥ 2% of subjects treated with doravirine. of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48)DRIVE-FORWARDDRIVE-AHEADPIFELTRO+2 NRTIsNRTI = nucleoside reverse transcriptase inhibitor.Once DailyN=383DRV+r+2 NRTIsOnce DailyN=383DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364NRTIs = FTC/TDF or ABC/3TC.Fatigue: includes fatigue, asthenia, malaiseAbdominal Pain: includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfortRash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustularNausea7%8%5%7%Headache6%3%4%4%Fatigue6%3%4%4%Diarrhea5%13%3%5%Abdominal Pain5%2%1%2%Dizziness3%2%7%32%Rash2%3%2%12%Abnormal Dreams1%<1%5%9%Insomnia1%2%4%5%Somnolence0%<1%3%7%The majority (72%) of adverse reactions associated with doravirine occurred at severity Grade 1 (mild).
Neuropsychiatric Adverse Events
For 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 DifferenceDELSTRIGO - EFV/FTC/TDFEstimate (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 disturbancesPredefined 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 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 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 subjects in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of subjects 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.
The percentages of subjects with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with PIFELTRO or DRV+r in DRIVE-FORWARD, or 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-FORWARD and DRIVE-AHEAD (Week 48)DRIVE-FORWARDDRIVE-AHEADLaboratory Parameter Preferred Term (Unit)/LimitPIFELTRO+2 NRTIsOnce DailyN=383DRV+r+2 NRTIsOnce DailyN=383DELSTRIGOOnce DailyN=364EFV/FTC/TDFOnce DailyN=364Blood ChemistryULN = Upper limit of normal range.Note: NRTIs = FTC/TDF or ABC/3TC.Total bilirubin1.1 - < 1.6 × ULN5%1%4%0%1.6 - <2.6 × ULN2%<1%2%0%≥2.6 × ULN0%0%<1%<1%Creatinine (mg/dL)>1.3 - 1.8 × ULN or Increase of >0.3 mg/dL above baseline3%4%2%1%>1.8 × ULN or Increase of ≥1.5 × above baseline2%3%2%1%Aspartate aminotransferase (IU/L)2.5 - <5.0 × ULN4%3%2%2%≥5.0 × ULN<1%2%<1%2%Alanine aminotransferase (IU/L)2.5 - <5.0 × ULN3%2%3%4%≥5.0 × ULN1%2%<1%2%Alkaline phosphatase (IU/L)2.5 - <5.0 × ULN<1%<1%0%<1%≥5.0 × ULN0%0%0%<1%Lipase1.5 - <3.0 × ULN4%5%5%4%≥3.0 × ULN3%2%1%2%Creatine kinase (IU/L) 6.0 - <10.0 × ULN2%3%2%2%≥10.0 × ULN3%4%2%3%Cholesterol, fasted (mg/dL)≥300 mg/dL0%<1%<1%<1%LDL cholesterol, fasted (mg/dL)≥190 mg/dL<1%3%<1%2%Triglycerides, fasted (mg/dL)>500 mg/dL<1%1%<1%3%
Change In Lipids From Baseline
For DRIVE-FORWARD and 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.The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority for doravirine 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-FORWARD and DRIVE-AHEAD (Week 48)Subjects on lipid-lowering agents at baseline were excluded from these analyses (in DRIVE-FORWARD: PIFELTRO n=12 and DRV+r n=14; in DRIVE-AHEAD: DELSTRIGO n=15 and EFV/FTC/TDF n=10). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (in DRIVE-FORWARD: PIFELTRO n=6 and DRV+r n=4; in DRIVE-AHEAD: DELSTRIGO n=3 and EFV/FTC/TDF n=8).DRIVE-FORWARDPIFELTRO+2 NRTIsOnce DailyN=320DRV+r+2 NRTIsOnce DailyN=311Laboratory Parameter Preferred TermBaselineChangeBaselineChangeDifference Estimates (95% CI)LDL-Cholesterol (mg/dL)p-values for the pre-specified hypothesis testing for treatment difference were <0.0001 in both DRIVE-FORWARD and DRIVE-AHEAD.91.4-4.692.39.5-14.4 (-18.0, -10.8)Non-HDL Cholesterol (mg/dL)113.6-5.4114.513.7-19.4 (-23.4, -15.4) Total Cholesterol (mg/dL) Not pre-specified for hypothesis testing.157.2-1.4157.818.0- Triglycerides (mg/dL) 111.0-3.1113.724.5- HDL-Cholesterol (mg/dL) 43.64.043.34.3- DRIVE-AHEADDELSTRIGO Once DailyN=320EFV/FTC/TDF Once DailyN=307Laboratory Parameter Preferred TermBaselineChangeBaselineChangeDifference Estimates (95% CI)LDL-Cholesterol (mg/dL)91.7-184.108.40.206-10.2 (-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) 156.8-2.2156.821.1-Triglycerides (mg/dL) 118.7-12.0122.621.6-HDL-Cholesterol (mg/dL) 42.11.841.68.4-
7.1 Effect Of Other Drugs On Pifeltro
Co-administration of PIFELTRO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce PIFELTRO efficacy [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. Co-administration of PIFELTRO and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.Table 5 shows significant drug interactions with PIFELTRO.Table 5: Drug Interactions with PIFELTROThis table is not all inclusive.Concomitant Drug Class:Drug NameEffect on ConcentrationClinical 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 a 4-week cessation period is recommended prior to initiation of PIFELTRO.Anticonvulsantscarbamazepineoxcarbazepinephenobarbitalphenytoin↓ doravirineCo-administration is contraindicated with these anticonvulsants.At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.AntimycobacterialsrifampinThe interaction between PIFELTRO and the concomitant drug was evaluated in a clinical study.rifapentine↓ doravirineCo-administration is contraindicated with rifampin or rifapentine.At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.rifabutin↓ doravirineIncrease PIFELTRO dosage to one tablet twice daily when co-administered with rifabutin [see Dosage and Administration (2.2)].At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.Cytotoxic Agentsmitotane↓ doravirineCo-administration is contraindicated with mitotane.At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.HIV Antiviral Agentsefavirenzetravirinenevirapine↓ doravirineUse with efavirenz, etravirine, or nevirapine is not recommended.Herbal ProductsSt. John's wort↓ doravirineCo-administration is contraindicated with St. John's wort.At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone [see Clinical Pharmacology (12.3)].
7.2 Effect Of Pifeltro On Other Drugs
No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam [see Clinical Pharmacology (12.3)].
Pregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk SummaryNo adequate human data are available to establish whether or not PIFELTRO poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures ≥8 times the exposure in humans at the recommended human dose (RHD) of PIFELTRO (see Data).The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). 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.
Animal DataDoravirine 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 gestation day 20.
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.It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Doravirine is present in the milk of lactating rats (see Data). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving PIFELTRO.
DataDoravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day 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.
Cardiac ElectrophysiologyAt a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of PIFELTRO, doravirine does not prolong the QT interval to any clinically relevant extent.
Specific PopulationsNo clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown.
Patients with Renal ImpairmentIn a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis [see Use in Specific Populations (8.6)].
Patients with Hepatic ImpairmentNo 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) [see Use in Specific Populations (8.7)].
Drug Interaction StudiesDoravirine 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 a 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 7. A single doravirine 100 mg dose was administered in these studies unless otherwise noted.Table 7: 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.CmaxC24CI = 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)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, ritonavir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam.
Mechanism of ActionDoravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ.
Antiviral Activity in Cell CultureDoravirine 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. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 0.6 nM to 10.0 nM.
Antiviral Activity in Combination with other HIV Antiviral AgentsThe antiviral activity of doravirine in cell culture was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.
In Cell CultureDoravirine-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, V106M, V106I, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F.
In Clinical TrialsIn the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747), 11 subjects showed the emergence of doravirine-associated resistance substitutions in their HIV among 28 (39%) 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 resistance data). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, V108I, E138G/K, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F. Seven of 11 (64%) subjects with emergent doravirine-associated resistance substitutions showed doravirine phenotypic resistance and all of them had at least a 100-fold reduction in doravirine susceptibility (range >97- to >211–fold reduction in doravirine susceptibility). The other 4 virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold. Of the 28 subjects in the resistance analysis subset, 8 subjects (29%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, lamivudine, emtricitabine, or TDF) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials. The resistance-associated substitutions that emerged were RT M41L (n=1), A62V (n=1), K65R (n=2), T69T/A (n=1), and M184V (n=5).In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no subjects showed the emergence of darunavir-associated resistance substitutions among 9 subjects with resistance data and none of the subjects had emergent resistance to lamivudine or TDF. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), 12 subjects showed the emergence of efavirenz-associated resistance substitutions among 20 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), and M184V/I (n=5).
Cross-ResistanceA panel of 96 diverse clinical isolates containing NNRTI-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.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 7 virologic failures who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 3 had partial resistance to etravirine based on the Monogram PhenoSense assay.
CarcinogenesisDoravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A 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.
MutagenesisDoravirine was not genotoxic in a 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.
Impairment of fertilityThere were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD.
Drug InteractionsInform patients that PIFELTRO 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. John's wort [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)]For patients concomitantly receiving rifabutin, take one tablet of PIFELTRO twice daily (approximately 12 hours apart) [see Dosage and Administration (2.2)].
Immune Reconstitution Syndrome Inform 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 body's 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 (5.2)].
Dosing InstructionsAdvise patients to take PIFELTRO every day at a 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 a patient forgets to take PIFELTRO, 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 2 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 in pregnant individuals exposed to PIFELTRO [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)].
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8.4 Pediatric Use
Safety and efficacy of PIFELTRO have not been established in pediatric patients less than 18 years of age.
8.5 Geriatric Use
Clinical trials of PIFELTRO 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 PIFELTRO in elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
8.6 Renal Impairment
No dosage adjustment of PIFELTRO is required in patients with mild, moderate, or severe renal impairment. PIFELTRO has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dosage adjustment of PIFELTRO is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. PIFELTRO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].
PIFELTRO is a film-coated tablet containing doravirine for oral administration.Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).Each tablet contains 100 mg of doravirine as the active ingredient. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablets are film coated with a coating material containing the following inactive ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The coated tablets are polished with carnauba wax.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 a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75.It has the following structural formula:Doravirine is practically insoluble in water.
12.1 Mechanism Of Action
Doravirine is an antiretroviral drug [see Microbiology (12.4)].
In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of PIFELTRO, (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.
Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are provided in Table 6.Table 6: Pharmacokinetic Properties of DoravirineParameterDoravirineAbbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration; C24=concentration at 24 hours; Tmax time to Cmax; Vdss= volume of distribution at steady state, t1/2=elimination half-life; CL/F=apparent clearance; CLrenal=apparent renal clearanceGeneral Steady State ExposureDoravirine 100 mg once daily to HIV-1 infected subjects,Presented as geometric mean (%CV: geometric coefficient of variation)AUC0-24(mcg∙h/mL)16.1 (29)Cmax(mcg/mL)0.962 (19)C24(mcg/mL)0.396 (63) Time to Steady State (Days)2 Accumulation Ratio1.2 to 1.4AbsorptionAbsolute Bioavailability64%Tmax (h)2 Effect of FoodGeometric mean ratio [high-fat meal/fasting] and (90% confidence interval) for PK parameters. High fat meal is approximately 1,000 kcal, 50% fat. The effect of food is not clinically relevant.AUC Ratio1.16 (1.06, 1.26)Cmax Ratio1.03 (0.89, 1.19)C24 Ratio1.36 (1.19, 1.55)DistributionVdss (L)Based on IV dose60.5Plasma Protein Binding76%Eliminationt1/2 (h)15CL/F (mL/min)106 (35.2)CLrenal (mL/min)9.3 (18.6) MetabolismPrimary Pathway(s)CYP3A ExcretionMajor Route of EliminationMetabolismUrine (unchanged)6%Biliary/Fecal (unchanged)Minor
The efficacy of PIFELTRO is based on the analyses of 48-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials (DRIVE-FORWARD, NCT02275780 and DRIVE-AHEAD, NCT02403674) in HIV-1 infected subjects with no antiretroviral treatment history (n=1494).In DRIVE-FORWARD, 766 subjects were randomized and received at least 1 dose of either PIFELTRO once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years, 16% were female, 27% were non-white, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC, and 87% received FTC/TDF; these characteristics were similar between treatment groups.In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either DELSTRIGO (DOR/3TC/TDF) 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 B or C co-infection, 14% had a 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 48 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 8. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.In DRIVE-FORWARD, the mean CD4+ T-cell counts in the PIFELTRO and DRV+r groups increased from baseline by 193 and 186 cells/mm3, respectively.In DRIVE-AHEAD, the mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 198 and 188 cells/mm3, respectively.Table 8: Virologic Outcome in DRIVE-FORWARD and DRIVE-AHEAD at Week 48 in HIV-1 Adults with No Antiretroviral Treatment History OutcomeDRIVE-FORWARDDRIVE-AHEADPIFELTRO + 2 NRTIsOnce DailyDRV+r + 2 NRTIsOnce DailyDELSTRIGOOnce DailyEFV/FTC/TDF Once DailyN=383N=383N=364N=364Note: NRTIs = FTC/3TC or ABC/3TC.HIV-1 RNA <50 copies/mL84%80%84%81% Treatment Differences (95% CI) The 95% CIs for the treatment differences were calculated using stratum-adjusted Mantel-Haenszel method.3.9% (-1.6%, 9.4%)3.5% (-2.0%, 9.0%)HIV-1 RNA ≥ 50 copies/mLIncludes subjects who discontinued study drug or study before Week 48 for lack or loss of efficacy and subjects with HIV-1 RNA equal to or above 50 copies/mL in the Week 48 window (relative day 295-378).11%13%11%10%No Virologic Data at Week 48 Window5%7%5%9% 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 48 window.1%3%2%7% 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.3%4%2%2% On study but missing data in window<1%<1%0<1%Proportion (%) of Subjects With HIV-1 RNA <50 copies/mL at Week 48 by Baseline and Demographic CategoryGender Male84% (n = 319)82% (n = 326)84% (n = 305)80% (n = 311) Female81% (n = 64)67% (n = 57)85% (n = 59)83% (n = 53)Race White87% (n = 280)83% (n = 280)84% (n = 177)81% (n = 170) Non-White75% (n = 103)73% (n = 103)84% (n = 187)80% (n = 194)Ethnicity Hispanic or Latino88% (n = 93)81% (n = 86)83% (n = 126)84% (n = 120) Not Hispanic or Latino82% (n = 284)79% (n = 290)85% (n = 236)79% (n = 238)NRTI Background Therapy FTC/TDF83% (n = 333)81% (n = 335)-- ABC/3TC86% (n = 50)75% (n = 48)--Baseline HIV-1 RNA (copies/mL) ≤100,000 copies/mL86% (n = 300)81% (n = 308)86% (n = 291)83% (n = 282) >100,000 copies/mL77% (n = 83)74% (n = 74)77% (n = 73)72% (n = 82)CD4+ T-cell Count (cells/mm3) ≤200 cells/mm381% (n = 42)66% (n = 67)66% (n = 44)78% (n = 46) >200 cells/mm384% (n = 341)83% (n = 316)87% (n = 320)81% (n = 318)Viral SubtypeViral subtype was not available for two subjects in DRIVE-AHEAD. Subtype B84% (n = 266)82% (n = 272)84% (n = 232)80% (n = 253) Subtype Non-B83% (n = 117)76% (n = 111)85% (n = 130)83% (n = 111)
16 How Supplied/Storage And Handling
Each PIFELTRO tablet contains 100 mg of doravirine, is white, oval-shaped and film-coated, and is debossed with the corporate logo and 700 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-3069-01) with silica gel desiccant and is closed with a child-resistant closure.
Storage And Handling
Store PIFELTRO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant.Store PIFELTRO at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
17 Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Spl Patient Package Insert
- Patient InformationPIFELTRO™ (pih-FEL-tro) (doravirine) tabletsWhat is PIFELTRO?PIFELTRO is a prescription medicine that is used together with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults who have not taken HIV-1 medicines before.HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).It is not known if PIFELTRO is safe and effective in children under 18 years of age.Who should not take PIFELTRO?Do not take PIFELTRO if you take any of the following medicines:carbamazepineoxcarbazepinephenobarbitalphenytoinenzalutamiderifampinrifapentinemitotaneSt. John's wortAsk your doctor 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 4 weeks, talk to your doctor or pharmacist before starting treatment with PIFELTRO.What should I tell my doctor before treatment with PIFELTRO?Before treatment with PIFELTRO, tell your doctor about all of your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if PIFELTRO can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with PIFELTRO.Pregnancy Registry: There is a pregnancy registry for people who take PIFELTRO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you take PIFELTRO.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if PIFELTRO can pass into your breast milk.Talk with your doctor about the best way to feed your baby.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some medicines interact with PIFELTRO. Keep a list of your medicines to show your doctor and pharmacist.Tell your doctor if you have taken rifabutin in the past 4 weeks.You can ask your doctor or pharmacist for a list of medicines that interact with PIFELTRO.Do not start taking a new medicine without telling your doctor. Your doctor can tell you if it is safe to take PIFELTRO with other medicines.How do I take PIFELTRO?Take PIFELTRO every day exactly as your doctor tells you to take it.Take PIFELTRO 1 time each day, at about the same time every day.If you take the medicine rifabutin during treatment with PIFELTRO, take PIFELTRO 2 times each day, about 12 hours apart, as prescribed by your doctor. You may not have enough doravirine in your blood if you take rifabutin during treatment with PIFELTRO.Take PIFELTRO with or without food.Do not change your dose or stop taking PIFELTRO without talking to your doctor. Stay under a doctor's care when taking PIFELTRO.It is important that you do not miss or skip doses of PIFELTRO.If you miss a dose of PIFELTRO, 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 2 doses of PIFELTRO at the same time.If you have any questions, call your doctor or pharmacist.When your PIFELTRO supply starts to run low, get more from your doctor or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to PIFELTRO and become harder to treat.What are the possible side effects of PIFELTRO?PIFELTRO can cause serious side effects, including: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 a long time. Tell your doctor right away if you start having any new symptoms after starting your HIV-1 medicine.The most common side effects of PIFELTRO include:nauseadizzinessheadachetirednessdiarrheastomach (abdominal) painabnormal dreamsThese are not all the possible side effects of PIFELTRO.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should I store PIFELTRO?Store PIFELTRO tablets at room temperature between 68°F to 77°F (20°C to 25°C).Keep PIFELTRO in the original bottle.Do not take the tablets out of the bottle to store in another container, such as a pill box.Keep the bottle tightly closed to protect PIFELTRO from moisture.The PIFELTRO bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant.Keep PIFELTRO and all medicines out of the reach of children.General information about the safe and effective use of PIFELTRO.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use PIFELTRO for a condition for which it was not prescribed. Do not give PIFELTRO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about PIFELTRO that is written for healthcare professionals.What are the ingredients in PIFELTRO?Active ingredient: doravirine.Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The tablet film coating contains hypromellose, lactose monohydrate, titanium dioxide and triacetin. The coated tablets are polished with carnauba wax.Manufactured by: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & 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 © 2018 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.usppi-mk1439-t-1808r000For more information, go to www.PIFELTRO.com or call 1-877-888-4231.This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 08/2018
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