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Doravirine Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Doravirine 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 the following structural formula:

Empirical formula: C17H11ClF3N5O3 - Molecular weight: 425.75 g/mol

Doravirine is practically insoluble in water.

2. INDICATIONS AND USAGE

Doravirine is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history.

3. DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage

The recommended dosage regimen of doravirine in adults is one 100 mg tablet taken orally once daily with or without food [see Clinical Pharmacology].

3.2 Dosage Adjustment with Rifabutin

If doravirine is co-administered with rifabutin, increase doravirine 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].

4. CONTRAINDICATIONS

Doravirine 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 doravirine [see Warnings and Precautions (5.1), Drug Interactions (7.1), and Clinical Pharmacology]. 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)

5. WARNINGS AND PRECAUTIONS

5.1 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of doravirine and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of doravirine and possible development of resistance [see Dosage and Administration (3.2), 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 doravirine therapy, review concomitant medications during doravirine 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.

Adverse Reactions in Adults with No Prior Antiretroviral Treatment History

The safety assessment of doravirine 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 doravirine 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 doravirine 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 DRIVEFORWARD and DRIVE-AHEAD are presented in Table 1.

Table 1: Adverse Reactions* (All Grades) Reported in ≥5% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48)

* Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator.

† No adverse reactions of Grade 2 or higher (moderate or severe) occurred in ≥ 2% of subjects treated with doravirine.

‡ NRTI = nucleoside reverse transcriptase inhibitor.

NRTIs = FTC/TDF or ABC/3TC.

Fatigue: includes fatigue, asthenia, malaise

Abdominal Pain: includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort

Rash: includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular

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/TDFtreated 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 Events* (Week 48)

* All causality and all grade events were included in the analysis.

† 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).

‡ Predefined using MedDRA preferred terms, including: abnormal dreams, hyposomnia, initial insomnia, insomnia, nightmare, sleep disorder, somnambulism.

§ Predefined using MedDRA preferred terms, including: altered state of consciousness, lethargy, somnolence, syncope.

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.

Laboratory Abnormalities

The percentages of subjects with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with doravirine 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)

ULN = Upper limit of normal range.

Note: NRTIs = FTC/TDF or ABC/3TC.

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: doravirine 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: doravirine n=6 and DRV+r n=4; in DRIVE-AHEAD: DELSTRIGO n=3 and EFV/FTC/TDF n=8).

* p-values for the pre-specified hypothesis testing for treatment difference were <0.0001 in both DRIVE-FORWARD and DRIVEAHEAD.

† Not pre-specified for hypothesis testing.

7. DRUG INTERACTIONS

7.1 Effect of Other Drugs on Doravirine

Co-administration of doravirine with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce doravirine efficacy [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology]. Co-administration of doravirine and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.

Table 5 shows significant drug interactions with doravirine.

Table 5: Drug Interactions with Doravirine*

↑ = increase, ↓ = decrease

* This table is not all inclusive.

† The interaction between doravirine and the concomitant drug was evaluated in a clinical study.

All other drug-drug interactions shown are anticipated based on the known metabolic and elimination pathways.

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].

7.2 Effect of Doravirine on Other Drugs

No clinically significant changes in concentration were observed for the following agents when coadministered 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].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to doravirine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

No adequate human data are available to establish whether or not doravirine 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 doravirine (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.

Data

Animal Data

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 embryofetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on gestation day 20.

8.2 Lactation

Risk Summary

The 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 doravirine.

Data

Doravirine 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.

8.4 Pediatric Use

Safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age.

8.5 Geriatric Use

Clinical trials of doravirine 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 doravirine 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].

8.6 Renal Impairment

No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients [see Clinical Pharmacology].

8.7 Hepatic Impairment

No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology].

10. MECHANISM OF ACTION

Doravirine is an antiretroviral drug.

Mechanism of Action

Doravirine 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 Culture

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. 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 Agents

The 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.

Resistance

In Cell Culture

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, V106M, V106I, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F.

In Clinical Trials

In 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-Resistance

A 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 resistanceassociated 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.

11. PHARMACODYNAMICS

In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of doravirine, (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 Electrophysiology

At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of doravirine, doravirine does not prolong the QT interval to any clinically relevant extent.

12. PHARMACOKINETICS

Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are provided in Table 6.

Table 6: Pharmacokinetic Properties of Doravirine

* Doravirine 100 mg once daily to HIV-1 infected subjects

† Presented as geometric mean (%CV: geometric coefficient of variation)

‡ Geometric 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.

§ Based on IV dose

Abbreviations: 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 clearance

Specific Populations

No 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 Impairment

In 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 Impairment

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) [see Use in Specific Populations (8.7)].

Drug Interaction Studies

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 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 Drug

CI = confidence interval; QD = once daily; BID = twice daily

* AUC0-∞ for single-dose, AUC0-24 for once daily.

† Changes in doravirine pharmacokinetic values are not clinically relevant.

‡ A single doravirine 50 mg dose (0.5 times the recommended approved dose) was administered.

§ The first day following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.

¶ 14 days following the cessation of efavirenz therapy and initiation of doravirine 100 mg QD.

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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

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 at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store PIFELTRO in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant.

Rx only

Rev 08/18