Pifeltro Product Monograph

Recent Major Label Changes

Table of Content

Sections or subsections that are not applicable at the time of authorization are not listed.

Recent Major Label Changes ................................................................................................. 2

Table of Content ................................................................................................................... 2

Part 1: Healthcare Professional Information.......................................................................... 4

1 Indications ................................................................................................................ 4

1.1 Pediatrics ................................................................................................................ 4

1.2 Geriatrics ................................................................................................................ 4

2 Contraindications ...................................................................................................... 4

4 Dosage and Administration ....................................................................................... 4

4.1 Dosing Considerations ........................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment ...................................................... 5

4.5 Missed Dose ........................................................................................................... 5

5 Overdosage ............................................................................................................... 5

6 Dosage Forms, Strengths, Composition, and Packaging .............................................. 6

7 Warnings And Precautions ........................................................................................ 6

7.1 Special Populations ................................................................................................ 7

7.1.1 Pregnancy ........................................................................................................... 7

7.1.2 Breastfeeding ..................................................................................................... 8

7.1.3 Pediatrics ............................................................................................................ 8

7.1.4 Geriatrics ............................................................................................................ 8

8 ADVERSE REACTIONS................................................................................................. 8

8.1 Adverse Reaction Overview ................................................................................... 8

8.2 Clinical Trial Adverse Reactions ............................................................................. 9

8.2.1 Clinical Trial Adverse Reactions – Pediatrics.................................................... 11

8.3 Less Common Clinical Trial Adverse Reactions .................................................... 11

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data ............................................................................................................. 12

8.5 Post-Market Adverse Reactions ........................................................................... 14

9 Drug Interactions .................................................................................................... 15

9.2 Drug Interactions Overview ................................................................................. 15

9.4 Drug-Drug Interactions ........................................................................................ 15

9.5 Drug-Food Interactions ........................................................................................ 20

9.6 Drug-Herb Interactions ........................................................................................ 20

9.7 Drug-Laboratory Test Interactions....................................................................... 20

10 Clinical Pharmacology ............................................................................................. 20

10.1 Mechanism of Action ........................................................................................... 20

10.2 Pharmacodynamics .............................................................................................. 20

10.3 Pharmacokinetics ................................................................................................. 20

11 Storage, Stability, and Disposal ................................................................................ 22

12 Special Handling Instructions ................................................................................... 22

Part 2: Scientific Information .............................................................................................. 23

13 Pharmaceutical Information .................................................................................... 23

14 Clinical Trials ........................................................................................................... 23

14.1 Clinical Trials by Indication .................................................................................. 23

15 Microbiology ........................................................................................................... 35

16 Non-Clinical Toxicology ........................................................................................... 37

Patient Medication Information ......................................................................................... 38

Part 1: Healthcare Professional Information

1 Indications

PIFELTRO® (doravirine) is indicated, in combination with other antiretroviral medicinal products, for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older and weighing at least 35kg without past or present evidence of viral resistance to doravirine.

1.1 Pediatrics

Pediatrics (≥ 12 to < 18 years of age): The safety and efficacy of PIFELTRO® in pediatric patients ≥ 12 years of age and weighing at least 35 kg receiving doravirine 100 mg once daily has been established (see 8.2.1 Clinical Trial Adverse Reactions – Pediatrics and 14 Clinical Trials).

Safety and efficacy of PIFELTRO® have not been established in patients younger than 12 years of age and weighing less than 35 kg.

1.2 Geriatrics

Geriatric (≥ 65 years of age): There are limited data available on the use of doravirine in patients aged 65 years and over.

2 Contraindications

PIFELTRO® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

PIFELTRO® is contraindicated with drugs that are strong cytochrome P450 CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of PIFELTRO® (see 9.4 Drug-Drug Interactions). These drugs include, but are not limited to, the following:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the androgen receptor inhibitor enzalutamide
• the antimycobacterials rifampin, rifapentine¹
• the cytotoxic agent mitotane
• St. John’s wort (Hypericum perforatum).

4 Dosage and Administration

4.1 Dosing Considerations

• PIFELTRO® is a tablet containing 100 mg of doravirine.
• PIFELTRO® can be taken with or without food.

As with all antiretroviral drugs, therapy should be initiated by a healthcare professional experienced in the management of HIV-1 infection.

4.2 Recommended Dose and Dosage Adjustment

Recommended Dosage

Adults and Pediatric Patients 12 Years and older and Weighing at Least 35 kg

The recommended dosage regimen of PIFELTRO® is one 100 mg tablet taken orally once daily.

Pediatrics (< 12 years of age)

Safety and efficacy of PIFELTRO® have not been established in patients younger than 12 years of age and weighing less than 35 kg.

Geriatrics (≥ 65 years of age)

There are limited data available on the use of doravirine in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see 10.3 Pharmacokinetics). No dose adjustment of PIFELTRO® is needed in elderly patients.

Dosage Adjustment in Adults

Renal Impairment

No dose 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 10.3 Pharmacokinetics).

Hepatic Impairment

No dose 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 10.3 Pharmacokinetics).

Co-administration with Rifabutin

If PIFELTRO® is co-administered with rifabutin, one tablet of PIFELTRO® should be taken twice daily (approximately 12 hours apart) (see 9.4 Drug-drug interactions).

4.5 Missed Dose

If the patient misses a dose of PIFELTRO®, the patient should take PIFELTRO® as soon as possible unless it is almost time for the next dose. The patient should not take 2 doses at one time and instead take the next dose at the regularly scheduled time.

5 Overdosage

There is no known specific treatment for overdose with PIFELTRO®. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition, and Packaging

PIFELTRO® is a film-coated tablet containing doravirine for oral administration.

Table 1 – Dosage Forms, Strengths, and Composition

Description

PIFELTRO® 100 mg tablet is a white oval-shaped, film-coated tablet, debossed with the corporate logo and 700 on one side and plain on the other side.

PIFELTRO® tablets are available in bottles of 30.

7 Warnings And Precautions

General

History of treatment failure and resistance

PIFELTRO® has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. In the Phase 3 study in patients with no antiretroviral treatment history, NNRTI-associated mutations detected at screening were part of exclusion criteria. In the Phase 3 study in virologically-suppressed patients, data in patients with a past history of NNRTI resistance were limited (see 15 Microbiology).

PIFELTRO® should not be used in antiretroviral-experienced patients with HIV-1 harboring NNRTI resistance-associated mutations which may confer resistance to doravirine or with suspected NNRTI resistance in virologically-suppressed patients if no genotype is available (see 15 Microbiology).

Driving and Operating Machinery

Patients should be informed that fatigue, dizziness, and somnolence have been seen during treatment with doravirine (see 8.2 Clinical Trial Adverse Reactions). Patients should be instructed that, if they experience any of these symptoms, they should avoid potentially hazardous tasks such as driving or operating machinery.

Drug Interactions

Caution should be given to prescribing PIFELTRO® with drugs that may reduce the exposure of doravirine (see 2 Contraindications, 9.4 Drug-Drug Interactions).

Endocrine and Metabolism

Serum Lipids and Blood Glucose

Serum lipid and blood glucose levels may increase during antiretroviral therapy (ART). Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders and blood glucose elevations should be managed as clinically appropriate.

Immune

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory 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, autoimmune hepatitis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution syndrome; however, the time to onset is more variable and can occur many months after initiation of treatment.

Reproductive Health: Female and Male Potential

• Fertility

  No human data on the effect of doravirine on fertility are available. Animal studies do not indicate harmful effects of doravirine on fertility at systemic exposures that were approximately 7 times higher than the exposure in humans at the recommended clinical dose (see section 16 Non-Clinical Toxicology).

Skin

In clinical trial data, drug related rash of moderate to severe intensity occurred in 0.3% of patients in DRIVE-FORWARD and DRIVE-AHEAD, respectively.

Severe skin reactions, including toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens (see section 8.5 Post-Market Adverse Reactions). Discontinue PIFELTRO®, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash, or hypersensitivity reactions develop. Clinical status should be closely monitored, and appropriate therapy should be initiated.

7.1 Special Populations

7.1.1 Pregnancy

PIFELTRO® has not been studied in pregnant women. PIFELTRO® should not be used in pregnant women unless the potential benefits outweigh the potential risks to the fetus.

Reproduction studies performed in rats and rabbits at exposures up to approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose (RHD) did not indicate harmful effects of doravirine with respect to pregnancy or embryofetal development.

In pregnant rats and rabbits, doravirine was able to cross the placenta.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant patients exposed to PIFELTRO®, an International Antiretroviral Pregnancy Registry has been established.

Physicians are encouraged to report pregnancy cases for inclusion in the registry. SM_APR@APRegistry.com (www.apregistry.com)

Telephone: 1-800-258-4263

Fax: 1-800-800-1052

7.1.2 Breastfeeding

HIV-1 infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV. Doravirine was excreted into the milk of lactating rats.

It is unknown whether doravirine is excreted in human milk. Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving PIFELTRO®.

7.1.3 Pediatrics

Pediatrics (≥ 12 years to < 18 years): The safety and efficacy of PIFELTRO® for the treatment of HIV-1 infection have been established in pediatric patients 12 years of age and older and weighing at least 35 kg (see 1.1 Pediatrics and 14 Clinical Trials).

Use of PIFELTRO® in pediatric patients 12 years and older and weighing at least 35 kg is supported by evidence from adequate and well-controlled trials in adults and an open-label trial in virologically-suppressed or treatment-naïve pediatric subjects. The safety, efficacy, and exposure of doravirine in these pediatric subjects were similar to that in adults (see 10.3 Pharmacokinetics ).

Pediatrics (< 12 years of age): The safety and efficacy of PIFELTRO® have not been established in patients younger than 12 years of age and weighing less than 35 kg.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): There are limited data available on the use of doravirine in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see 10.3 Pharmacokinetics). No dose adjustment of PIFELTRO® is needed in elderly patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety assessment of PIFELTRO® in antiretroviral treatment-naïve, HIV-1-infected subjects, is based on the analyses of data through 48- and 96 Weeks from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)).

In subjects receiving PIFELTRO®, the serious adverse reactions of nausea, vomiting, asthenia, insomnia, and nightmares were reported, and these reactions were reported by <1% subjects. The most frequently reported adverse reaction with doravirine was nausea (6 %). There were no adverse reactions of moderate to severe intensity with an incidence of greater than or equal to 2%.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Clinical Trials in Antiretroviral Treatment-Naïve Adults

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 in a double-blind design, each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC). By Week 48, 1.6% in the PIFELTRO® group and 3.1% in the DRV+r group had adverse events leading to discontinuation of study medication.

In DRIVE-AHEAD, 728 adult subjects received either DELSTRIGO® (doravirine/lamivudine/tenofovir DF) (n=364) or efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) once daily (n=364). By Week 48, 3.0% in the DELSTRIGO® group and 6.6% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication.

Adverse reactions reported in greater than or equal to 2% of subjects in any treatment group in adults with no antiretroviral treatment history in DRIVE-FORWARD and DRIVE-AHEAD are presented in Table 2.

Table 2 - Adverse Reactions^Þ (All Grades) Reported in >2%^† of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in DRIVE-FORWARD and DRIVE-AHEAD (Week 48)

Overall, the clinical adverse experiences at Week 96 were consistent with those observed at Week 48.

Clinical Trials in Virologically-Suppressed Adults

The safety of PIFELTRO® in virologically-suppressed adults was based on Week 48 data from 670 subjects in the DRIVE-SHIFT trial (see Virologically-Suppressed Adult Subjects). Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no antiretroviral treatment history.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The safety of doravirine as a component of DELSTRIGO® was evaluated in 45 HIV-1-infected virologically-suppressed or treatment-naïve pediatric patients 12 to less than 18 years of age through Week 24 in an open-label trial (IMPAACT 2014 (Protocol 027)) (see Pediatric Subjects). The safety profile in pediatric subjects was similar to that in adults. There were no serious or Grade 3 or 4 adverse reactions. No subjects discontinued due to an adverse event.

8.3 Less Common Clinical Trial Adverse Reactions

Other adverse reactions reported in <2% of patients in the DRIVE-FORWARD, DRIVE-AHEAD or DRIVE-SHIFT trials through Week 96 and Week 48 respectively are listed below.

Blood and Lymphatic Systems Disorders: lymph node pain, neutropenia.

Cardiac Disorders: palpitations.

Ear and Labyrinth Disorders: motion sickness, vertigo.

Eye Disorders: vision blurred.

Gastrointestinal Disorders: abdominal discomfort, abdominal distension, abdominal pain, abnormal feces, change in bowel habits, constipation, dry mouth, dyspepsia, dysphagia, epigastric discomfort, feces soft, flatulence, frequent bowel movements, gastritis, gastrointestinal motility disorder, gastroesophageal reflux disease, irritable bowel syndrome, rectal tenesmus.

General Disorders and Administration Site Conditions: asthenia, chest discomfort, chest pain, chills, generalized oedema, malaise, pain, pyrexia, thirst.

Hepatobiliary Disorders: hepatitis, hepatocellular injury, hyperbilirubinemia.

Immune System Disorders: immune reconstitution inflammatory syndrome.

Infections and Infestations: acute sinusitis, angular cheilitis, conjunctivitis, folliculitis, gastroenteritis, lymphogranuloma venereum, oral herpes, nasopharyngitis, rash pustular.

Investigations: alanine aminotransferase increased*, amylase increased, aspartate aminotransferase increased, blood creatinine phosphokinase increased, blood triglycerides increased, bone density decreased, gastric pH decreased, hemoglobin decreased, lipase increased, weight decreased, neutrophil count decreased, weight increased.

Metabolism and Nutrition Disorders: alcohol intolerance, decreased appetite, hypertriglyceridemia, hypomagnesemia, hypophosphatemia, obesity, vitamin D deficiency.

Musculoskeletal and Connective Tissue Disorders: arthralgia, back pain, muscle spasms, musculoskeletal pain, myalgia.

Nervous System Disorders: burning sensation, cognitive disorder, disturbance in attention, dysgeusia, hyperesthesia, hypertonia, memory impairment, mental impairment, migraine, paresthesia, poor quality sleep, presyncope.

Psychiatric Disorders: adjustment disorder, aggression, anxiety, confusional state, depressed mood, depression, generalized anxiety disorder, hallucination, irritability, libido disorder, major depression, mood altered, mood swings, persistent depressive disorder, somnambulism, suicidal ideation.

Renal and Urinary Disorders: acute kidney injury, calculus urinary, nephrolithiasis, pollakiuria, polyuria, renal failure, renal pain, renal disorder.

Reproductive and Breast Disorders: erectile dysfunction.

Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea, tonsillar hypertrophy.

Skin and Subcutaneous Tissue Disorders: acne, alopecia, dermatitis allergic, hyperhidrosis, pruritus, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rosacea, seborrheic dermatitis, skin lesion, urticaria.

Vascular Disorders: hypertension.

*Reported in 2.1% in DRIVE-SHIFT

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The percentages of subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade 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 Grade 2 to 4 Laboratory Abnormalities Reported in DRIVE-FORWARD and DRIVE-AHEAD (Week 48)

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. Changes from baseline at Week 96 were similar to those seen at Week 48.

PIFELTRO® had a neutral effect on LDL and non-HDL cholesterol, total cholesterol, and triglycerides, as indicated by the differences in the mean change from baseline at Week 48. The LDL and non-HDL comparisons were pre-specified and the differences were statistically significant, showing superiority for doravirine for both parameters.

For DRIVE-SHIFT, improvements in LDL and non-HDL cholesterol, total cholesterol, and triglycerides from baseline were observed in virologically-suppressed subjects who switched to DELSTRIGO® from a ritonavir boosted PI regimen as shown in Table 4.

Table 4 - Mean Change from Baseline in Fasting Lipids in DRIVE-FORWARD, DRIVE-AHEAD and DRIVE-SHIFT

8.5 Post-Market Adverse Reactions

The following adverse reactions have been identified during postmarketing experience in patients receiving doravirine-containing regimens. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: toxic epidermal necrolysis (TEN)

Hepatobiliary Disorders: hepatitis

Investigations: hepatic enzyme increased

9 Drug Interactions

9.2 Drug Interactions Overview

Established and Other Potentially Significant Drug Interactions

Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of PIFELTRO® and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine and reduce the therapeutic effect of doravirine (see 2 Contraindications, 7 Warnings And Precautions, and 9.4 Drug-Drug Interactions). Co-administration of PIFELTRO® and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.

9.4 Drug-Drug Interactions

Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of drugs metabolized by CYP enzymes.

Table 5 shows the established and other potentially significant drug interactions with PIFELTRO® but is not inclusive.

Table 5 - Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Drugs with No Observed or Predicted Interactions with PIFELTRO®

Drug-drug interactions with PIFELTRO® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug (see section below Drug Interaction Studies): aluminum hydroxide/magnesium hydroxide/simethicone-containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, midazolam, sofosbuvir/ledipasvir, elbasvir/grazoprevir, dolutegravir, lamivudine, or tenofovir DF.

No clinically relevant drug-drug interaction is expected when PIFELTRO® is co-administered with abacavir, emtricitabine, enfuvirtide, raltegravir, maraviroc, tenofovir alafenamide, buprenorphine, naloxone, daclatasvir, simeprevir, diltiazem, verapamil, rosuvastatin, simvastatin, canagliflozin, liraglutide, sitagliptin, lisinopril, or omeprazole.

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. 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 of other drugs on the C_max, AUC, and C₂₄ values of doravirine are summarized in Table 6. The effects of co-administration of doravirine on the C_max and AUC values of other drugs are summarized in Table 7.

Table 6 - Drug Interactions: Changes in Pharmacokinetic Parameter Values of Doravirine in the Presence of Co-administered Drug

Table 7 - Drug Interactions: Changes in Pharmacokinetic Parameter Values for Co-administered Drugs in the Presence of Doravirine

9.5 Drug-Food Interactions

The single dose administration of the 100 mg PIFELTRO® tablet with a high-fat meal to healthy subjects resulted in a 16% and 36% increase in doravirine AUC and C₂₄, respectively, and C_max was not significantly affected (3% increase), in comparison to fasting.

PIFELTRO® can be taken with or without food.

9.6 Drug-Herb Interactions

Co-administration of St. John’s wort, a potent CYP3A inducer, may significantly decrease doravirine plasma concentrations, which may result in loss of therapeutic effect and possible development of resistance.

Co-administration of PIFELTRO® with St. John’s wort is contraindicated.

9.7 Drug-Laboratory Test Interactions

Interactions with clinical laboratory tests have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

PIFELTRO® contains the antiviral drug doravirine, which is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 (see 15 Microbiology).

10.2 Pharmacodynamics

Effects on Electrocardiogram

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

10.3 Pharmacokinetics

The pharmacokinetics of doravirine were studied in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Steady state is generally achieved by day 2 of once daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC0-24, Cmax, and C24. Doravirine steady state pharmacokinetics following administration of 100 mg once daily to HIV-1-infected subjects, based on a population pharmacokinetic analysis, are provided below.

Absorption

Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has an absolute bioavailability of approximately 64% for the 100 mg tablet.

Distribution

Based on administration of an IV microdose, the volume of distribution of doravirine is 60.5 L. Doravirine is approximately 76% bound to plasma proteins.

Metabolism

Based on in vitro data, doravirine is primarily metabolized by CYP3A.

Elimination

Doravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism. Excretion of unchanged drug via urinary excretion is minor. Biliary excretion of unchanged drug is not expected to be significant.

Special Populations and Conditions

• Pediatrics

Mean doravirine exposures were similar in 54 pediatric patients aged 12 to less than 18 years and weighing at least 35 kg in IMPAACT 2014 (Protocol 027) relative to adults following administration of a single dose of 100 mg doravirine or once daily DELSTRIGO®.

Table 8: Steady State Pharmacokinetics for Doravirine Following Administration of a Single 100 mg Dose of Doravirine or Once Daily DELSTRIGO® in HIV-1-Infected Pediatric Patients Aged 12 to Less than 18 Years and Weighing at Least 35 kg

The pharmacokinetics and dosing recommendations of PIFELTRO® in patients younger than 12 years of age and weighing less than 35 kg have not been established.

• Geriatrics

  No clinically relevant differences in the pharmacokinetics of doravirine have been identified in subjects at least 65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a population pharmacokinetic analysis.

• Sex

  No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine.

• Ethnic Origin

  No clinically relevant racial differences in the pharmacokinetics of doravirine have been identified based on a population pharmacokinetic analysis of doravirine in healthy and HIV-1-infected subjects.

• Hepatic Insufficiency

  Doravirine is primarily metabolized and eliminated by the liver. There was no clinically relevant difference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 subjects without hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).

• Renal Insufficiency

  Renal excretion of doravirine is minor: approximately 6% of the administered dose is excreted unchanged in urine. 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. No dose adjustment is required in patients with mild, moderate or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis

11 Storage, Stability, and Disposal

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

Store PIFELTRO® at room temperature (15°C to 30°C).

12 Special Handling Instructions

There are no special handling instructions.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name: doravirine

Chemical name: 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

Molecular formula and molecular mass: C₁₇H₁₁ClF₃N₅O₃, 425.75

Structural formula:

Physicochemical properties: Doravirine is practically insoluble in water

14 Clinical Trials

14.1 Clinical Trials by Indication

Table 9 - Summary of Subject Demographics for Clinical Trials in HIV-I-Infected Patients

Adult Subjects with No Antiretroviral Treatment History

The efficacy of PIFELTRO® (doravirine) is based on the analyses of 48-Week data from two randomized, multicenter, double-blind, active-controlled Phase 3 trials (DRIVE-FORWARD and DRIVE-AHEAD), in antiretroviral treatment-naïve, HIV-1 infected subjects (n=1494).

In DRIVE-FORWARD, 766 subjects were randomized and received at least 1 dose of either PIFELTRO® once daily or DRV+r 800/100 mg once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the demographic characteristics were similar between treatment groups.

In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either DELSTRIGO® or EFV/FTC/TDF once daily. At baseline, the demographic characteristics were similar between treatment groups.

The demographic and baseline characteristics of patients in DRIVE-FORWARD and DRIVE-AHEAD and are summarized in Table 10.

Table 10– Demographic and Baseline Characteristics in DRIVE-FORWARD and DRIVE-AHEAD at Week 48 in HIV-1 Adult Subjects with No Antiretroviral Treatment History

Week 48 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 11. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

In DRIVE-FORWARD, PIFELTRO® demonstrated consistent efficacy at 48-Weeks across demographic and baseline prognostic factors, including gender, race, ethnicity, NRTI background therapy, baseline HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ T-cell count, and viral subtypes. Mean CD4+ T-cell counts in the PIFELTRO® and DRV+r groups increased from baseline by 193 and 186 cells/mm³, respectively. At Week 96, efficacy in the DOR treatment group was higher than in the DRV+r treatment group, using the FDA snapshot approach: 73.1% [277/379] and 66.0% [248/376] of participants in the DOR and DRV+r treatment groups, respectively, achieved HIV-1 RNA <50 copies/mL, with an estimated treatment difference of 7.1% (95% CI: 0.5, 13.7). These results support the non-inferiority of PIFELTRO® to DRV+r previously established at Week 48.

In DRIVE-AHEAD, DELSTRIGO® demonstrated consistent efficacy at 48-Weeks across demographic and baseline prognostic factors, including gender, race, ethnicity, baseline HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ T-cell count, and viral subtypes. Mean CD4+ T-cell counts in the DELSTRIGO® and EFV/FTC/TDF groups increased from baseline by 198 and 188 cells/mm³, respectively. At Week 96, efficacy in the DELSTRIGO® treatment group was similar to that in the EFV/FTC/TDF treatment group with regard to the proportion of participants with HIV-1 RNA <50 copies/mL, using the FDA snapshot approach; this supports the non-inferiority of DELSTRIGO® to EFV/FTC/TDF previously established at Week 48. Specifically, 77.5% [282/364] and 73.6% [268/364] of participants in the DELSTRIGO® and EFV/FTC/TDF treatment groups, respectively, achieved HIV-1 RNA <50 copies/mL, with an estimated treatment difference of 3.8% (95% CI: -2.4, 10.0).

Table 11 – Virologic Outcomes at Week 48 in HIV-1 Adult Subjects with No Antiretroviral Treatment History

^Þ The 95% CIs for the treatment differences were calculated using stratum-adjusted Mantel-Haenszel method.

^† Includes 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).

^¶ Viral subtype was not available for two subjects.

^‡ Includes subjects who discontinued because of adverse event (AE) or death if this resulted in no virologic data in the Week 48 window.

^§ Other Reasons include: lost to follow-up, non-compliance with study drug, physician decision, pregnancy, protocol deviation, screen failure, withdrawal by subject.

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

Virologically-Suppressed Adult Subjects

The demographic and baseline characteristics of patients in DRIVE-SHIFT are summarized in Table 12.

Table 12 – Demographic and Baseline Characteristics in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Subjects

The efficacy of switching from a baseline regimen consisting of two NRTIs in combination with a ritonavir- or cobicistat-boosted PI, or cobicistat-boosted elvitegravir, or an NNRTI to DELSTRIGO® was evaluated in a randomized, open-label trial (DRIVE-SHIFT), in virologically-suppressed HIV-1 infected adults. Subjects must have been virologically-suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure. Subjects were randomized to either switch to DELSTRIGO® at baseline [n = 447, ISG], or stay on their baseline regimen until Week 24, at which point they switched to DELSTRIGO® [n = 223, DSG].

In the DRIVE-SHIFT trial, an immediate switch to DELSTRIGO® was demonstrated to be non-inferior at Week 48 compared to continuation of the baseline regimen at Week 24 as assessed by the proportion of subjects with HIV-1 RNA <50 copies/mL. Consistent results were seen for the comparison at Study Week 24 in each treatment group. Treatment results are shown in Table 13.

Table 13 - Virologic Outcomes in DRIVE-SHIFT in HIV-1 Virologically-Suppressed Subjects Who Switched to DELSTRIGO®

Pediatric Subjects

Table 14 - Summary of Subject Demographics for Clinical Trials in HIV-I-Infected Pediatric Patients 12 Years of Age and Older and Weighing at Least 35 kg

The efficacy of DELSTRIGO® (DOR/3TC/TDF) was evaluated in cohort 2 of an open-label, single-arm 2-cohort trial in HIV-1-infected pediatric patients 12 to less than 18 years of age (IMPAACT 2014 (Protocol 027)). In cohort 1, virologically-suppressed subjects (n=9) received a single 100 mg dose of PIFELTRO® followed by intensive PK sampling. In cohort 2, virologically-suppressed subjects (n=43) were switched to DELSTRIGO® and treatment-naïve subjects (n=2) were started on DELSTRIGO®.

In cohort 2, at baseline the median age of subjects was 15 years (range: 12 to 17), the median weight was 52 kg (range: 45 to 80), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm³ (range 84 to 1397). After switching to DELSTRIGO®, 95% (41/43) of virologically-suppressed subjects remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naïve subjects achieved HIV-1 RNA <50 copies/mL at Week 24. The other treatment-naïve subject met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥ 200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir was detected (see 15 Microbiology).

Table 15 - Virologic Outcomes in IMPAACT 2014 at Week 24 in HIV-1 Pediatric Subjects (Cohort 2)

^a Includes subjects who discontinued study drug or study before Week 24 for lack or loss of efficacy and subjects with HIV-1 RNA equal to or above 50 copies/mL in the Week 24 window (relative day 141-210).

NA = Not Applicable

15 Microbiology

Mechanism of Action

Doravirine is a pyridinone NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). The inhibitory concentration at 50% (IC₅₀) of doravirine for RNA-dependent DNA polymerization of recombinant wild-type HIV-1 RT in a biochemical assay was 12.2±2.0 nM (n=3). Doravirine does not inhibit the human cellular DNA polymerases α, β, 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 1.2 nM to 10.0 nM.

Antiviral Activity in Combination with other HIV Antiviral Agents

The antiviral activity of doravirine 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 indinavir¹; the 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, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine.

¹ Not marketed in Canada

In Clinical Trials

In Adult Subjects with No Antiretroviral Treatment History

In the doravirine treatment arms of the treatment-naïve trials DRIVE-FORWARD and DRIVE-AHEAD (n=747) through Week 48, emergent doravirine resistance-associated substitutions were observed in 7 of 30 subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or at early study discontinuation and having resistance data). In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no emergent darunavir resistance-associated substitutions were observed in the 11 subjects in the resistance analysis subset. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), emergent efavirenz resistance-associated substitutions were observed in 12 out of 24 subjects in the resistance analysis subset.

Emergent doravirine resistance-associated substitutions in RT included one or more of the following: A98G, V106A, V106I, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F.

In the doravirine treatment-arm of DRIVE-FORWARD between Weeks 48 and 96, one subject developed RT V106A and P225H doravirine resistance-associated substitutions. The resistance-associated substitutions that emerged were RT V106A and P225H and conferred >95-fold reduction in doravirine susceptibility. In the DRIVE-FORWARD trial between Week 48 and 96, no subjects showed the emergence of darunavir resistance-associated substitutions. In the DRIVE-AHEAD trial between Weeks 48 and 96, 3 subjects in the EFV/FTC/TDF treatment arm showed the emergence of efavirenz resistance-associated substitutions.

In Virologically-Suppressed Adult Subjects

In the DRIVE-SHIFT clinical trial, no subject developed genotypic or phenotypic resistance to doravirine, lamivudine, or TDF during treatment with DELSTRIGO® in either the immediate (n=447) or delayed switch (n=209) groups. One subject developed RT M184M/I mutation and phenotypic resistance to lamivudine and emtricitabine during treatment with their baseline regimen. None of the 24 subjects (11 immediate switch group [day 1], 13 delayed switch group [Week 24]) with baseline NNRTI mutations (RT K103N, G190A, or Y181C) experienced virologic failure through Week 48 or at time of discontinuation.

In Pediatric Subjects

In the IMPAACT 2014 (Protocol 027) clinical trial, no subject who was virologically-suppressed at baseline met the criteria for resistance analysis. One treatment-naïve subject who met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥200 copies/mL at or after Week 24) was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine was detected (see Pediatric Subjects).

Cross-Resistance

Laboratory strains of HIV-1 harboring the common NNRTI-associated mutations K103N, Y181C, or K103N/Y181C substitutions in RT exhibit less than a 3-fold decrease in susceptibility to doravirine compared to wild-type virus when evaluated in the presence of 100% NHS. Doravirine was able to suppress the following NNRTI-associated substitutions, K103N, Y181C, G190A, and E138K mutants under clinically relevant concentrations.

A panel of 96 diverse clinical isolates containing NNRTI-associated substitutions was evaluated for susceptibility to doravirine. Isolates that showed potentially clinically meaningful reduced (>100-fold) susceptibility to doravirine contained the following substitutions: Y188L alone or in combination with K103N or V106I; V106A in combination with G190A and F227L; and E138K in combination with Y181C and M230L.

In phase 3 trials, the following amino acid substitutions were observed in clinical isolates obtained from patients with treatment failure who had both genotypic and phenotypic resistance data available: Y188L alone, F227C in combination with A98G, A98G/V106I/H221Y, V106I, V106I/H221Y or V106M; and V106A in combination with P225H and Y318F. Clinical isolates with these substitutions showed a greater than 100-fold reduced susceptibility to doravirine.

Treatment-emergent doravirine resistance associated substitutions may confer cross resistance to efavirenz, rilpivirine, nevirapine, and etravirine. Of the 8 virologic failure subjects who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 4 had partial resistance to etravirine based on the Monogram Phenosense assay.

16 Non-Clinical Toxicology

Carcinogenicity: Long-term oral carcinogenicity studies of doravirine in transgenic RasH2 mice (6 months, 6 times the RHD exposure) and rats (2 years, 7 times the RHD exposure) showed no evidence of carcinogenic potential.

Genotoxicity: Doravirine 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.

Reproductive and Developmental Toxicology:

Reproduction

There were no effects of doravirine on fertility, mating performance or early embryonic development up to systemic exposures that were approximately 7 times the exposure in humans at the RHD.