This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Pifeltro® 100 mg film-coated tablets.

2. Qualitative and quantitative composition

Each film-coated tablet contains 100 mg of doravirine.

Excipient with known effect

Each film-coated tablet contains 222 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet

White, oval-shaped, tablet of dimensions 19.00 mm x 9.50 mm, debossed with the corporate logo and 700 on one side and plain on the other side.

4. Clinical particulars
4.1 Therapeutic indications

Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class (see sections 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

The recommended dose is one 100 mg tablet taken orally once daily with or without food.

Dose adjustment

If Pifeltro is co-administered with rifabutin, one 100 mg tablet of Pifeltro should be taken twice daily (approximately 12 hours apart) (see section 4.5).

Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, one 100 mg tablet of Pifeltro should be taken twice daily (approximately 12 hours apart).

Missed dose

If the patient misses a dose of Pifeltro within 12 hours of the time it is usually taken, the patient should take as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 12 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not take 2 doses at one time.

Special populations

Elderly

No dose adjustment of doravirine is needed in elderly patients (see section 5.2).

Renal impairment

No dose adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease and has not been studied in dialysis patients (see section 5.2).

Hepatic impairment

No dose 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). It is not known whether the exposure to doravirine will increase in patients with severe hepatic impairment. Therefore, caution is advised when doravirine is administered to patients with severe hepatic impairment (see section 5.2).

Paediatric population

Safety and efficacy of doravirine have not been established in patients younger than 18 years of age. No data are available.

Method of administration

Pifeltro must be taken orally, once daily with or without food and swallowed whole (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with medicinal products that are strong cytochrome P450 CYP3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of Pifeltro (see sections 4.4 and 4.5). These medicinal products include, but are not limited, to the following:

• carbamazepine, oxcarbazepine, phenobarbital, phenytoin

• rifampicin, rifapentine

• St. John's wort (Hypericum perforatum)

• mitotane

• enzalutamide

• lumacaftor

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission of HIV-1, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

NNRTI substitutions and use of doravirine

Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase 2b/3-studies. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established (see section 5.1). There is not sufficient clinical evidence to support the use of doravirine in patients infected with HIV-1 with evidence of resistance to the NNRTI class.

Use with CYP3A inducers

Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine (see sections 4.3 and 4.5).

Immune reactivation syndrome

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

Lactose

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on doravirine

Doravirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine (see section 5.2). Doravirine should not be co-administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine (see sections 4.3 and 5.2).

Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2).

Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2).

Co-administration of doravirine and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors.

Effects of doravirine on other medicinal products

Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolised by CYP enzymes.

However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer. Therefore caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus and sirolimus).

Interactions table

Table 1 shows the established and other potential medicinal product interactions with doravirine but is not all inclusive (increase is indicated as ↑, decrease is indicated as ↓, and no change as ↔).

Table 1: Interactions of doravirine with other medicinal products

Medicinal Product by Therapeutic Area

Effects on Medicinal Product Levels Geometric Mean Ratio (90 % CI)*

Recommendation Concerning Co-administration with doravirine

Acid-Reducing Agents

antacid (aluminium and magnesium hydroxide oral suspension)

(20 mL SD, doravirine 100 mg SD)

↔ doravirine

AUC 1.01 (0.92, 1.11)

Cmax 0.86 (0.74, 1.01)

C24 1.03 (0.94, 1.12)

No dose adjustment is required.

pantoprazole

(40 mg QD, doravirine 100 mg SD)

↓ doravirine

AUC 0.83 (0.76, 0.91)

Cmax 0.88 (0.76, 1.01)

C24 0.84 (0.77, 0.92)

No dose adjustment is required.

omeprazole

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

Angiotensin Converting Enzyme Inhibitors

lisinopril

Interaction not studied.

Expected:

↔ lisinopril

No dose adjustment is required.

Antiandrogens

enzalutamide

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antibiotics

nafcillin

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Anticonvulsants

carbamazepine

oxcarbazepine

phenobarbital

phenytoin

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antidiabetics

metformin

(1000 mg SD, doravirine 100 mg QD)

↔ metformin

AUC 0.94 (0.88, 1.00)

Cmax 0.94 (0.86, 1.03)

No dose adjustment is required.

canagliflozin

liraglutide

sitagliptin

Interaction not studied.

Expected:

↔ canagliflozin

↔ liraglutide

↔ sitagliptin

No dose adjustment is required.

Antidiarrhoeals

telotristat ethyl

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Antigout and Uricosuric Agents

lesinurad

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Antimycobacterials

Single dose rifampicin

(600 mg SD, doravirine 100 mg SD)

 
 

Multiple dose rifampicin

(600 mg QD, doravirine 100 mg SD)

↔ doravirine

AUC 0.91 (0.78, 1.06)

Cmax 1.40 (1.21, 1.63)

C24 0.90 (0.80, 1.01)

↓ doravirine

AUC 0.12 (0.10, 0.15)

Cmax 0.43 (0.35, 0.52)

C24 0.03 (0.02, 0.04)

(Induction of CYP3A)

Co-administration is contraindicated.

rifapentine

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

rifabutin

(300 mg QD, doravirine 100 mg SD)

↓ doravirine

AUC 0.50 (0.45, 0.55)

Cmax 0.99 (0.85, 1.15)

C24 0.32 (0.28, 0.35)

(Induction of CYP3A)

If doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (approximately 12 hours apart).

Antineoplastics

mitotane

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antipsychotics

thioridazine

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Azole Antifungal Agents

ketoconazole

(400 mg QD, doravirine 100 mg SD)

↑ doravirine

AUC 3.06 (2.85, 3.29)

Cmax 1.25 (1.05, 1.49)

C24 2.75 (2.54, 2.98)

(Inhibition of CYP3A)

No dose adjustment is required.

fluconazole

itraconazole

posaconazole

voriconazole

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A4)

No dose adjustment is required.

Calcium Channel Blockers

diltiazem

verapamil

Interaction not studied.

Expected:

↑ doravirine

(CYP3A inhibition)

No dose adjustment is required.

Cystic Fibrosis Treatment

lumacaftor

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Endothelin Receptor Antagonists

bosentan

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Hepatitis C Antiviral Agents

elbasvir + grazoprevir

(50 mg elbasvir QD + 200 mg grazoprevir QD, doravirine 100 mg QD)

↑ doravirine

AUC 1.56 (1.45, 1.68)

Cmax 1.41 (1.25, 1.58)

C24 1.61 (1.45, 1.79)

(Inhibition of CYP3A)

↔ elbasvir

AUC 0.96 (0.90, 1.02)

Cmax 0.96 (0.91, 1.01)

C24 0.96 (0.89, 1.04)

↔ grazoprevir

AUC 1.07 (0.94, 1.23)

Cmax 1.22 (1.01, 1.47)

C24 0.90 (0.83, 0.96)

No dose adjustment is required.

ledipasvir + sofosbuvir

(90 mg ledipasvir SD + 400 mg sofosbuvir SD, doravirine 100 mg SD)

↑ doravirine

AUC 1.15 (1.07, 1.24)

Cmax 1.11 (0.97, 1.27)

C24 1.24 (1.13, 1.36)

↔ ledipasvir

AUC 0.92 (0.80, 1.06)

Cmax 0.91 (0.80, 1.02)

↔ sofosbuvir

AUC 1.04 (0.91, 1.18)

Cmax 0.89 (0.79, 1.00)

↔ GS-331007

AUC 1.03 (0.98, 1.09)

Cmax 1.03 (0.97, 1.09)

No dose adjustment is required.

sofosbuvir/velpatasvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

sofosbuvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

daclatasvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

ombitasvir/ paritaprevir/ritonavir and dasabuvir+/-ritonavir

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A due to ritonavir)

No dose adjustment is required.

dasabuvir

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

glecaprevir, pibrentasvir

Interaction not studied.

Expected:

↑ doravirine

(inhibition of CYP3A)

No dose adjustment is required.

ribavirin

Interaction not studied.

Expected:

↔ doravirine

No dose adjustment is required.

Herbal Supplements

St. John's wort

(Hypericum perforatum)

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

HIV Antiviral Agents

Fusion and Entry Inhibitors

enfuvirtide

Interaction not studied.

Expected:

↔ doravirine

↔ enfuviritide

No dose adjustment is required.

maraviroc

Interaction not studied.

Expected:

↔ doravirine

↔ maraviroc

No dose adjustment is required.

Protease Inhibitors

ritonavir- boosted PIs

(atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir, tipranavir)

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A)

↔ boosted PIs

No dose adjustment is required.

cobicistat-boosted PIs

(darunavir, atazanavir)

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A)

↔ boosted PIs

No dose adjustment is required.

Integrase Strand Transfer Inhibitors

dolutegravir

(50 mg QD, doravirine 200 mg QD)

↔ doravirine

AUC 1.00 (0.89, 1.12)

Cmax 1.06 (0.88, 1.28)

C24 0.98 (0.88, 1.09)

↑ dolutegravir

AUC 1.36 (1.15, 1.62)

Cmax 1.43 (1.20, 1.71)

C24 1.27 (1.06, 1.53)

(Inhibition of BCRP)

No dose adjustment is required.

raltegravir

Interaction not studied.

Expected:

↔ doravirine

↔ raltegravir

No dose adjustment is required.

ritonavir-boosted elvitegravir

Interaction not studied.

Expected:

↑ doravirine

(CYP3A inhibition)

↔ elvitegravir

No dose adjustment is required.

cobicistat-boosted elvitegravir

Interaction not studied.

Expected:

↑ doravirine

(CYP3A inhibition)

↔ elvitegravir

No dose adjustment is required.

Nucleoside Reverse Transcriptase Inhibitors

tenofovir disoproxil

(245 mg QD, doravirine 100 mg SD)

↔ doravirine

AUC 0.95 (0.80, 1.12)

Cmax 0.80 (0.64, 1.01)

C24 0.94 (0.78, 1.12)

No dose adjustment is required.

lamivudine + tenofovir disoproxil

(300 mg lamivudine SD + 245 mg tenofovir disoproxil SD, doravirine 100 mg SD)

↔ doravirine

AUC 0.96 (0.87, 1.06)

Cmax 0.97 (0.88, 1.07)

C24 0.94 (0.83, 1.06)

↔ lamivudine

AUC 0.94 (0.88, 1.00)

Cmax 0.92 (0.81, 1.05)

↔ tenofovir

AUC 1.11 (0.97, 1.28)

Cmax 1.17 (0.96, 1.42)

No dose adjustment is required.

abacavir

Interaction not studied.

Expected:

↔ doravirine

↔ abacavir

No dose adjustment is required.

emtricitabine

Interaction not studied.

Expected:

↔ doravirine

↔ emtricitabine

No dose adjustment is required.

tenofovir alafenamide

Interaction not studied.

Expected:

↔ doravirine

↔ tenofovir alafenamide

No dose adjustment is required.

Immunosuppressants

tacrolimus

sirolimus

Interaction not studied.

Expected:

↔ doravirine

↓ tacrolimus, sirolimus

(Induction of CYP3A)

Monitor blood concentrations of tacrolimus and sirolimus as the dose of these agents may need to be adjusted.

Kinase Inhibitors

dabrafenib

Interaction not studied.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Opioid Analgesics

methadone

20-200 mg QD individualised dose, doravirine 100 mg QD

↓ doravirine

AUC 0.74 (0.61, 0.90)

Cmax 0.76 (0.63, 0.91)

C24 0.80 (0.63, 1.03)

↔ R-methadone

AUC 0.95 (0.90, 1.01)

Cmax 0.98 (0.93, 1.03)

C24 0.95 (0.88, 1.03)

↔ S-methadone

AUC 0.98 (0.90, 1.06)

Cmax 0.97 (0.91, 1.04)

C24 0.97 (0.86, 1.10)

No dose adjustment is required.

buprenorphine

naloxone

Interaction not studied.

Expected:

↔ buprenorphine

↔ naloxone

No dose adjustment is required.

Oral Contraceptives

0.03 mg ethinyl oestradiol/ 0.15 mg levonorgestrel SD, doravirine 100 mg QD

↔ ethinyl oestradiol

AUC 0.98 (0.94, 1.03)

Cmax 0.83 (0.80, 0.87)

↑ levonorgestrel

AUC 1.21 (1.14, 1.28)

Cmax 0.96 (0.88, 1.05)

No dose adjustment is required.

norgestimate/ethinyl oestradiol

Interaction not studied.

Expected:

↔ norgestimate/ethinyl oestradiol

No dose adjustment is required.

Pharmacokinetic Enhancers

ritonavir

(100 mg BID, doravirine 50 mg SD)

↑ doravirine

AUC 3.54 (3.04, 4.11)

Cmax 1.31 (1.17, 1.46)

C24 2.91 (2.33, 3.62)

(Inhibition of CYP3A)

No dose adjustment is required.

cobicistat

Interaction not studied.

Expected:

↑ doravirine

(Inhibition of CYP3A)

No dose adjustment is required.

Psychostimulants

modafinil

Interaction not studied.

Expected:

↓doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, one tablet of doravirine should be taken twice daily (approximately 12 hours apart).

Sedatives/Hypnotics

midazolam

(2 mg SD, doravirine 120 mg QD)

↓ midazolam

AUC 0.82 (0.70, 0.97)

Cmax 1.02 (0.81, 1.28)

No dose adjustment is required.

Statins

atorvastatin

(20 mg SD, doravirine 100 mg QD)

↔ atorvastatin

AUC 0.98 (0.90, 1.06)

Cmax 0.67 (0.52, 0.85)

No dose adjustment is required.

rosuvastatin

simvastatin

Interaction not studied.

Expected:

↔ rosuvastatin

↔ simvastatin

No dose adjustment is required.

↑ = increase, ↓ = decrease, ↔ = no change

CI = Confidence Interval; SD = Single Dose; QD = Once Daily; BID = Twice Daily

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

The interaction was evaluated with ritonavir only.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of doravirine in pregnant women.

Antiretroviral pregnancy registry

To monitor maternal-foetal outcomes in patients exposed to antiretroviral medicinal products while pregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Animal studies with doravirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of doravirine during pregnancy.

Breast-feeding

It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (see section 5.3).

Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in breast-feeding infants, mothers should be instructed not to breast-feed if they are receiving Pifeltro.

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 exposure levels higher than the exposure in humans at the recommended clinical dose (see section 5.3).

4.7 Effects on ability to drive and use machines

Pifeltro may have a minor influence on the ability to drive or use machines. Patients should be informed that fatigue, dizziness, and somnolence have been reported during treatment with doravirine (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions considered possibly or probably related to doravirine were nausea (4 %) and headache (3 %).

Tabulated summary of adverse reactions

The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 2: Tabulated summary of adverse reactions associated with doravirine used in combination with other antiretrovirals

Frequency

Adverse reactions

Infections and infestations

Rare

rash pustular

Metabolism and nutrition disorders

Uncommon

hypophosphataemia

Rare

hypomagnesaemia

Psychiatric disorders

Common

abnormal dreams, insomnia1

Uncommon

nightmare, depression2, anxiety3, irritability, confusional state, suicidal ideation

Rare

aggression, hallucination, adjustment disorder, mood altered, somnambulism

Nervous system disorders

Common

headache, dizziness, somnolence

Uncommon

disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep

Vascular disorders

Uncommon

hypertension

Respiratory, thoracic and mediastinal disorders

Rare

dyspnoea, tonsillar hypertrophy

Gastrointestinal disorders

Common

nausea, diarrhoea, flatulence, abdominal pain4, vomiting

Uncommon

constipation, abdominal discomfort5, abdominal distension, dyspepsia, faeces soft6, gastrointestinal motility disorder7

Rare

rectal tenesmus

Skin and subcutaneous tissue disorders

Common

rash8

Uncommon

pruritus

Rare

dermatitis allergic, rosacea

Musculoskeletal and connective tissue disorders

Uncommon

myalgia, arthralgia

Rare

musculoskeletal pain

Renal and urinary disorders

Rare

acute kidney injury, renal disorder, calculus urinary, nephrolithiasis

General disorders and administration site conditions

Common

fatigue

Uncommon

asthenia, malaise

Rare

chest pain, chills, pain, thirst

Investigations

Common

alanine aminotransferase increased9

Uncommon

lipase increased, aspartate aminotransferase increased, amylase increased, haemoglobin decreased

Rare

blood creatine phosphokinase increased

1insomnia includes: insomnia, initial insomnia and sleep disorder

2depression includes: depression, depressed mood, major depression, and persistent depressive disorder

3anxiety includes: anxiety and generalised anxiety disorder

4abdominal pain includes: abdominal pain, and abdominal pain upper

5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort

6faeces soft includes: faeces soft and abnormal faeces

7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements

8rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, and urticarial

9alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no information on potential acute symptoms and signs of overdose with doravirine.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, ATC code: J05AG06

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 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 medicinal products

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 disoproxil, or zidovudine; the PIs darunavir or indinavir; 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, V106M, V106I, V108I, F227L, F227C, F227V, H221Y, M230I, L234I, P236L, and Y318F. Common NNRTI-resistant mutations (K103N, Y181C) were not selected in the in vitro study. V106A (yielding a fold change of around 19) appeared as an initial substitution in subtype B virus, and V106A or M in subtype A and C virus. Subsequently F227(L/C/V) or L234I emerged in addition to V106 substitution (double mutants yielding a fold change of > 100).

In clinical trials

Treatment-naïve adult subjects

The Phase 3 studies, DRIVE-FORWARD and DRIVE-AHEAD, included previously untreated patients (n = 747) where the following NNRTI substitutions were part of exclusion criteria: L100I, K101E, K101P, K103N, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, M230I, M230L, P225H, F227C, F227L, F227V.

The following de novo resistance was seen 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).

Table 3: Resistance development up to week 96 in protocol defined virologic failure population + early discontinuation population

DRIVE-FORWARD

DRIVE-AHEAD

DOR + NRTIs* (383)

DRV + r + NRTIs* (383)

DOR/TDF/3TC (364)

EFV/TDF/FTC (364)

Successful genotype, n

15

18

32

33

Genotypic resistance to

DOR or control (DRV or EFV)

2 (DOR)

0 (DRV)

8 (DOR)

14 (EFV)

NRTI backbone

M184I/V only

K65R only

K65R + M184I/V

2**

2

0

0

0

0

0

0

6

4

1

1

5

4

0

1

*NRTIs in DOR arm: FTC/TDF (333) or ABC/3TC (50); NRTIs in DRV+r arm: FTC/TDF (335) or ABC/3TC (48)

**Subjects received FTC/TDF

ABC = abacavir; FTC = emtricitabine; DRV = darunavir; r = ritonavir

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

Virologically suppressed adult subjects

The DRIVE-SHIFT study included virologically suppressed patients (N=670) with no history of treatment failure (see section, Clinical experience). A documented absence of genotypic resistance (prior to starting first therapy) to doravirine, lamivudine, and tenofovir was part of the inclusion criteria for patients who switched from a PI- or INI-based regimen. Exclusionary NNRTI substitutions were those listed above (DRIVE-FORWARD and DRIVE-AHEAD), with the exception of substitutions RT K103N, G190A and Y181C (accepted in DRIVE-SHIFT). Documentation of pre-treatment resistance genotyping was not required for patients who switched from a NNRTI-based regimen.

In the DRIVE-SHIFT clinical trial, no subjects developed genotypic or phenotypic resistance to DOR, 3TC, or TDF during the initial 48 weeks (immediate switch, N=447) or 24 weeks (delayed switch, N=209) of treatment with DOR/3TC/TDF. One subject developed RT M184M/I mutation and phenotypic resistance to 3TC and FTC during treatment with their baseline regimen. None of the 24 subjects (11 in the immediate switch group, 13 in the delayed switch group) with baseline NNRTI mutations (RT K103N, G190A, or Y181C) experienced virologic failure through Week 48, or at time of discontinuation.

Cross-resistance

Doravirine has been evaluated in a limited number of patients with NNRTI resistance (K103N n=7, G190A n=1); all patients were suppressed to < 40 copies/mL at week 48. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established.

Laboratory strains of HIV-1 harbouring 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 % normal human serum. In in vitro studies, doravirine was able to suppress the following NNRTI-associated substitutions; K103N, Y181C, and G190A under clinically relevant concentrations.

A panel of 96 diverse clinical isolates containing NNRTI-associated mutations was evaluated for susceptibility to doravirine in the presence of 10 % foetal bovine serum. Clinical isolates containing the Y188L substitution or V106 substitutions in combination with A98G, H221Y, P225H, F227C or Y318F showed a greater than 100-fold reduced susceptibility to doravirine. Other established NNRTI substitutions yielded a fold change of 5-10 (G190S (5.7), K103N/P225H (7.9), V108I/Y181C (6.9), Y181V (5.1)). The clinical relevance of a 5-10 fold reduction in susceptibility is unknown.

Treatment emergent doravirine resistance associated substitutions may confer cross resistance to efavirenz, rilpivirine, nevirapine, and etravirine. Of the 7 subjects who developed high level doravirine resistance in the pivotal studies, 6 had phenotypic resistance to EFV and nevirapine, 3 to rilpivirine, and 2 had partial resistance to etravirine based on the Monogram Phenosense assay.

Clinical experience

Treatment-naïve adult subjects

The efficacy of doravirine is based on the analyses of 96-week data from two randomised, multicentre, double-blind, active controlled Phase 3 trials, (DRIVE-FORWARD and DRIVE-AHEAD) in antiretroviral treatment-naïve, HIV-1 infected subjects (n = 1494). Refer to Resistance section for NNRTI substitutions that were part of exclusion criteria.

In DRIVE-FORWARD, 766 subjects were randomised and received at least 1 dose of either doravirine 100 mg or darunavir + ritonavir 800+100 mg once daily, each in combination with emtricitabine/tenofovir disoproxil (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years (range 18 to 69 years), 86 % had CD4+ T cell count greater than 200 cells per mm3, 84 % were male, 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 per mL, 13 % received ABC/3TC and 87 % received FTC/TDF; these characteristics were similar between treatment groups.

In DRIVE-AHEAD, 728 subjects were randomised and received at least 1 dose of either doravirine/lamivudine/tenofovir disoproxil 100/300/245 mg (DOR/3TC/TDF) or efavirenz/emtricitabine/tenofovir disoproxil (EFV/FTC/TDF) once daily. At baseline, the median age of subjects was 31 years (range 18-70 years), 85 % were male, 52 % were non-white, 3% had hepatitis B or C co-infection, 14 % had a history of AIDS, 21 % had HIV-1 RNA > 100,000 copies per mL, and 12 % had CD4+ T cell count < 200 cells per mm3; these characteristics were similar between treatment groups.

Week 48 and 96 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 4. The doravirine-based regimens demonstrated consistent efficacy across demographic and baseline prognostic factors.

Table 4: Efficacy response (< 40 copies/mL, Snapshot approach) in the pivotal studies

DRIVE-FORWARD

DRIVE-AHEAD

DOR + 2 NRTIs (383)

DRV + r + 2 NRTIs (383)

DOR/3TC/TDF (364)

EFV/FTC/TDF (364)

Week 48

83 %

79 %

84 %

80 %

Difference (95 % CI)

4.2 % (-1.4%, 9.7 %)

4.1 % (-1.5 %, 9.7 %)

Week 96*

72 % (N=379)

64 % (N=376)

76 % (N=364)

73 % (N=364)

Difference (95 % CI)

7.6 % (1.0 %, 14.2 %)

3.3 % (-3.1 %, 9.6 %)

Week 48 outcome (< 40 copies/mL) by baseline factors

HIV-1 RNA copies/mL

≤ 100,000

256/285 (90 %)

248/282 (88 %)

251/277 (91 %)

234/258 (91 %)

> 100,000

63/79 (80 %)

54/72 (75 %)

54/69 (78 %)

56/73 (77 %)

CD4 count , cells/µL

≤ 200

34/41 (83 %)

43/61 (70 %)

27/42 (64 %)

35/43 (81 %)

> 200

285/323 (88 %)

260/294 (88 %)

278/304 (91 %)

255/288 (89 %)

NRTI background therapy

TDF/FTC

276/316 (87 %)

267/312 (86 %)

NA

ABC/3TC

43/48 (90 %)

36/43 (84 %)

Viral subtype

B

222/254 (87 %)

219/255 (86 %)

194/222 (87 %)

199/226 (88 %)

non-B

97/110 (88 %)

84/100 (84 %)

109/122 (89 %)

91/105 (87 %)

Mean CD4 change from baseline

Week 48

193

186

198

188

Week 96

224

207

238

223

*For Week 96, certain subjects with missing HIV-1 RNA were excluded from the analysis.

P007 was a Phase 2b trial in antiretroviral treatment-naïve HIV-1 infected adult subjects (n = 340). In Part I, subjects were randomised to receive one of 4 doses of doravirine or EFV, each in combination with FTC/TDF. After week 24, all subjects randomised to receive doravirine were switched to (or maintained on) doravirine 100 mg. Additional subjects were randomised in Part II to receive either doravirine 100 mg or EFV, each in combination with FTC/TDF. In both parts of the trial, doravirine and EFV were administered as blinded-therapy and FTC/TDF was administered open-label.

Table 5: Efficacy response at week 24 (Snapshot approach)

Doravirine 25 mg

(N=40)

n (%)

Doravirine 50 mg

(N=43)

n (%)

Doravirine 100 mg

(N=42)

n (%)

Doravirine 200 mg

(N=41)

n (%)

Efavirenz 600 mg

(N=42)

n (%)

HIV-1 RNA < 40 copies/mL

32 (80)

32 (74)

30 (71)

33 (80)

27 (64)

Treatment differences

(95 % CI) ††

16 (-4, 34)

10 (-10, 29)

6.6 (-13, 26)

16 (-3, 34)

Mean CD4 change from baseline (cells/mm3) **

154

113

134

141

121

A positive value favours doravirine over efavirenz.

††The 95 % CIs were calculated using Miettinen and Nurminen's method with weights proportional to the size of each stratum (screening HBV-1 RNA > 100,000 copies/mL or ≤ 100,000 copies/mL.

**Approach to handle missing data: Observed Failure (OF) approach. Baseline CD4 cell count was carried forward for subjects who discontinued assigned therapy due to lack of efficacy.

Note: Both doravirine and efavirenz were administered with emtricitabine/tenofovir disoproxil (FTC/TDF).

Virologically suppressed adult subjects

The efficacy of switching from a baseline regimen consisting of two nucleoside reverse transcriptase inhibitors in combination with a ritonavir- or cobicistat-boosted PI, or cobicistat-boosted elvitegravir, or an NNRTI to DOR/3TC/TDF was evaluated in a randomised, open-label trial (DRIVE-SHIFT), in virologically suppressed HIV-1 infected adults. Subjects must have been virologically suppressed (HIV-1 RNA < 40 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure, and a documented absence of RT substitutions conferring resistance to doravirine, lamivudine and tenofovir (see section Resistance). Subjects were randomised to either switch to DOR/3TC/TDF at baseline [N = 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to DOR/3TC/TDF [N = 223, Delayed Switch Group (DSG)]. At baseline, the median age of subjects was 43 years, 16 % were female, and 24 % were non-white.

In the DRIVE-SHIFT trial, an immediate switch to DOR/3TC/TDF 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 < 40 copies/mL. Treatment results are shown in Table 6. Consistent results were seen for the comparison at study Week 24 in each treatment group.

Table 6: Efficacy response (Snapshot approach) in the DRIVE-SHIFT study

Outcome

DOR/3TC/TDF

Once Daily ISG

Baseline Regimen DSG

Week 48

N=447

Week 24

N=223

HIV-1 RNA < 40 copies/mL

90 %

93 %

ISG-DSG, Difference (95 % CI)*

-3.6 % (-8.0 %, 0.9 %)

Proportion (%) of Subjects With HIV-1 RNA < 40 copies/mL by Baseline Regimen Received

Ritonavir- or Cobicistat-boosted PI

280/316 (89 %)

145/156 (93 %)

Cobicistat-boosted elvitegravir

23/25 (92 %)

11/12 (92 %)

NNRTI

98/106 (92 %)

52/55 (95 %)

Proportion (%) of Subjects With HIV-1 RNA < 40 copies/mL by Baseline CD4+ T cell Count (cells/mm3)

< 200 cells/mm3

10/13 (77 %)

3/4 (75 %)

≥ 200 cells/mm3

384/426 (90 %)

202/216 (94 %)

HIV-1 RNA ≥ 40 copies/mL

3 %

4 %

No Virologic Data Within the Time Window

8 %

3 %

Discontinued study due to AE or Death

3 %

0

Discontinued study for Other Reasons§

4 %

3 %

On study but missing data in window

0

0

*The 95 % CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method.

Includes subjects who discontinued study drug or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and subjects with HIV-1 RNA ≥ 40 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG.

Includes subjects who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window.

§Other reasons include: lost to follow-up, non-compliance with study drug, physician decision, protocol deviation, withdrawal by subject.

Baseline Regimen = ritonavir or cobicistat-boosted PI (specifically atazanavir, darunavir, or lopinavir), or cobicistat-boosted elvitegravir, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs.

Discontinuation due to adverse events

In a pooled analysis combining data from two treatment-naïve trials (P007 and DRIVE-AHEAD), a lower proportion of subjects who discontinued due to an adverse event by week 48 was seen for the combined doravirine (100 mg) treatment groups (2.8 %) compared with the combined EFV treatment group (6.1 %) (treatment difference -3.4 %, p-value 0.012).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with doravirine in one or more subsets of the paediatric population in treatment of human immunodeficiency virus-1 (HIV-1) infection, as per Paediatric Investigation Plan (PIP) decision in the granted indication. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Absorption

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 was 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 pharmacokinetics analysis, are provided below.

Parameter

GM (% CV)

AUC0-24

μM hr

Cmax

μM

C24

nM

Doravirine

100 mg

once daily

37.8 (29)

2.26 (19)

930 (63)

GM: Geometric mean, % CV: Geometric coefficient of variation

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

Effect of food on oral absorption

The administration of a single doravirine tablet with a high-fat meal to healthy subjects resulted in a 16 % and 36 % increase in doravirine AUC and C24, respectively, while Cmax was not significantly affected.

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.

Biotransformation

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

Elimination

Doravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism mediated by CYP3A4. Biliary excretion of unchanged medicinal product may contribute to the elimination of doravirine, but this elimination route is not expected to be significant. Excretion of unchanged medicinal product via urinary excretion is minor.

Renal impairment

Renal excretion of doravirine is minor. In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 31 % higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, which included subjects with CrCl between 17 and 317 mL/min, 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 (see section 4.2).

Hepatic impairment

Doravirine is primarily metabolised 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 (classified as Child-Pugh score B primarily due to increased encephalopathy and ascites scores) 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) (see section 4.2).

Elderly

Although a limited number of subjects aged 65 years and over has been included (n=36), 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. No dose adjustment is required.

Gender

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

Race

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.

5.3 Preclinical safety data

Reproductive toxicity

Reproduction studies with orally administered doravirine have been performed in rats and rabbits at exposures approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose (RHD) with no effects on embryo-foetal (rats and rabbits) or pre/postnatal (rats) development. Studies in pregnant rats and rabbits showed that doravirine is transferred to the foetus through the placenta, with foetal plasma concentrations of up to 40 % (rabbits) and 52 % (rats) that of maternal concentrations observed on gestation Day 20.

Doravirine was excreted into the milk of lactating rats following oral administration, with milk concentrations approximately 1.5 times that of maternal plasma concentrations.

Carcinogenesis

Long-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence of carcinogenic potential at estimated exposures up to 6 times (mice) and 7 times (rats) the human exposures at the RHD.

Mutagenesis

Doravirine was not genotoxic in a battery of in vitro or in vivo assays.

Impairment of fertility

There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to 7 times the exposure in humans at the RHD.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Croscarmellose sodium (E468)

Hypromellose acetate succinate

Lactose monohydrate

Magnesium stearate (E470b)

Microcrystalline cellulose (E460)

Silica, colloidal anhydrous (E551)

Film-coating

Carnauba wax (E903)

Hypromellose (E464)

Lactose monohydrate

Titanium dioxide (E171)

Triacetin (E1518)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

After first opening of the bottle use within 35 days.

6.4 Special precautions for storage

Store in the original bottle and keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant. This medicinal product does not require any special temperature storage conditions. For storage conditions after first opening of the bottle see section 6.3.

6.5 Nature and contents of container

Each carton contains a high density polyethylene (HDPE) bottle with a polypropylene child-resistant closure with silica gel desiccant.

The following pack sizes are available:

• 1 bottle with 30 film-coated tablets.

• 90 film-coated tablets (3 bottles of 30 film-coated tablets).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

8. Marketing authorisation number(s)

EU/1/18/1332/001

EU/1/18/1332/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 22 November 2018

10. Date of revision of the text

13 November 2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

© Merck Sharp & Dohme Limited, 2019. All rights reserved.

SPC.PIF.19.UK.7063.IB-008