Leaflet PIFELTRO 100mg film-coated tablets
Indicated for: HIV-1 infection
Route of administration: oral
Substance: doravirine (non-nucleoside reverse transcriptase inhibitor)
ATC: J05AG06 (Antiinfectives for systemic use | Direct acting antivirals | Non-nucleoside reverse transcriptase inhibitors)
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Doravirine is an antiretroviral medication used to treat HIV-1 infection in adult patients. It belongs to the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and works by blocking the enzyme necessary for HIV replication.
The medication is taken orally, usually once daily, in combination with other antiretroviral drugs. It is important for patients to strictly adhere to the treatment regimen prescribed by their doctor.
Side effects may include nausea, headaches, fatigue, or insomnia. In rare cases, severe allergic reactions or liver disorders may occur.
Patients should inform their doctor about any other medications they are taking and undergo regular check-ups to monitor treatment effectiveness. Pregnant or breastfeeding women should consult a specialist before use.
General data about PIFELTRO 100mg
- Substance: doravirine
- Date of latest medicines list: 01-06-2026
- Product code: W65374001
- Concentration: 100mg
- Pharmaceutical form: film-coated tablets
- Quantity: 30
- Product type: Original
- Price: 1158.94 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet PIFELTRO 100mg
Combinations with other substances
Compensation lists for PIFELTRO 100mg Merck Sharp & Dohme
NHP 1.A (C2) - People with HIV/AIDS and post-exposure treatment
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1158.94 RON
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Contents of the package leaflet for the medicine PIFELTRO 100mg film-coated tablets
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 effectEach 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 (tablet).
White, oval-shaped, tablet of dimensions 19.00 mm x 9.50 mm, debossed with the corporate logo and700 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 ofadults, and adolescents aged 12 years and older weighing at least 35 kg infected with humanimmunodeficiency virus type 1 (HIV-1) without past or present evidence of resistance to the non-nucleoside reverse transcriptase inhibitors (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.
PosologyThe recommended dose is one 100 mg tablet taken orally once daily with or without food.
Dose adjustmentIf 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, butdecreased doravirine concentrations are expected. If co-administration with other moderate CYP3Ainducers (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 hoursapart).
Missed doseIf the patient misses a dose of Pifeltro within 12 hours of the time it is usually taken, the patient shouldtake as soon as possible and resume the normal dosing schedule. If a patient misses a dose by morethan 12 hours, the patient should not take the missed dose and instead take the next dose at theregularly scheduled time. The patient should not take 2 doses at one time.
Special populationsElderly
No dose adjustment of doravirine is required in elderly patients (see section 5.2).
Renal impairmentNo dose adjustment of doravirine is required in patients with mild, moderate, or severe renalimpairment. Doravirine has not been studied in patients with end-stage renal disease and has not beenstudied in dialysis patients (see section 5.2).
Hepatic impairmentNo 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 severehepatic impairment (Child-Pugh Class C). It is not known whether the exposure to doravirine willincrease in patients with severe hepatic impairment. Therefore, caution is advised when doravirine isadministered to patients with severe hepatic impairment (see section 5.2).
Paediatric populationSafety and efficacy of Pifeltro in children aged less than 12 years or weighing less than 35 kg have notbeen established. No data are available.
Method of administrationPifeltro 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 inducersis 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 productsinclude, 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
NNRTI substitutions and use of doravirine
Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviraltherapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase2b/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). Thereis not sufficient clinical evidence to support the use of doravirine in patients infected with HIV-1 withevidence of resistance to the NNRTI class.
Severe cutaneous adverse reactions (SCARs)Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS)/toxicepidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens (see section 4.8). At the time of prescription, patients should be advised of thesigns and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive ofthese reactions appear, doravirine-containing regimens should be withdrawn immediately and analternative treatment considered (as appropriate). Clinical status should be closely monitored, andappropriate therapy should be initiated. If the patient has developed a serious reaction such as TEN,with the use of doravirine-containing regimens, treatment with doravirine-containing regimens mustnot be restarted in this patient at any time.
Use with CYP3A inducers
Caution should be given to prescribing doravirine with medicinal products that may reduce theexposure of doravirine (see sections 4.3 and 4.5).
Immune reactivation syndromeImmune reactivation syndrome has been reported in patients treated with combination antiretroviraltherapy. During the initial phase of combination antiretroviral treatment, patients whose immunesystem responds may develop an inflammatory response to indolent or residual opportunisticinfections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveciipneumonia [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, thetime to onset is more variable and can occur many months after initiation of treatment.
LactoseThe tablets contain lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.
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 CYP3Aare 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 decreasesin doravirine plasma concentrations are expected to occur, which may decrease the effectiveness ofdoravirine (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 beincreased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (seesection 4.2).
Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, butdecreased doravirine concentrations are expected. If co-administration with other moderate CYP3Ainducers (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 betaken approximately 12 hours apart) (see section 4.2).
Co-administration of doravirine and medicinal products that are inhibitors of CYP3A may result inincreased plasma concentrations of doravirine. However, no dose adjustment is needed whendoravirine 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 theplasma concentrations of medicinal products that are dependent on transport proteins for absorptionand/or elimination or that are metabolised by CYP enzymes.
However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a18 % 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 aresensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus andsirolimus).
Interactions table
Table 1 shows the established and other potential medicinal product interactions with doravirine but isnot 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 Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Acid-reducing agentsantacid (aluminium and doravirinemagnesium hydroxide oral AUC 1.01 (0.92, 1.11)suspension) Cmax 0.86 (0.74, 1.01) No dose adjustment is required.(20 mL SD, C24 1.03 (0.94, 1.12)doravirine 100 mg SD) doravirinepantoprazole
AUC 0.83 (0.76, 0.91)(40 mg QD, No dose adjustment is required.
Cmax 0.88 (0.76, 1.01)doravirine 100 mg SD)
C24 0.84 (0.77, 0.92)
Interaction not studied.
omeprazole No dose adjustment is required.
Expected: doravirine
Angiotensin converting enzyme inhibitors
Interaction not studied.
lisinopril No dose adjustment is required.
Expected:↔ lisinopril
Antiandrogens
Interaction not studied.
Co-administration isenzalutamide Expected:
contraindicated. doravirine(Induction of CYP3A)
Antibiotics
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet ofnafcillin↓ doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Anticonvulsantscarbamazepine Interaction not studied.oxcarbazepine
Co-administration isphenobarbital Expected:
contraindicated.phenytoin doravirine(Induction of CYP3A)
Antidiabeticsmetformin metformin(1 000 mg SD, AUC 0.94 (0.88, 1.00) No dose adjustment is required.doravirine 100 mg QD) Cmax 0.94 (0.86, 1.03)
Interaction not studied.
canagliflozin
Expected:
liraglutide No dose adjustment is required.↔ canagliflozinsitagliptin↔ liraglutide↔ sitagliptin
Antidiarrhoeals
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet oftelotristat ethyl↓ doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Antigout and uricosuric agents
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet oflesinurad↓ doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Antimycobacterials
Single dose rifampicin doravirine(600 mg SD, AUC 0.91 (0.78, 1.06)doravirine 100 mg SD) Cmax 1.40 (1.21, 1.63)
C24 0.90 (0.80, 1.01)
Co-administration is
Multiple dose rifampicin doravirine contraindicated.(600 mg QD, AUC 0.12 (0.10, 0.15)doravirine 100 mg SD) Cmax 0.43 (0.35, 0.52)
C24 0.03 (0.02, 0.04)(Induction of CYP3A)
Interaction not studied.
Co-administration isrifapentine Expected:
contraindicated. doravirine(Induction of CYP3A) doravirine If doravirine is co-administeredrifabutin AUC 0.50 (0.45, 0.55) with rifabutin, the doravirine dose(300 mg QD, Cmax 0.99 (0.85, 1.15) should be increased to 100 mgdoravirine 100 mg SD) C24 0.32 (0.28, 0.35) twice daily (approximately(Induction of CYP3A) 12 hours apart).
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Antineoplastics
Interaction not studied.
Co-administration ismitotane Expected:
contraindicated. doravirine(Induction of CYP3A)
Antipsychotics
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet ofthioridazine↓ doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Azole antifungal agents doravirineketoconazole AUC 3.06 (2.85, 3.29)(400 mg QD, Cmax 1.25 (1.05, 1.49) No dose adjustment is required.doravirine 100 mg SD) C24 2.75 (2.54, 2.98)(Inhibition of CYP3A)
Interaction not studied.
fluconazoleitraconazole
Expected: No dose adjustment is required.posaconazole doravirinevoriconazole(Inhibition of CYP3A4)
Calcium channel blockers
Interaction not studied.
diltiazem
Expected: No dose adjustment is required.
verapamil doravirine(CYP3A inhibition)
Cystic fibrosis treatment
Interaction not studied.
Co-administration islumacaftor Expected:
contraindicated. doravirine(Induction of CYP3A)
Endothelin receptor antagonists
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet ofbosentan↓ doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Hepatitis C antiviral agents 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 + grazoprevir elbasvir(50 mg elbasvir QD +
AUC 0.96 (0.90, 1.02) No dose adjustment is required.
200 mg grazoprevir QD,
Cdoravirine 100 mg QD) max 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) doravirine
AUC 1.15 (1.07, 1.24)
Cmax 1.11 (0.97, 1.27)
C24 1.24 (1.13, 1.36) ledipasvirledipasvir + sofosbuvir AUC 0.92 (0.80, 1.06)(90 mg ledipasvir SD + Cmax 0.91 (0.80, 1.02)
No dose adjustment is required.400 mg sofosbuvir SD,doravirine 100 mg SD) 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)
Interaction not studied.
sofosbuvir/velpatasvir No dose adjustment is required.
Expected: doravirine
Interaction not studied.
sofosbuvir No dose adjustment is required.
Expected: doravirine
Interaction not studied.
daclatasvir
No dose adjustment is required.
Expected:↔ doravirine
Interaction not studied.
ombitasvir/
Expected:
paritaprevir/ritonavir and No dose adjustment is required. doravirinedasabuvir+/-ritonavir(Inhibition of CYP3A due toritonavir)
Interaction not studied.
dasabuvir Expected: No dose adjustment is required. doravirine
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Interaction not studied.
glecaprevir, pibrentasvir Expected: No dose adjustment is required. doravirine(inhibition of CYP3A)
Interaction not studied.
ribavirin No dose adjustment is required.
Expected: doravirine
Herbal supplements
Interaction not studied.
St. John’s wort
Co-administration is(Hypericum perforatum) Expected:contraindicated.
doravirine(Induction of CYP3A)
HIV antiviral agents
Fusion and entry inhibitors
Interaction not studied.
enfuvirtide Expected: No dose adjustment is required.↔ doravirine↔ enfuviritide
Interaction not studied.
maraviroc Expected: No dose adjustment is required.↔ doravirine↔ maraviroc
Protease inhibitors
Interaction not studied.
ritonavir†- boosted PIs(atazanavir, darunavir, Expected:fosamprenavir, indinavir, doravirine No dose adjustment is required.lopinavir, saquinavir, (Inhibition of CYP3A)tipranavir)↔ boosted PIs
Interaction not studied.
Expected:cobicistat-boosted PIs doravirine No dose adjustment is required.(darunavir, atazanavir)(Inhibition of CYP3A)↔ boosted PIs
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Integrase strand transfer inhibitors doravirine
AUC 1.00 (0.89, 1.12)
Cmax 1.06 (0.88, 1.28)
C24 0.98 (0.88, 1.09)dolutegravir(50 mg QD, No dose adjustment is required.doravirine 200 mg QD) 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)
Interaction not studied.
raltegravir Expected: No dose adjustment is required.↔ doravirine↔ raltegravir
Interaction not studied.
Expected:ritonavir†-boosted doravirine No dose adjustment is required.elvitegravir(CYP3A inhibition)↔ elvitegravir
Interaction not studied.
cobicistat-boosted Expected:
No dose adjustment is required.
elvitegravir doravirine(CYP3A inhibition)↔ elvitegravir
Nucleoside reverse transcriptase inhibitors (NRTI) doravirinetenofovir disoproxil
AUC 0.95 (0.80, 1.12)(245 mg QD, No dose adjustment is required.
C 0.80 (0.64, 1.01)doravirine 100 mg SD) max
C24 0.94 (0.78, 1.12) doravirine
AUC 0.96 (0.87, 1.06)
Cmax 0.97 (0.88, 1.07)lamivudine + tenofovir C24 0.94 (0.83, 1.06)disoproxil(300 mg lamivudine SD + lamivudine
No dose adjustment is required.245 mg tenofovir disoproxil AUC 0.94 (0.88, 1.00)
SD, Cmax 0.92 (0.81, 1.05)doravirine 100 mg SD) tenofovir
AUC 1.11 (0.97, 1.28)
Cmax 1.17 (0.96, 1.42)abacavir Interaction not studied. No dose adjustment is required.
Expected:↔ doravirine↔ abacavir
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Interaction not studied.
emtricitabine Expected: No dose adjustment is required.↔ doravirine↔ emtricitabine
Interaction not studied.
tenofovir alafenamide Expected: No dose adjustment is required.↔ doravirine↔ tenofovir alafenamide
Immunosuppressants
Interaction not studied.
Monitor blood concentrations oftacrolimus and sirolimus as thetacrolimus Expected:dose of these agents may need tosirolimus doravirinebe adjusted.
↓ tacrolimus, sirolimus(Induction of CYP3A)
Kinase inhibitors
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet ofdabrafenib↓ doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Opioid analgesics doravirine
AUC 0.74 (0.61, 0.90)
Cmax 0.76 (0.63, 0.91)
C24 0.80 (0.63, 1.03)methadone R-methadone20-200 mg QD AUC 0.95 (0.90, 1.01)
No dose adjustment is required.individualised dose, Cmax 0.98 (0.93, 1.03)doravirine 100 mg QD 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)
Interaction not studied.
buprenorphine
Expected: No dose adjustment is required.
naloxone↔ buprenorphine↔ naloxone
Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic area levels geometric mean ratio co-administration with(90 % CI)* doravirine
Oral contraceptives0.03 mg ethinyl oestradiol/ ethinyl oestradiol0.15 mg levonorgestrel SD, AUC 0.98 (0.94, 1.03)doravirine 100 mg QD Cmax 0.83 (0.80, 0.87)
No dose adjustment is required. levonorgestrel
AUC 1.21 (1.14, 1.28)
Cmax 0.96 (0.88, 1.05)
Interaction not studied.
norgestimate/ethinyl
No dose adjustment is required.
oestradiol Expected: norgestimate/ethinyl oestradiol
Pharmacokinetic enhancers doravirineritonavir AUC 3.54 (3.04, 4.11)(100 mg BID, Cmax 1.31 (1.17, 1.46) No dose adjustment is required.doravirine 50 mg SD) C24 2.91 (2.33, 3.62)(Inhibition of CYP3A)
Interaction not studied.
cobicistat Expected: No dose adjustment is required. doravirine(Inhibition of CYP3A)
Psychostimulants
Interaction not studied. Co-administration should beavoided. If co-administration
Expected: cannot be avoided, one tablet ofmodafinil↓doravirine doravirine should be taken twice(Induction of CYP3A) daily (approximately 12 hoursapart).
Sedatives/hypnoticsmidazolam midazolam(2 mg SD, AUC 0.82 (0.70, 0.97) No dose adjustment is required.doravirine 120 mg QD) Cmax 1.02 (0.81, 1.28)
Statinsatorvastatin atorvastatin(20 mg SD, AUC 0.98 (0.90, 1.06) No dose adjustment is required.doravirine 100 mg QD) Cmax 0.67 (0.52, 0.85)
Interaction not studied.rosuvastatin Expected:
No dose adjustment is required.simvastatin ↔ rosuvastatin↔ simvastatin = increase, ↓ = decrease, ↔ = no change
CI = Confidence Interval; SD = Single Dose; QD = Once Daily; BID = Twice Daily
*AUC for single dose, AUC for once daily. 0- 0-24†The interaction was evaluated with ritonavir only.
4.6 Fertility, pregnancy and lactation
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 whilepregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged toregister patients in this registry.
Animal studies with doravirine do not indicate direct or indirect harmful effects with respect toreproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of doravirine during pregnancy.
Breast-feedingIt is unknown whether doravirine is excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (seesection 5.3).
It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.
FertilityNo human data on the effect of doravirine on fertility are available. Animal studies do not indicateharmful effects of doravirine on fertility at exposure levels higher than the exposure in humans at therecommended clinical dose (see section 5.3).
4.7 Effects on ability to drive and use machines
Pifeltro has a minor influence on the ability to drive and use machines. Patients should be informedthat fatigue, dizziness, and somnolence have been reported during treatment with doravirine (seesection 4.8). This should be considered when assessing a patient's ability to drive or operatemachinery.
4.8 Undesirable effects
In phase 3 clinical trials with doravirine plus 2 nucleoside reverse transcriptase inhibitors (NRTIs), themost frequently reported adverse reactions were nausea (4 %) and headache (3 %).
Tabulated summary of adverse reactionsThe adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE FORWARD,
DRIVE SHIFT and DRIVE AHEAD) and postmarketing experience are listed below by body systemorgan class and frequency. Within each frequency grouping, undesirable effects are presented in orderof decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), or not known (cannot beestimated from the available data).
Table 2: Tabulated summary of adverse reactions associated with doravirine used incombination with other antiretrovirals
Frequency Adverse reactions
Infections and infestationsRare rash pustular
Frequency Adverse reactions
Metabolism and nutrition disordersUncommon hypophosphataemia
Rare hypomagnesaemia
Psychiatric disordersCommon abnormal dreams, insomnia1
Uncommon nightmare, depression2, anxiety3,irritability, confusional state, suicidalideation
Rare aggression, hallucination, adjustmentdisorder, mood altered, somnambulism
Nervous system disordersCommon headache, dizziness, somnolence
Uncommon disturbance in attention, memoryimpairment, paraesthesia, hypertonia, poorquality sleep
Vascular disordersUncommon hypertension
Respiratory, thoracic and mediastinal disordersRare dyspnoea, tonsillar hypertrophy
Gastrointestinal disordersCommon nausea, diarrhoea, flatulence, abdominalpain4, vomiting
Uncommon constipation, abdominal discomfort5,abdominal distension, dyspepsia, faecessoft6, gastrointestinal motility disorder7
Rare rectal tenesmus
Hepatobiliary disordersNot known hepatitis
Skin and subcutaneous tissue disordersCommon rash8
Uncommon pruritus
Rare dermatitis allergic, rosacea
Not known toxic epidermal necrolysis
Musculoskeletal and connective tissue disordersUncommon myalgia, arthralgia
Rare musculoskeletal pain
Renal and urinary disordersRare acute kidney injury, renal disorder,calculus urinary, nephrolithiasis
General disorders and administration site conditionsCommon fatigue
Uncommon asthenia, malaise
Rare chest pain, chills, pain, thirst
InvestigationsCommon alanine aminotransferase increased9
Uncommon lipase increased, aspartateaminotransferase increased, amylaseincreased, haemoglobin decreased
Rare blood creatine phosphokinase increased1insomnia includes: insomnia, initial insomnia and sleep disorder2depression includes: depression, depressed mood, major depression, and persistent depressive disorder3anxiety includes: anxiety and generalised anxiety disorder4abdominal pain includes: abdominal pain, and abdominal pain upper5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort6faeces soft includes: faeces soft and abnormal faeces
Frequency Adverse reactions7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowelmovements8rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular,and urticarial9alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury
Description of selected adverse reactionsImmune reactivation syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).
Severe cutaneous adverse reactions (SCARs)Severe cutaneous adverse reactions (SCARs), such as toxic epidermal necrolysis (TEN), have beenreported in association with doravirine-containing treatment regimens (see section 4.4).
Paediatric populationThe safety of doravirine as a component of doravirine/lamivudine/tenofovir disoproxil was evaluatedin 45 HIV-1 infected virologically suppressed or treatment-naïve paediatric patients 12 to less than18 years of age through Week 48 in an open-label trial (IMPAACT 2014 (Protocol 027)). The safetyprofile in paediatric subjects was similar to that in adults.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
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 actionDoravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does notinhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ.
Antiviral activity in cell cultureDoravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1when tested in the presence of 100 % normal human serum using MT4-GFP reporter cells. Doravirinedemonstrated 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 fusioninhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transferinhibitor raltegravir.
ResistanceIn cell culture
Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of differentorigins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutionsin RT included: V106A, V106M, V106I, V108I, F227L, F227C, F227I, F227V, H221Y, M230I,
L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318Fsubstitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F incombination with V106A, V106M, V108I, or F227C conferred greater decreases in susceptibility todoravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine.
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 substitutions (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 untreatedpatients (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 RNAgreater than 400 copies per mL at virologic failure or at early study discontinuation and havingresistance data).
Table 3: Resistance development up to Week 96 in protocol defined virologic failurepopulation + early discontinuation population
DRIVE-FORWARD DRIVE-AHEAD
DOR + DRV + r + DOR/TDF/3T EFV/TDF/FTC
NRTIs* NRTIs* C (364)(383) (383) (364)
Successful genotype, n 15 18 32 33
Genotypic resistance to
DOR or control (DRV or 2 (DOR) 0 (DRV) 8 (DOR) 14 (EFV)
EFV)
NRTI backbone 2† 0 6 5
M184I/V only 2 0 4 4
K65R only 0 0 1 0
K65R + M184I/V 0 0 1 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 oftreatment 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 inclusioncriteria for patients who switched from a PI- or INI-based regimen. Exclusionary NNRTI substitutionswere those listed above (DRIVE-FORWARD and DRIVE-AHEAD), with the exception ofsubstitutions 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-basedregimen.
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 andphenotypic resistance to 3TC and FTC during treatment with their baseline regimen. None of the24 subjects (11 in the immediate switch group, 13 in the delayed switch group) with baseline NNRTImutations (RT K103N, G190A, or Y181C) experienced virologic failure through Week 48, or at timeof discontinuation.
Paediatric subjects
In the IMPAACT 2014 (Protocol 027) clinical trial, no subject who was virologically suppressed atbaseline met the criteria for resistance analysis. One treatment-naïve subject who met theprotocol-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 emergenceof genotypic or phenotypic resistance to doravirine was detected.
Cross-resistanceDoravirine 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 reductionin susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinicalefficacy 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 doravirinecompared to wild-type virus when evaluated in the presence of 100 % normal human serum. In in vitrostudies, 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 forsusceptibility to doravirine in the presence of 10 % foetal bovine serum. Clinical isolates containingthe 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 NNRTIsubstitutions 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 toefavirenz, rilpivirine, nevirapine, and etravirine. Of the 8 subjects who developed high level doravirineresistance in the pivotal studies, 6 had phenotypic resistance to EFV and nevirapine, 3 to rilpivirine,and 3 had partial resistance to etravirine based on the Monogram Phenosense assay.
Clinical experienceTreatment-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) inantiretroviral treatment-naïve, HIV-1 infected subjects (n = 1 494). 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 eitherdoravirine 100 mg or darunavir + ritonavir 800+100 mg once daily, each in combination withemtricitabine/tenofovir disoproxil (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by theinvestigator. 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 % hadhepatitis B and/or C virus co-infection, 10 % had a history of AIDS, 20 % had HIV-1 RNA greaterthan 100 000 copies per mL, 13 % received ABC/3TC and 87 % received FTC/TDF; thesecharacteristics were similar between treatment groups.
In DRIVE-AHEAD, 728 subjects were randomised and received at least 1 dose of eitherdoravirine/lamivudine/tenofovir disoproxil 100/300/245 mg (DOR/3TC/TDF) orefavirenz/emtricitabine/tenofovir disoproxil (EFV/FTC/TDF) once daily. At baseline, the median ageof 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, and12 % had CD4+ T cell count < 200 cells per mm3; these characteristics were similar between treatmentgroups.
Week 48 and 96 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 4. Thedoravirine-based regimens demonstrated consistent efficacy across demographic and baselineprognostic factors.
Table 4: Efficacy response (< 40 copies/mL, Snapshot approach) in the pivotal studies
DRIVE-FORWARD DRIVE-AHEAD
DOR + 2 NRTIs DRV + r + 2 DOR/3TC/TDF EFV/FTC/TDF(383) NRTIs (383) (364) (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 combinationwith FTC/TDF. After Week 24, all subjects randomised to receive doravirine were switched to (ormaintained on) doravirine 100 mg. Additional subjects were randomised in Part II to receive eitherdoravirine 100 mg or EFV, each in combination with FTC/TDF. In both parts of the trial, doravirineand EFV were administered as blinded-therapy and FTC/TDF was administered open-label.
Table 5: Efficacy response at Week 24 (Snapshot approach)
Doravirine Doravirine Doravirine Doravirine Efavirenz25 mg 50 mg 100 mg 200 mg 600 mg(N=40) (N=43) (N=42) (N=41) (N=42)n (%) n (%) n (%) n (%) n (%)
HIV-1 RNA < 40 copies/mL 32 (80) 32 (74) 30 (71) 33 (80) 27 (64)
Treatment differences * 16 (-4, 34) 10 (-10, 6.6 (-13, 16 (-3, 34)(95 % CI) † 29) 26)
Mean CD4 change from 154 113 134 141 121baseline (cells/mm3) ‡
*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 forsubjects 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 transcriptaseinhibitors 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), invirologically 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, withno history of virologic failure, and a documented absence of RT substitutions conferring resistance todoravirine, lamivudine and tenofovir (see section, Resistance). Subjects were randomised to eitherswitch to DOR/3TC/TDF at baseline [N = 447, Immediate Switch Group (ISG)], or stay on theirbaseline 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 theproportion 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
DOR/3TC/TDF Baseline Regimen
Once Daily ISG DSG
Week 48 Week 24
Outcome N=447 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 ( 7 5 % )≥ 200 cells/mm3 384/426 (90 %) 2 0 2 / 2 1 6 ( 9 4 %)
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 treatment or study before Week 48 for ISG or before Week 24 for DSG forlack 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 ontreatment during the specified window.
§Other reasons include: lost to follow-up, non-compliance with study treatment, physician decision, protocol deviation,withdrawal by subject.
Baseline regimen = ritonavir or cobicistat-boosted PI (specifically atazanavir, darunavir, or lopinavir), orcobicistat-boosted elvitegravir, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), eachadministered with two NRTIs.
Discontinuation due to adverse events
In a pooled analysis combining data from two treatment-naïve trials (P007 and DRIVE-AHEAD), alower proportion of subjects who discontinued due to an adverse event by Week 48 was seen for thecombined doravirine (100 mg) treatment groups (2.8 %) compared with the combined EFV treatmentgroup (6.1 %) (treatment difference -3.4 %, p-value 0.012).
Paediatric populationThe efficacy of doravirine was evaluated in combination with lamivudine and tenofovir disoproxil(DOR/3TC/TDF) in an open-label, single-arm trial in HIV-1 infected paediatric patients 12 to lessthan 18 years of age (IMPAACT 2014 (Protocol 027)).
At baseline, the median age of subjects was 15 years (range: 12 to 17), 58% were female, 78% were
Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm3 (range: 84 to1,397). After switching to DOR/3TC/TDF, 95% (41/43) of virologically suppressed subjects remainedsuppressed (HIV-1 RNA < 50 copies/mL) at Week 24 and 93% (40/43) remained suppressed (HIV-1
RNA < 50 copies/mL) at Week 48.
The European Medicines Agency has deferred the obligation to submit the results of studies withdoravirine in one or more subsets of the paediatric population in treatment of humanimmunodeficiency virus-1 (HIV-1) infection. See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
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 statewas 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 mgonce daily to HIV-1 infected subjects, based on a population pharmacokinetics analysis, are providedbelow.
Parameter AUC0-24 Cmax C24
GM (% CV) µg*h/mL µg/mL µg/mL
Doravirine100 mg 16.1 (29) 0.962 (19) 0.396 (63)once daily
GM: Geometric mean, % CV: Geometric coefficient of variation
Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine hasan estimated absolute bioavailability of approximately 64 % for the 100 mg tablet.
Effect of food on oral absorptionThe administration of a single doravirine tablet with a high-fat meal to healthy subjects resulted in a16 % and 36 % increase in doravirine AUC and C24, respectively, while Cmax was not significantlyaffected.
DistributionBased on administration of an intravenous microdose, the volume of distribution of doravirine is60.5 L. Doravirine is approximately 76 % bound to plasma proteins.
BiotransformationBased on in vitro data, doravirine is primarily metabolised by CYP3A.
EliminationDoravirine has a terminal half-life (t1/2) of approximately 15 hours. Doravirine is primarily eliminatedvia oxidative metabolism mediated by CYP3A4. Biliary excretion of unchanged medicinal productmay contribute to the elimination of doravirine, but this elimination route is not expected to besignificant. Excretion of unchanged medicinal product via urinary excretion is minor.
Renal impairmentRenal excretion of doravirine is minor. In a study comparing 8 subjects with severe renal impairmentto 8 subjects without renal impairment, the single dose exposure of doravirine was 31 % higher insubjects with severe renal impairment. In a population pharmacokinetic analysis, which includedsubjects with CrCl between 17 and 317 mL/min, renal function did not have a clinically relevant effecton doravirine pharmacokinetics. No dose adjustment is required in patients with mild, moderate orsevere renal impairment. Doravirine has not been studied in patients with end-stage renal disease or inpatients undergoing dialysis (see section 4.2).
Hepatic impairmentDoravirine is primarily metabolised and eliminated by the liver. There was no clinically relevantdifference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderatehepatic impairment (classified as Child-Pugh score B primarily due to increased encephalopathy andascites scores) to 8 subjects without hepatic impairment. No dose adjustment is required in patientswith mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severehepatic impairment (Child-Pugh score C) (see section 4.2).
Paediatric populationMean doravirine exposures were similar in 54 paediatric patients aged 12 to less than 18 years andweighing at least 35 kg who received doravirine or doravirine/lamivudine/tenofovir disoproxil in
IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine ordoravirine/lamivudine/tenofovir disoproxil (Table 7).
Table 7: Steady state pharmacokinetics for doravirine following administration of doravirine ordoravirine/lamivudine/tenofovir disoproxil in HIV infected paediatric patients aged 12 to lessthan 18 years and weighing at least 35 kg
Parameter* Doravirine†
AUC0-24 16.4 (24)(µg*h/mL)
Cmax 1.03 (16)(µg/mL)
C24 0.379 (42)(µg/mL)
*Presented as geometric mean (%CV: geometric coefficient of variation)†From population PK analysis (n=54)
Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration;
C24=concentration at 24 hours
ElderlyAlthough a limited number of subjects aged 65 years and over has been included (n=36), no clinicallyrelevant differences in the pharmacokinetics of doravirine have been identified in subjects at least65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a populationpharmacokinetic analysis. No dose adjustment is required.
GenderNo clinically relevant pharmacokinetic differences have been identified between men and women fordoravirine.
RaceNo clinically relevant racial differences in the pharmacokinetics of doravirine have been identifiedbased on a population pharmacokinetic analysis of doravirine in healthy and HIV-1 infected subjects.
5.3 Preclinical safety data
Reproduction studies with orally administered doravirine have been performed in rats and rabbits atexposures approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at therecommended 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 thefoetus 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 milkconcentrations approximately 1.5 times that of maternal plasma concentrations.
CarcinogenesisLong-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence ofcarcinogenic potential at estimated exposures up to 6 times (mice) and 7 times (rats) the humanexposures at the RHD.
MutagenesisDoravirine was not genotoxic in a battery of in vitro or in vivo assays.
Impairment of fertilityThere were no effects on fertility, mating performance or early embryonic development whendoravirine was administered to rats up to 7 times the exposure in humans at the RHD.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Croscarmellose sodium (E468)
Hypromellose acetate succinate
Lactose monohydrate
Magnesium stearate (E470b)
Microcrystalline cellulose (E460)
Silica, colloidal anhydrous (E551)
Film-coatingCarnauba 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 notremove the desiccant. This medicinal product does not require any special temperature storageconditions. 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-resistantclosure 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 localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.