Pifeltro 100 mg film-coated tablets

Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults, and adolescents aged 12 years and older weighing at least 35 kg infected with human immunodeficiency 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).

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 required 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 Pifeltro in children aged less than 12 years or weighing less than 35 kg have not been established. 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).

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

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 medicinal product.

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

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).

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

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).

Pifeltro has a minor influence on the ability to drive and 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.

Summary of the safety profile

In phase 3 clinical trials with doravirine plus 2 NRTIs, the most frequently reported adverse reactions were nausea (4 %) and headache (3 %).

Tabulated summary of adverse reactions

The adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE FORWARD, DRIVE SHIFT and DRIVE AHEAD) 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

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).

Paediatric population

The safety of doravirine as a component of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically suppressed or treatment-naï ve paediatric patients 12 to less than 18 years of age through Week 48 in an open-label trial (IMPAACT 2014 (Protocol 027)). The safety profile in paediatric subjects was similar to that in adults.

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.

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

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, F227I, F227V, H221Y, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. 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-naï ve 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

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.

Paediatric subjects

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

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 8 subjects who developed high level doravirine resistance 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 experience

Treatment-naï ve 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-naï ve, 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

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

P007 was a Phase 2b trial in antiretroviral treatment-naï ve 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)

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

Discontinuation due to adverse events

In a pooled analysis combining data from two treatment-naï ve 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 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 less than 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 to 1,397). After switching to DOR/3TC/TDF, 95% (41/43) of virologically suppressed subjects remained suppressed (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 with doravirine in one or more subsets of the paediatric population in treatment of human immunodeficiency virus-1 (HIV-1) infection. See section 4.2 for information on paediatric use.

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 AUC_0-24, C_max, 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.

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 C_24, respectively, while C_max was not significantly affected.

Distribution

Based on administration of an intravenous 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 (t_1/2) 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).

Paediatric population

Mean doravirine exposures were similar in 54 paediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or doravirine/lamivudine/tenofovir disoproxil in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil (Table 7).

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.

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.

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)

Not applicable.

30 months

After first opening of the bottle use within 35 days.

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.

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.

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