Delstrigo is indicated for the treatment of adults 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, lamivudine, or tenofovir (see sections 4.4 and 5.1).

Delstrigo is also indicated for the treatment of adolescents aged 12 years and older weighing at least 35 kg who are infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir and who have experienced toxicities which preclude the use of other regimens that do not contain tenofovir disoproxil (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 of Delstrigo is one 100/300/245 mg tablet taken orally once daily with or without food.

Dose adjustment

If Delstrigo is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily. This is achieved by adding one 100 mg tablet of doravirine (as a single agent), to be taken approximately 12 hours apart from the dose of Delstrigo (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 doravirine should be taken daily, approximately 12 hours after the dose of Delstrigo (see section 4.5).

Missed dose

If the patient misses a dose of Delstrigo within 12 hours of the time it is usually taken, the patient should take Delstrigo as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Delstrigo 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

There are limited data available on the use of doravirine, lamivudine, and tenofovir disoproxil in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2). Special care is advised in this age group due to age associated changes such as decreases in renal function (see section 4.4).

Renal impairment

No dose adjustment of Delstrigo is required in patients with estimated creatinine clearance (CrCl) ≥ 50 mL/min.

Delstrigo should not be initiated in patients with estimated CrCl < 50 mL/min (see sections 4.4 and 5.2). Delstrigo should be discontinued if estimated CrCl declines below 50 mL/min (see section 4.4). Patients with moderate or severe renal impairment require a dose interval adjustment of lamivudine and tenofovir disoproxil that cannot be achieved with the combination tablet (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment of doravirine/lamivudine/tenofovir disoproxil 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/lamivudine/tenofovir disoproxil is administered to patients with severe hepatic impairment (see section 5.2).

Paediatric population

Safety and efficacy of Delstrigo in children aged less than 12 years or weighing less than 35 kg have not been established. No data are available.

Method of administration

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

Hypersensitivity to the active substances 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 Delstrigo (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.

Severe acute exacerbation of hepatitis B in patients co-infected with HIV-1 and HBV

All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy.

Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are co-infected with HIV-1 and HBV, and have discontinued lamivudine or tenofovir disoproxil, two of the components of Delstrigo. Patients who are co-infected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with Delstrigo. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

New onset or worsening renal impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported with the use of tenofovir disoproxil, a component of Delstrigo.

Delstrigo should be avoided with concurrent or recent use of nephrotoxic medicinal products (e.g., high-dose or multiple nonsteroidal anti-inflammatory medicinal products [NSAIDs]) (see section 4.5). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir disoproxil. Some patients required hospitalisation and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at risk patients.

It is recommended that estimated CrCl be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with Delstrigo. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated CrCl, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Delstrigo and more frequent renal function monitoring should be assessed as appropriate per the patient's medical condition during Delstrigo therapy.

Lamivudine and tenofovir disoproxil are primarily excreted by the kidney. Delstrigo should be discontinued if estimated CrCl declines below 50 mL/min as dose interval adjustment required for lamivudine and tenofovir disoproxil cannot be achieved with the fixed dose combination tablet (see section 4.2).

Bone loss and mineralisation defects

Bone mineral density

In clinical trials in HIV-1 infected adults, tenofovir disoproxil was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil. In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor.

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.

The effects of tenofovir disoproxil associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1 infected adult patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

Mineralisation defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir disoproxil . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphataemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir disoproxil (see section 4.4).

Co-administration with other antiviral products

Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal products containing lamivudine, or with medicinal products containing tenofovir disoproxil, or tenofovir alafenamide, or with adefovir dipivoxil (see section 4.5). Doravirine/lamivudine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g., with rifabutin) (see sections 4.2 and 4.5).

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

Delstrigo contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Delstrigo is a complete regimen for the treatment of HIV-1 infection; therefore, Delstrigo should not be administered with other antiretroviral medicinal products. Information regarding potential medicinal product interactions with other antiretroviral medicinal products is not provided.

Interaction studies have only been performed in adults.

Delstrigo contains doravirine, lamivudine, and tenofovir disoproxil, therefore any interactions identified for these individually are relevant to Delstrigo and are presented in Table 1.

Effects of other medicinal products on doravirine, lamivudine, and tenofovir disoproxil

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/lamivudine/tenofovir disoproxil 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/lamivudine/tenofovir disoproxil (see sections 4.3 and 5.2).

Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When Delstrigo is co-administered with rifabutin, a 100 mg dose of doravirine should be given daily, approximately 12 hours after doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2).

Co-administration of doravirine/lamivudine/tenofovir disoproxil 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., debrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, a 100 mg dose of doravirine should be administered daily, approximately 12 hours after the administration of doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2).

Co-administration of doravirine/lamivudine/tenofovir disproxil 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.

Lamivudine

Because lamivudine is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine.

Tenofovir disoproxil

Because tenofovir is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via OAT1, OAT3 or MRP4 may increase serum concentrations of tenofovir.

Due to the tenofovir disoproxil component of doravirine/lamivudine/tenofovir disoproxil, use of the product should be avoided with concurrent or recent use of nephrotoxic medicinal products. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (see section 4.4).

Effects of doravirine, lamivudine, and tenofovir disoproxil on other medicinal products

Doravirine

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).

Lamivudine

Lamivudine does not inhibit or induce CYP enzymes.

Tenofovir

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.

Interaction table

Table 1 shows the established and other potential medicinal product interactions with the individual components of Delstrigo but is not all inclusive (increase is indicated as ↑ , decrease is indicated as ↓ , and no change as ↔ ). For potential medicinal product interactions with tenofovir disoproxil or lamivudine, (see sections 4.4 and 5.2).

Table 1: Interactions between the individual components of Delstrigo and other medicinal products

Pregnancy

There are no or limited amount of data from the use of doravirine in pregnant women. A large amount of data on pregnant women (more than 3 000 outcomes from first trimester) taking the individual active component lamivudine in combination with other antiretrovirals indicates no malformative toxicity. A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.

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).

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

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (see section 5.3). Placental transfer of lamivudine has been shown to occur in humans. Lamivudine may inhibit cellular DNA replication (see section 5.3). The clinical relevance of this finding is unknown.

As a precautionary measure, it is preferable to avoid the use of Delstrigo 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).

Lamivudine has been identified in breast-fed newborns/infants of treated women. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breast-fed infants of mothers treated for HIV are very low (< 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breast-fed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.

Tenofovir is excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants.

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 Delstrigo on fertility are available. Animal studies do not indicate harmful effects of doravirine, lamivudine, or tenofovir disoproxil on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose (see section 5.3).

Delstrigo 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 Delstrigo (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 nucleoside analogue reverse transcriptase inhibitors (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), rare (≥ 1/10 000 to < 1/1 000), or very rare (< 1/10 000).

Table 2: Tabulated summary of adverse reactions associated with doravirine/lamivudine/tenofovir disoproxil

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).

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medicinal products known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

Paediatric population

The safety 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.

Doravirine

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

Lamivudine

Because a negligible amount of lamivudine was removed via (4-hour) haemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous haemodialysis would provide clinical benefit in a lamivudine overdose event.

Tenofovir disoproxil

Tenofovir disoproxil is efficiently removed by haemodialysis with an extraction coefficient of approximately 54 %. Following a single 245 mg dose of tenofovir disoproxil, a 4-hour haemodialysis session removed approximately 10 % of the administered tenofovir dose.

Pharmacotherapeutic group: Antivirals for systemic use, ATC code: J05AR24

Mechanism of action

Doravirine

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 .

Lamivudine

Lamivudine is a nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5´ - triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Tenofovir disoproxil

Tenofovir disoproxil is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5´ -triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α , β , and mitochondrial DNA polymerase γ .

Antiviral activity in cell culture

Doravirine

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. The antiviral activity of doravirine was not antagonistic when combined with lamivudine and tenofovir disoproxil.

Lamivudine

The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and peripheral blood mononuclear cells (PBMCs) using standard susceptibility assays. EC₅₀ values were in the range of 0.003 to 15 microM (1 microM = 0.23 micrograms per mL). The median EC₅₀ values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.

Tenofovir disoproxil

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC₅₀ values for tenofovir were in the range of 0.04-8.5 microM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC₅₀ values ranged from 0.5-2.2 microM).

Resistance

In cell culture

Doravirine

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 substitutions (double mutants yielding a fold change of > 100).

Lamivudine

Lamivudine-resistant variants of HIV-1 have been selected in cell culture and in subjects treated with lamivudine. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 RT at codon 184 changing the methionine to either isoleucine or valine (M184V/I).

Tenofovir disoproxil

HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2-4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.

In clinical trials

Treatment-naï ve adult subjects

Doravirine

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 at 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 Delstrigo. 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, lamivudine or tenofovir was detected.

Cross-resistance

No significant cross-resistance has been demonstrated between doravirine-resistant HIV-1 variants and lamivudine/emtricitabine or tenofovir or between lamivudine- or tenofovir-resistant variants and doravirine.

Doravirine

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 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 change 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.

Lamivudine

Cross-resistance has been observed among NRTIs. The M184I/V lamivudine resistance substitution confers resistance to emtricitabine. Lamivudine-resistant HIV-1 mutants were also cross resistant to didanosine (ddI). In some subjects treated with zidovudine plus didanosine, isolates resistant to multiple RT inhibitors, including lamivudine, have emerged.

Tenofovir disoproxil

Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbours the K65R substitution. The K70E substitution selected clinically by tenofovir disoproxil results in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 isolates from patients (n = 20) whose HIV-1 expressed a mean of 3 zidovudine associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (n = 8) had reduced response to tenofovir disoproxil. Limited data are available for patients whose virus expressed a Y115F substitution (n = 3), Q151M substitution (n = 2), or T69 insertion (n = 4) in HIV-1 RT, all of whom had a reduced response in clinical trials.

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.

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 Delstrigo 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 Delstrigo at baseline [N= 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to Delstrigo [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 Delstrigo was demonstrated to be non-inferior at Week 48 compared to continuation of the baseline regimen at Week 24 as assessed by the proportion of subjects with HIV-1 RNA < 40 copies/mL. Treatment results are shown in Table 5. Consistent results were seen for the comparison at study Week 24 in each treatment group.

Table 5: Efficacy response (Snapshot approach) in the DRIVE-SHIFT study

Discontinuation due to adverse events

In DRIVE-AHEAD, a lower proportion of subjects who discontinued due to an adverse event by Week 48 was seen for the Delstrigo group (3.0 %) compared with the EFV/FTC/TDF group (6.6 %).

Paediatric population

The efficacy of DOR/3TC/TDF was evaluated 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 Delstrigo 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.

Single-dose administration of one doravirine/lamivudine/tenofovir disoproxil tablet to healthy subjects (N = 24) under fasted conditions provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus tenofovir disoproxil tablets (245 mg). The administration of a single Delstrigo tablet with a high-fat meal to healthy subjects resulted in a 26 % increase in doravirine C₂₄, while AUC and C_max were not significantly affected. Lamivudine C_max decreased by 19 % with a high fat meal, while AUC was not significantly affected. Tenofovir C_max decreased by 12 % and AUC increased by 27 % with a high fat meal. These differences in pharmacokinetics are not clinically relevant.

Doravirine

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.

Absorption

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.

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

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.

Lamivudine

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state C_max (C_max,ss) was 2.04 ± 0.54 microgram per mL (mean ± SD) and the 24-hour steady-state AUC (AUC_24,ss) was 8.87 ± 1.83 mcg• hour per mL. Binding to plasma protein is low. Approximately 71 % of an intravenous dose of lamivudine is recovered as unchanged medicinal product in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulphoxide metabolite (approximately 5 % of an oral dose after 12 hours). In most single-dose trials in HIV-1 infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t_½ ) ranged from 5 to 7 hours. In HIV-1– infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD).

Tenofovir disoproxil

Following oral administration of a single 245 mg dose of tenofovir disoproxil to HIV-1-infected subjects in the fasted state, C_max was achieved in one hour. C_max and AUC values were 0.30 ± 0.09 micrograms per mL and 2.29 ± 0.69 µ g• hr per mL, respectively. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted subjects is approximately 25 %. Less than 0.7 % of tenofovir binds to human plasma proteins in vitro over the range of 0.01 to 25 micrograms per mL. Approximately 70-80 % of the intravenous dose of tenofovir is recovered as unchanged medicinal product in the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with CrCl greater than 80 mL per minute of 243.5 ± 33.3 mL per minute (mean ± SD). Following oral administration, the terminal half-life of tenofovir is approximately 12 to 18 hours. In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes.

Renal impairment

Doravirine

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).

Lamivudine

Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Based on the lamivudine data, Delstrigo is not recommended for patients with CrCl of < 50 mL/min.

Tenofovir disoproxil

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV infected adult subjects with varying degrees of renal impairment defined according to baseline CrCl (normal renal function when CrCl > 80 mL/min; mild with CrCl = 50-79 mL/min; moderate with CrCl = 30-49 mL/min and severe with CrCl = 10-29 mL/min). Compared with subjects with normal renal function, the mean (% CV) tenofovir exposure increased from 2,185 (12 %) ng• h/mL in subjects with CrCl > 80 mL/min to respectively 3,064 (30 %) ng• h/mL, 6,009 (42 %) ng• h/mL and 15,985 (45 %) ng• h/mL in subjects with mild, moderate, and severe renal impairment.

The pharmacokinetics of tenofovir in non-haemodialysis adult subjects with CrCl < 10 mL/min and in subjects with end-stage renal disease managed by peritoneal or other forms of dialysis have not been studied.

Hepatic impairment

Doravirine

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).

Lamivudine

The pharmacokinetic properties of lamivudine have been determined in subjects with moderate to severe hepatic impairment. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

Tenofovir disoproxil

The pharmacokinetics of tenofovir following a 245 mg dose of tenofovir disoproxil have been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.

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 IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil. Exposures of lamivudine and tenofovir in paediatric subjects following the administration of doravirine/lamivudine/tenofovir disoproxil were similar to those in adults following administration of lamivudine and tenofovir disoproxil (Table 6).

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. The pharmacokinetics of lamivudine and tenofovir have not been studied in subjects older than 65 years. No dose adjustment is required.

Gender

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

Race

Doravirine

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.

Lamivudine

There are no significant or clinically relevant racial differences in pharmacokinetics of lamivudine.

Tenofovir disoproxil

There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of tenofovir disoproxil.

Reproductive toxicity

Doravirine

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.

Lamivudine

Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.

Tenofovir disoproxil

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.

Carcinogenesis

Doravirine

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.

Lamivudine

Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the RHD.

Tenofovir disoproxil

Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high-dose in mice. These tumours are unlikely to be of relevance to humans.

Mutagenesis

Doravirine

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

Lamivudine

Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Tenofovir disoproxil

Tenofovir disoproxil was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil was negative when administered to male mice.

Impairment of fertility

Doravirine

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

Lamivudine

Lamivudine did not affect male or female fertility in rats.

Tenofovir disoproxil

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters.

Repeat dose toxicity

Doravirine

Administration of doravirine in animal toxicity studies was not associated with toxicity.

Lamivudine

Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney function were seen together with occasional reductions in liver weight. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.

Tenofovir disoproxil

Findings in repeat-dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use included kidney and bone changes and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.

Tablet core

Croscarmellose sodium (E468)

Hypromellose acetate succinate

Magnesium stearate (E470b)

Microcrystalline cellulose (E460)

Silica, colloidal anhydrous (E551)

Sodium stearyl fumarate

Film-coating

Carnauba wax (E903)

Hypromellose (E464)

Iron oxide yellow (E172)

Lactose monohydrate

Titanium dioxide (E171)

Triacetin (E1518)

Not applicable.

30 months

Store in the original bottle and keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. This medicinal product does not require any special temperature storage conditions.

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

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.