DELSTRIGO 100mg / 300mg / 245mg film-coated tablets medication leaflet

Delstrigo 100 mg/300 mg/245 mg film-coated tablets

Each film-coated tablet contains 100 mg of doravirine, 300 mg of lamivudine (3TC), and 245 mg oftenofovir disoproxil as tenofovir disoproxil fumarate (TDF).

Each film-coated tablet contains 8.6 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Yellow, oval-shaped, tablet of dimensions 21.59 mm x 11.30 mm, debossed with the corporate logoand 776 on one side and plain on the other side.

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 transcriptaseinhibitors (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 least35 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 otherregimens 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.

The recommended dose of Delstrigo is one 100/300/245 mg tablet taken orally once daily with orwithout food.

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

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

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

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 4.4and 5.2). Delstrigo should be discontinued if estimated CrCl declines below 50 mL/min (seesection 4.4). Patients with moderate or severe renal impairment require a dose interval adjustment oflamivudine and tenofovir disoproxil that cannot be achieved with the combination tablet (seesections 4.4 and 5.2).

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 beenstudied in patients with severe hepatic impairment (Child-Pugh Class C). It is not known whether theexposure to doravirine will increase in patients with severe hepatic impairment. Therefore, caution isadvised when doravirine/lamivudine/tenofovir disoproxil is administered to patients with severehepatic impairment (see section 5.2).

Safety and efficacy of Delstrigo in children aged less than 12 years or weighing less than 35 kg havenot been established. No data are available.

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 inducersis 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 medicinalproducts 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 antiretroviraltherapy. 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 NNRTIsubstitutions, that is associated with a reduction in clinical efficacy has not been established (seesection 5.1). There is not sufficient clinical evidence to support the use of doravirine in patientsinfected with HIV-1 with evidence of resistance to the NNRTI class.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS)/toxicepidermal necrolysis (TEN), have been reported during the post-marketing experience withdoravirine-containing regimens (see section 4.8). At the time of prescription, patients should beadvised of the signs and symptoms and monitored closely for skin reactions. If signs and symptomssuggestive of these reactions appear, doravirine-containing regimens should be withdrawnimmediately and an alternative treatment considered (as appropriate). Clinical status should be closelymonitored, and appropriate therapy should be initiated. If the patient has developed a serious reactionsuch as TEN, with the use of doravirine-containing regimens, treatment with doravirine-containingregimens must not be restarted in this patient at any time.

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 initiatingantiretroviral therapy.

Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have beenreported in patients who are co-infected with HIV-1 and HBV, and have discontinued lamivudine ortenofovir 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 severalmonths after stopping treatment with Delstrigo. If appropriate, initiation of anti-hepatitis B therapymay be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatmentexacerbation 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 injurywith severe hypophosphataemia), has been reported with the use of tenofovir disoproxil, a componentof 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 tenofovirdisoproxil. 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 weaknessmay be manifestations of proximal renal tubulopathy and should prompt an evaluation of renalfunction in at risk patients.

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

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

Bone effects in adult population

Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone painand, which can infrequently contribute to fractures may be associated with tenofovir disoproxilinduced proximal renal tubulopathy (see section 4.8).

Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil inrandomised controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients.

These BMD decreases generally improved after treatment discontinuation.

In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seenin patients treated with tenofovir disoproxil as part of a regimen containing a boosted proteaseinhibitor.

Overall, in view of the bone abnormalities associated with tenofovir disoproxil and the limitations oflong-term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternativetreatment regimens should be considered for patients with osteoporosis or with a history of bonefractures.

If bone abnormalities are suspected or detected, then appropriate consultation should be obtained.

Bone effects in paediatric population

There are uncertainties associated with the long-term effects of bone toxicity. Therefore, amultidisciplinary approach is recommended to adequately weigh on a case-by-case basis thebenefit/risk balance of treatment, decide the appropriate monitoring during treatment (includingdecision for treatment withdrawal) and consider the need for supplementation.

Tenofovir disoproxil may cause a reduction in BMD. The effects of tenofovir disoproxil-associatedchanges in BMD on long-term bone health and future fracture risk are uncertain.

If bone abnormalities are detected or suspected in paediatric patients, consultation with anendocrinologist and/or nephrologist should be obtained.

Co-administration with other antiviral products

Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal productscontaining lamivudine, or with medicinal products containing tenofovir disoproxil, or tenofoviralafenamide, or with adefovir dipivoxil (see section 4.5). Doravirine/lamivudine/tenofovir disoproxilshould 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 theexposure of doravirine (see sections 4.3 and 4.5).

Immune 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.

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

Delstrigo is a complete regimen for the treatment of HIV-1 infection; therefore, Delstrigo should notbe administered with other antiretroviral medicinal products. Information regarding potentialmedicinal 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 interactionsidentified 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 CYP3Aare expected to affect the clearance of doravirine (see section 5.2). Doravirine/lamivudine/tenofovirdisoproxil should not be co-administered with medicinal products that are strong CYP3A enzymeinducers as significant decreases in doravirine plasma concentrations are expected to occur, whichmay decrease the effectiveness of doravirine/lamivudine/tenofovir disoproxil (see sections 4.3and 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 shouldbe given daily, approximately 12 hours after doravirine/lamivudine/tenofovir disoproxil dose (seesection 4.2).

Co-administration of doravirine/lamivudine/tenofovir disoproxil with other moderate CYP3A inducershas not been evaluated, but decreased doravirine concentrations are expected. If co-administrationwith 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 administereddaily, approximately 12 hours after the administration of doravirine/lamivudine/tenofovir disoproxildose (see section 4.2).

Co-administration of doravirine/lamivudine/tenofovir disproxil and medicinal products that areinhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no doseadjustment is needed when doravirine is co-administered with CYP3A inhibitors.

Lamivudine

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

Tenofovir disoproxil

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

Due to the tenofovir disoproxil component of doravirine/lamivudine/tenofovir disoproxil, use of theproduct should be avoided with concurrent or recent use of nephrotoxic medicinal products. Someexamples 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 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).

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, thepotential for CYP-mediated interactions involving tenofovir with other medicinal products is low.

Table 1 shows the established and other potential medicinal product interactions with the individualcomponents 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 orlamivudine, (see sections 4.4 and 5.2).

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

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Acid-reducing agentsantacid (aluminium and doravirinemagnesium hydroxide oral

AUC 1.01 (0.92, 1.11)suspension) No dose adjustment is required.

C 0.86 (0.74, 1.01)(20 mL SD, max

C 1.03 (0.94, 1.12)doravirine 100 mg SD) 24 doravirinepantoprazole

AUC 0.83 (0.76, 0.91)(40 mg QD, No dose adjustment is required.

C 0.88 (0.76, 1.01)doravirine 100 mg SD) max

C24 0.84 (0.77, 0.92)

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofoviromeprazole disoproxil. No dose adjustment is required.

Expected: doravirine

Angiotensin converting enzyme inhibitors

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirlisinopril disoproxil. No dose adjustment is required.

Expected: lisinopril

Antiandrogens

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdisoproxil. Co-administration isenzalutamidecontraindicated.

Expected: doravirine(Induction of CYP3A)

Antibiotics

Interaction not studied with Co-administration should bedoravirine or avoided. If co-administrationdoravirine/lamivudine/tenofovir cannot be avoided, a 100 mg dosedisoproxil. of doravirine should be takennafcillindaily, approximately12 h after the

Expected: dose of↓ doravirine doravirine/lamivudine/tenofovir(Induction of CYP3A) disoproxil.

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Anticonvulsants

Interaction not studied withcarbamazepine doravirine oroxcarbazepine doravirine/lamivudine/tenofovirphenobarbital disoproxil. Co-administration isphenytoin contraindicated.

Expected: 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 withdoravirine ordoravirine/lamivudine/tenofovircanagliflozin disoproxil.liraglutide No dose adjustment is required.sitagliptin Expected:

 canagliflozin liraglutide sitagliptin

Antidiarrhoeals

Interaction not studied with

Co-administration should betelotristat ethyl doravirine oravoided. If co-administrationdoravirine/lamivudine/tenofovircannot be avoided, a 100 mg dosedisoproxil.

of doravirine should be takendaily, 12 h after the dose of

Expected:doravirine/lamivudine/tenofovir↓ doravirinedisoproxil.

(Induction of CYP3A)

Antigout and uricosuric agents

Interaction not studied with Co-administration should bedoravirine or avoided. If co-administrationdoravirine/lamivudine/tenofovir cannot be avoided, a 100 mg doselesinurad disoproxil. of doravirine should be takendaily, approximately 12 h after the

Expected: dose of↓ doravirine doravirine/lamivudine/tenofovir(Induction of CYP3A) disoproxil.

Antimycobacterials doravirine

AUC 0.91 (0.78, 1.06)

Single dose rifampicin

Cmax 1.40 (1.21, 1.63)(600 mg SD,

Cdoravirine 100 mg SD) 24 0.90 (0.80, 1.01)

Co-administration is doravirine contraindicated.

Multiple dose rifampicin(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)

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdisoproxil. Co-administration isrifapentinecontraindicated.

Expected: doravirine(Induction of CYP3A)

If doravirine/ lamivudine/ doravirinetenofovir disoproxil is co-

AUC 0.50 (0.45, 0.55)administered with rifabutin, a

Cmax 0.99 (0.85, 1.15)rifabutin 100 mg dose of doravirine should

C24 0.32 (0.28, 0.35)(300 mg QD, be taken daily, approximately 12 h(Induction of CYP3A)doravirine 100 mg SD) after dose ofdoravirine/lamivudine/tenofovirdisoproxil.

Antineoplastics

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdisoproxil. Co-administration ismitotanecontraindicated.

Expected: doravirine(Induction of CYP3A)

Antipsychotics

Interaction not studied with Co-administration should bedoravirine or avoided. If co-administrationdoravirine/lamivudine/tenofovir cannot be avoided, a 100 mg dosedisoproxil. of doravirine should be takenthioridazine daily, approximately 12 h after the

Expected: dose of↓ doravirine doravirine/lamivudine/tenofovir(Induction of CYP3A) disoproxil.

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 withdoravirine orfluconazole doravirine/lamivudine/tenofoviritraconazole disoproxil.

No dose adjustment is required.posaconazolevoriconazole Expected:

 doravirine(Inhibition of CYP3A)

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Calcium channel blockers

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdiltiazem disoproxil.

No dose adjustment is required.

verapamil

Expected: doravirine(Inhibition of CYP3A)

Cystic fibrosis treatment

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirlumacaftor disoproxil. Co-administration iscontraindicated.

Expected: doravirine(Induction of CYP3A)

Endothelin receptor antagonists

Interaction not studied with Co-administration should bedoravirine or avoided. If co-administrationdoravirine/lamivudine/tenofovir cannot be avoided, a 100 mg dosedisoproxil. of doravirine should be takenbosentan daily, approximately12 h after the

Expected: dose of↓ doravirine doravirine/lamivudine/tenofovir(Induction of CYP3A) disoproxil.

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,

C 0.96 (0.91, 1.01)doravirine 100 mg QD) max

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)

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil↑ doravirine

AUC 1.15 (1.07, 1.24)

Cmax 1.11 (0.97, 1.27)

C24 1.24 (1.13, 1.36) ledipasvir

AUC 0.92 (0.80, 1.06) Patients receiving

Cmax 0.91 (0.80, 1.02) doravirine/lamivudine/tenofovirdiledipasvir + sofosbuvirsoproxil concomitantly with(90 mg ledipasvir SD + sofosbuvir ledipasvir/sofosbuvir400 mg sofosbuvir SD,

AUC 1.04 (0.91, 1.18) should be monitored for adversedoravirine 100 mg SD)

Cmax 0.89 (0.79, 1.00) reactions associated with tenofovirdisoproxil. GS-331007

AUC 1.03 (0.98, 1.09)

Cmax 1.03 (0.97, 1.09)

Expected:↑ tenofovir

Interaction not studied with

Patients receivingdoravirine ordoravirine/lamivudine/tenofovirdoravirine/lamivudine/tenofovirdisoproxil concomitantly withdisoproxil.sofosbuvir/velpatasvir sofosbuvir/velpatasvir should bemonitored for adverse reactions

Expected:

associated with tenofovir doravirinedisoproxil.↑ tenofovir

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirsofosbuvir disoproxil. No dose adjustment is required.

Expected: doravirine

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdaclatasvirdisoproxil. No dose adjustment is required.

Expected: doravirine

Interaction not studied withdoravirine orombitasvir/paritaprevir/ doravirine/lamivudine/tenofovirritonavir and dasabuvir +/- disoproxil.ritonavir No dose adjustment is required.

Expected: doravirine(Inhibition of CYP3A due toritonavir)

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdasabuvir disoproxil. No dose adjustment is required.

Expected: doravirine

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirdisoproxil.

glecaprevir, pibrentasvir No dose adjustment is required.

Expected: doravirine(inhibition of CYP3A)

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirribavirin disoproxil. No dose adjustment is required.

Expected: doravirine

Herbal supplements

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovir

St. John’s wortdisoproxil. Co-administration is(Hypericum perforatum)contraindicated.

Expected: doravirine(Induction of CYP3A)

HIV antiviral agents doravirinetenofovir disoproxil

AUC 0.95 (0.80, 1.12)(300 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 AUC 0.94 (0.88, 1.00)disoproxil 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)

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Immunosuppressants

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovir

Monitor blood concentrations oftacrolimus disoproxil.

tacrolimus and sirolimus as thesirolimusdose of these agents may need to

Expected:

be adjusted. doravirine↓ tacrolimus, sirolimus(Induction of CYP3A)

Kinase inhibitors

Interaction not studied with Co-administration should bedoravirine or avoided. If co-administrationdoravirine/lamivudine/tenofovir cannot be avoided, a 100 mg dosedisoproxil. of doravirine should be takendabrafenib daily, approximately 12 h after the

Expected: dose of↓ doravirine doravirine/lamivudine/tenofovir(Induction of CYP3A) disoproxil.

Miscellaneous

Single dose lamivudine oral solution When possible, avoid chronic co-300 mg administration ofdoravirine/lamivudine/tenofovirlamivudine disoproxil with medicinal

AUC  14 %; 32 %; 35 % products containing sorbitol orsorbitol solution (3.2 g,

Cmax  28 %; 52 %; 55 % other osmotic acting poly-alcohols10.2 g, 13.4 g)/lamivudine(e.g., xylitol, mannitol, lactitol,maltitol). Consider more frequentmonitoring of HIV-1 viral loadwhen chronic co-administrationcannot be avoided.

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-methadone(20-200 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)

Recommendation concerning

Medicinal product by Effects on medicinal product levels co-administration withtherapeutic area geometric mean ratio (90 % CI)* doravirine/lamivudine/tenofovirdisoproxil

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirbuprenorphine disoproxil.

No dose adjustment is required.

naloxone

Expected: buprenorphine naloxone

Oral contraceptives ethinyl oestradiol

AUC 0.98 (0.94, 1.03)0.03 mg ethinyl oestradiol/ Cmax 0.83 (0.80, 0.87)0.15 mg levonorgestrel SD, No dose adjustment is required.doravirine 100 mg QD  levonorgestrel

AUC 1.21 (1.14, 1.28)

Cmax 0.96 (0.88, 1.05)

Interaction not studied withdoravirine ordoravirine/lamivudine/tenofovirnorgestimate/ethinyldisoproxil. No dose adjustment is required.

oestradiol

Expected: norgestimate/ethinyl oestradiol

Psychostimulants

Interaction not studied with Co-administration should bedoravirine or avoided. If co-administrationdoravirine/lamivudine/tenofovir cannot be avoided, a 100 mg dosedisoproxil. of doravirine should be takenmodafinil daily, approximately12 h after the

Expected: dose of↓ doravirine doravirine/lamivudine/tenofovir(Induction of CYP3A) disoproxil.

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 withdoravirine ordoravirine/lamivudine/tenofovirrosuvastatin disoproxil.

No dose adjustment is required.

simvastatin

Expected: rosuvastatin simvastatin = increase, ↓ = decrease, ↔ = no change

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

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

There are no or limited amount of data from the use of doravirine in pregnant women. A large amountof data on pregnant women (more than 3 000 outcomes from first trimester) taking the individualactive component lamivudine in combination with other antiretrovirals indicates no malformativetoxicity. 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 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).

Animal studies with tenofovir disoproxil do not indicate direct or indirect harmful effects of tenofovirdisoproxil 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. Lamivudinemay inhibit cellular DNA replication (see section 5.3). The clinical relevance of this finding isunknown.

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

It is unknown whether doravirine is excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk (seesection 5.3).

Lamivudine has been identified in breast-fed newborns/infants of treated women. Based on more than200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breast-fed infants ofmothers treated for HIV are very low (< 4 % of maternal serum concentrations) and progressivelydecrease to undetectable levels when breast-fed infants reach 24 weeks of age. There are no dataavailable 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 innewborns/infants.

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

No human data on the effect of Delstrigo on fertility are available. Animal studies do not indicateharmful effects of doravirine, lamivudine, or tenofovir disoproxil on fertility at exposure levels higherthan 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 informedthat fatigue, dizziness, and somnolence have been reported during treatment with Delstrigo (seesection 4.8). This should be considered when assessing a patient's ability to drive or operatemachinery.

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 %).

The adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE-FORWARD,

DRIVE-SHIFT and DRIVE-AHEAD) and post-marketing 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), very rare (< 1/10 000), ornot known (cannot be estimated from the available data).

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

Frequency Adverse reactions

Rare rash pustular

Blood and lymphatic systems disorders

Uncommon neutropenia*, anaemia*, thrombocytopenia*

Very rare pure red cell aplasia*

Uncommon hypophosphataemia, hypokalaemia*

Rare hypomagnesaemia, lactic acidosis*

Common abnormal dreams, insomnia1,

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

Rare aggression, hallucination, adjustment disorder,mood altered, somnambulism

Common headache, dizziness, somnolence

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

Very rare peripheral neuropathy (or paraesthesia)*

Uncommon hypertension

Common cough*, nasal symptoms*

Rare dyspnoea, tonsillar hypertrophy

Common nausea, diarrhoea, abdominal pain4, vomiting,flatulence

Uncommon constipation, abdominal discomfort5, abdominaldistension, dyspepsia, faeces soft6,gastrointestinal motility disorder7, pancreatitis*

Rare rectal tenesmus

Rare hepatic steatosis*, hepatitis†

Frequency Adverse reactions

Common alopecia*, rash8

Uncommon pruritus

Rare dermatitis allergic, rosacea, angioedema*

Not known toxic epidermal necrolysis

Common muscle disorders*, bone mineral densitydecreased*

Uncommon myalgia, arthralgia, rhabdomyolysis*‡,muscular weakness*‡

Rare musculoskeletal pain, osteomalacia (manifestedas bone pain and infrequently contributing tofractures)*, myopathy*

Uncommon increased creatinine*, proximal renaltubulopathy (including Fanconi syndrome)*

Rare acute kidney injury, renal disorder, calculusurinary, nephrolithiasis, acute renal failure*,renal failure*, acute tubular necrosis*, nephritis(including acute interstitial)*, nephrogenicdiabetes insipidus*

Common fatigue, fever*

Uncommon asthenia, malaise

Rare chest pain, chills, pain, thirst

Common alanine aminotransferase increased9

Uncommon aspartate aminotransferase increased, lipaseincreased, amylase increased, haemoglobindecreased

Rare blood creatine phosphokinase increased

*This adverse reaction was not identified as an adverse reaction associated with doravirine from the Phase 3 clinicalstudies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but is included in this table as an adverse reactionbased on the Summary of Product Characteristics (SmPC) of 3TC and/or TDF. The highest frequency categoryreported in the 3TC or TDF SmPC is used.†This adverse reaction was not identified as an adverse reaction associated with doravirine from the Phase 3 clinicalstudies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but was seen during post-marketing use ofdoravirine-containing regimens and is an adverse reaction listed in the SmPC of 3TC and TDF. The highest frequencycategory reported in the 3TC and TDF SmPCs is used.‡This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causallyassociated with tenofovir disoproxil in the absence of this condition.1insomnia includes: insomnia, initial insomnia and sleep disorder.2depression includes: depression, depressed mood, major depression, and persistent depressive disorder.3anxiety includes: anxiety and generalised anxiety disorder.4abdominal pain includes: abdominal pain, and abdominal pain upper.5abdominal discomfort includes: abdominal discomfort, and epigastric discomfort.6faeces soft includes: faeces soft and abnormal faeces.7gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements.8rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, andurticarial.9alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury.

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).

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination withother antiretrovirals. Patients with predisposing factors such as patients with decompensated liverdisease, or patients receiving concomitant medicinal products known to induce lactic acidosis are atincreased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, includingfatal outcomes.

Severe cutaneous adverse reactions (SCARs), such as toxic epidermal necrolysis (TEN), have beenreported in association with doravirine-containing treatment regimens (see section 4.4).

The safety of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infectedvirologically suppressed or treatment-naïve 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 paediatricsubjects was similar to that in adults.

Reporting 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.

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, continuousambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuoushaemodialysis would provide clinical benefit in a lamivudine overdose event.

Tenofovir disoproxil

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

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

Doravirine

Doravirine 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.

Lamivudine

Lamivudine is a nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active5´- triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of3TC-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 analogue of adenosinemonophosphate. Tenofovir disoproxil requires initial diester hydrolysis for conversion to tenofovir andsubsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovirdiphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine5´-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphateis a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Doravirine

Doravirine 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. The antiviral activity of doravirinewas 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 includingmonocytes 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). Themedian 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-Gand group O viruses (n = 3 except n = 2 for clade B) respectively. Ribavirin (50 microM) used in thetreatment 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 antiviralactivity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from0.5-2.2 microM).

Doravirine

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).

Lamivudine

Lamivudine-resistant variants of HIV-1 have been selected in cell culture and in subjects treated withlamivudine. Genotypic analysis showed that the resistance was due to a specific amino acidsubstitution 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 a2-4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has beenselected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine,lamivudine, and tenofovir.

In clinical trials

Treatment-naïve adult subjects

Doravirine

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/FT

NRTIs* NRTIs* C C(383) (383) (364) (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

*NRTI in DOR arm: FTC/TDF (333) or ABC/3TC (50); NRTI 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 ofpre-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 Delstrigo. One subject developed RT M184M/I mutation and phenotypicresistance to 3TC and FTC during treatment with their baseline regimen. None of the 24 subjects (11in 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 ofdiscontinuation.

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, lamivudine or tenofovir was detected.

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

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 areduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reductionin 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 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 substitutions yieldeda fold change of 5-10 (G190S (5.7); K103N/P225H (7.9), V108I/Y181C (6.9), Y181V (5.1)). Theclinical 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.

Lamivudine

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

Tenofovir disoproxil

Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected bytenofovir is also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1isolates with the K65R substitution also showed reduced susceptibility to emtricitabine andlamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virusharbours the K65R substitution. The K70E substitution selected clinically by tenofovir disoproxilresults 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 RTamino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-folddecrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitutionwithout zidovudine resistance-associated substitutions (n = 8) had reduced response to tenofovirdisoproxil. 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 reducedresponse in clinical trials.

Treatment-naïve adult subjects

The efficacy of doravirine is based on the analyses of 96-week data from two randomised, multicentre,double-blind, active controlled Phase 3 trials, (DRIVE-FORWARD and DRIVE-AHEAD) 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 % hadhepatitis B or C co-infection, 14 % had a history of AIDS, 21 % had HIV-1 RNA > 100 000 copies permL, and 12 % had CD4+ T cell count < 200 cells per mm3; these characteristics were similar betweentreatment groups.

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 (383) DRV+r + 2 NRTIs DOR/3TC/TDF EFV/FTC/TDF(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 %) NA

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.

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 Delstrigo 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 Delstrigo at baseline [N= 447, Immediate Switch Group (ISG)], or stay on their baselineregimen 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 % werenon-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 proportionof subjects with HIV-1 RNA < 40 copies/mL. Treatment results are shown in Table 5. Consistentresults were seen for the comparison at study Week 24 in each treatment group.

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

Delstrigo 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 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 %).

The efficacy of DOR/3TC/TDF was evaluated in an open-label, single-arm trial in HIV-1 infectedpaediatric 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 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 with

Delstrigo in one or more subsets of the paediatric population in treatment of human immunodeficiencyvirus-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, andtenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plustenofovir disoproxil tablets (245 mg). The administration of a single Delstrigo tablet with a high-fatmeal to healthy subjects resulted in a 26 % increase in doravirine C24, while AUC and Cmax were notsignificantly affected. Lamivudine Cmax decreased by 19 % with a high fat meal, while AUC was notsignificantly affected. Tenofovir Cmax decreased by 12 % and AUC increased by 27 % with a high fatmeal. 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 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.

Based on administration of an intravenous microdose, the volume of distribution of doravirine is60.5 L. Doravirine is approximately 76 % bound to plasma proteins.

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

Doravirine

Doravirine 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.

Lamivudine

Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Aftermultiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects,steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 microgram per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,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 medicinalproduct in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the onlyknown metabolite is the trans-sulphoxide metabolite (approximately 5 % of an oral dose after12 hours). In most single-dose trials in HIV-1 infected subjects, or healthy subjects with serumsampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to7 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-infectedsubjects in the fasted state, Cmax was achieved in one hour. Cmax and AUC values were0.30 ± 0.09 micrograms per mL and 2.29 ± 0.69 µg*hr per mL, respectively. The oral bioavailability oftenofovir from tenofovir disoproxil in fasted subjects is approximately 25 %. Less than 0.7 % oftenofovir 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 medicinalproduct in the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerularfiltration and active tubular secretion with a renal clearance in adults with CrCl greater than 80 mL perminute 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 neithertenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes.

Doravirine

Renal 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).

Lamivudine

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

Tenofovir disoproxil

Pharmacokinetic parameters of tenofovir were determined following administration of a single dose oftenofovir disoproxil 245 mg to 40 non-HIV infected adult subjects with varying degrees of renalimpairment defined according to baseline CrCl (normal renal function when CrCl > 80 mL/min; mildwith 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) tenofovirexposure increased from 2,185 (12 %) ng*h/mL in subjects with CrCl > 80 mL/min to respectively3,064 (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 insubjects with end-stage renal disease managed by peritoneal or other forms of dialysis have not beenstudied.

Doravirine

Doravirine 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).

Lamivudine

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

Tenofovir disoproxil

The pharmacokinetics of tenofovir following a 245 mg dose of tenofovir disoproxil have been studiedin non-HIV infected subjects with moderate to severe hepatic impairment. No clinically relevantdifferences in tenofovir pharmacokinetics were observed between subjects with hepatic impairmentand unimpaired subjects.

Mean 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

IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine ordoravirine/lamivudine/tenofovir disoproxil. Exposures of lamivudine and tenofovir in paediatricsubjects following the administration of doravirine/lamivudine/tenofovir disoproxil were similar tothose in adults following administration of lamivudine and tenofovir disoproxil (Table 6).

Table 6: Steady state pharmacokinetics for doravirine, lamivudine, and tenofovir followingadministration of doravirine or doravirine/lamivudine/tenofovir disoproxil in HIV infectedpaediatric patients aged 12 to less than 18 years and weighing at least 35 kg

Parameter* Doravirine† Lamivudine‡ Tenofovir‡

AUC0-24 16.4 (24) 11.3 (28) 2.55 (14)(µg*h/mL)

Cmax 1.03 (16) 2.1 (24) 0.293 (37)(µg/mL)

C24 0.379 (42) 0.0663 (55) 0.0502 (9)(µg/mL)

*Presented as geometric mean (%CV: geometric coefficient of variation)†From population PK analysis (n=54)‡From intensive PK analysis (n=10)

Abbreviations: AUC=area under the time concentration curve; Cmax=maximum concentration;

C24=concentration at 24 hours

Although a limited number of subjects aged 65 years and over has been included (n = 36), noclinically relevant differences in the pharmacokinetics of doravirine have been identified in subjects atleast 65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a populationpharmacokinetic analysis. The pharmacokinetics of lamivudine and tenofovir have not been studied insubjects older than 65 years. No dose adjustment is required.

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

Doravirine

No 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.

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 adequatelydetermine potential pharmacokinetic differences among these populations following the administrationof tenofovir disoproxil.

Doravirine

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.

Lamivudine

Lamivudine was not teratogenic in animal studies but there were indications of an increase in earlyembryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved inhumans. 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 orfoetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in aperi-postnatal toxicity study at maternally toxic doses.

Doravirine

Long-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.

Lamivudine

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

Tenofovir disoproxil

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

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 cytogeneticassay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicityassay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrowcytogenetic 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 vitrobacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxilwas negative when administered to male mice.

Doravirine

There were no effects on fertility, mating performance or early embryonic development whendoravirine 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 orfoetal parameters.

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 anymajor organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidneyfunction were seen together with occasional reductions in liver weight. The clinically relevant effectsnoted 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 orequal to clinical exposure levels and with possible relevance to clinical use included kidney and bonechanges and a decrease in serum phosphate concentration. Bone toxicity was diagnosed asosteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicityin young adult rats and dogs occurred at exposures ≥ 5-fold the exposure in paediatric or adultpatients; bone toxicity occurred in juvenile infected monkeys at very high exposures followingsubcutaneous dosing (≥ 40-fold the exposure in patients). Findings in the rat and monkey studiesindicated that there was a substance related decrease in intestinal absorption of phosphate withpotential secondary reduction in BMD.

Croscarmellose sodium (E468)

Hypromellose acetate succinate

Magnesium stearate (E470b)

Microcrystalline cellulose (E460)

Silica, colloidal anhydrous (E551)

Sodium stearyl fumarate

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 removethe 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-resistantclosure 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 localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/18/1333/001

EU/1/18/1333/002

Date of first authorisation: 22 November 2018

Date of latest renewal: 23 June 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu