4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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

Posology

The recommended dose 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).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

NNRTI substitutions and use of doravirine

Doravirine has not been evaluated in patients with previous virologic failure to any other 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 cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine‑containing regimens (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, doravirine-containing regimens should be withdrawn immediately and an alternative treatment considered (as appropriate). Clinical status should be closely monitored, and appropriate therapy should be initiated. If the patient has developed a serious reaction such as TEN, with the use of doravirine-containing regimens, treatment with doravirine-containing regimens 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 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 effects in adult population

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

Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil in randomised 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 seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor.

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

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, a multidisciplinary approach is recommended to adequately weigh on a case-by-case basis the benefit/risk balance of treatment, decide the appropriate monitoring during treatment (including decision for treatment withdrawal) and consider the need for supplementation.

Tenofovir disoproxil may cause a reduction in BMD. The effects of tenofovir disoproxil-associated changes 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 an endocrinologist and/or nephrologist should be obtained.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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

Medicinal product by therapeutic area

Effects on medicinal product levels geometric mean ratio (90 % CI)*

Recommendation concerning co-administration with doravirine/lamivudine/tenofovir disoproxil

Acid-reducing agents

antacid (aluminium and magnesium hydroxide oral suspension)

(20 mL SD, doravirine 100 mg SD)

↔ doravirine

AUC 1.01 (0.92, 1.11)

Cmax 0.86 (0.74, 1.01)

C24 1.03 (0.94, 1.12)

No dose adjustment is required.

pantoprazole

(40 mg QD, doravirine 100 mg SD)

↓ doravirine

AUC 0.83 (0.76, 0.91)

Cmax 0.88 (0.76, 1.01)

C24 0.84 (0.77, 0.92)

No dose adjustment is required.

omeprazole

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

No dose adjustment is required.

Angiotensin converting enzyme inhibitors

lisinopril

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ lisinopril

No dose adjustment is required.

Antiandrogens

enzalutamide

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antibiotics

nafcillin

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Anticonvulsants

carbamazepine

oxcarbazepine

phenobarbital

phenytoin

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antidiabetics

metformin

(1 000 mg SD, doravirine 100 mg QD)

↔ metformin

AUC 0.94 (0.88, 1.00)

Cmax 0.94 (0.86, 1.03)

No dose adjustment is required.

canagliflozin

liraglutide

sitagliptin

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ canagliflozin

↔ liraglutide

↔ sitagliptin

No dose adjustment is required.

Antidiarrhoeals

telotristat ethyl

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Antigout and uricosuric agents

lesinurad

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Antimycobacterials

Single dose rifampicin

(600 mg SD, doravirine 100 mg SD)

Multiple dose rifampicin

(600 mg QD, doravirine 100 mg SD)

↔ doravirine

AUC 0.91 (0.78, 1.06)

Cmax 1.40 (1.21, 1.63)

C24 0.90 (0.80, 1.01)

↓ doravirine

AUC 0.12 (0.10, 0.15)

Cmax 0.43 (0.35, 0.52)

C24 0.03 (0.02, 0.04)

(Induction of CYP3A)

Co-administration is contraindicated.

rifapentine

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

rifabutin

(300 mg QD, doravirine 100 mg SD)

↓ doravirine

AUC 0.50 (0.45, 0.55)

Cmax 0.99 (0.85, 1.15)

C24 0.32 (0.28, 0.35)

(Induction of CYP3A)

If doravirine/ lamivudine/ tenofovir disoproxil is co-administered with rifabutin, a 100 mg dose of doravirine should be taken daily, approximately 12 h after dose of doravirine/lamivudine/tenofovir disoproxil.

Antineoplastics

mitotane

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Antipsychotics

thioridazine

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Azole antifungal agents

ketoconazole

(400 mg QD, doravirine 100 mg SD)

↑ doravirine

AUC 3.06 (2.85, 3.29)

Cmax 1.25 (1.05, 1.49)

C24 2.75 (2.54, 2.98)

(Inhibition of CYP3A)

No dose adjustment is required.

fluconazole

itraconazole

posaconazole

voriconazole

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↑ doravirine

(Inhibition of CYP3A)

No dose adjustment is required.

Calcium channel blockers

diltiazem

verapamil

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↑ doravirine

(Inhibition of CYP3A)

No dose adjustment is required.

Cystic fibrosis treatment

lumacaftor

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

Endothelin receptor antagonists

bosentan

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Hepatitis C antiviral agents

elbasvir + grazoprevir

(50 mg elbasvir QD + 200 mg grazoprevir QD,

doravirine 100 mg QD)

↑ doravirine

AUC 1.56 (1.45, 1.68)

Cmax 1.41 (1.25, 1.58)

C24 1.61 (1.45, 1.79)

(Inhibition of CYP3A)

↔ elbasvir

AUC 0.96 (0.90, 1.02)

Cmax 0.96 (0.91, 1.01)

C24 0.96 (0.89, 1.04)

↔ grazoprevir

AUC 1.07 (0.94, 1.23)

Cmax 1.22 (1.01, 1.47)

C24 0.90 (0.83, 0.96)

No dose adjustment is required.

ledipasvir + sofosbuvir

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

↑ doravirine

AUC 1.15 (1.07, 1.24)

Cmax 1.11 (0.97, 1.27)

C24 1.24 (1.13, 1.36)

↔ ledipasvir

AUC 0.92 (0.80, 1.06)

Cmax 0.91 (0.80, 1.02)

↔ sofosbuvir

AUC 1.04 (0.91, 1.18)

Cmax 0.89 (0.79, 1.00)

↔ GS-331007

AUC 1.03 (0.98, 1.09)

Cmax 1.03 (0.97, 1.09)

Expected:

↑ tenofovir

Patients receiving doravirine/lamivudine/tenofovirdisoproxil concomitantly with ledipasvir/sofosbuvir

should be monitored for adverse reactions associated with tenofovir disoproxil.

sofosbuvir/velpatasvir

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

↑ tenofovir

Patients receiving doravirine/lamivudine/tenofovir disoproxil concomitantly with sofosbuvir/velpatasvir should be monitored for adverse reactions associated with tenofovir disoproxil.

sofosbuvir

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

No dose adjustment is required.

daclatasvir

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

No dose adjustment is required.

ombitasvir/paritaprevir/ ritonavir and dasabuvir +/- ritonavir

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↑ doravirine

(Inhibition of CYP3A due to ritonavir)

No dose adjustment is required.

dasabuvir

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

No dose adjustment is required.

glecaprevir, pibrentasvir

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↑ doravirine

(inhibition of CYP3A)

No dose adjustment is required.

ribavirin

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

No dose adjustment is required.

Herbal supplements

St. John's wort

(Hypericum perforatum)

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration is contraindicated.

HIV antiviral agents

tenofovir disoproxil

(300 mg QD, doravirine 100 mg SD)

↔ doravirine

AUC 0.95 (0.80, 1.12)

Cmax 0.80 (0.64, 1.01)

C24 0.94 (0.78, 1.12)

No dose adjustment is required.

lamivudine + tenofovir disoproxil

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

↔ doravirine

AUC 0.96 (0.87, 1.06)

Cmax 0.97 (0.88, 1.07)

C24 0.94 (0.83, 1.06)

↔lamivudine

AUC 0.94 (0.88, 1.00)

Cmax 0.92 (0.81, 1.05)

↔ tenofovir

AUC 1.11 (0.97, 1.28)

Cmax 1.17 (0.96, 1.42)

No dose adjustment is required.

Immunosuppressants

tacrolimus

sirolimus

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ doravirine

↓ tacrolimus, sirolimus

(Induction of CYP3A)

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

Kinase inhibitors

dabrafenib

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately 12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Miscellaneous

sorbitol solution (3.2 g, 10.2 g, 13.4 g)/lamivudine

Single dose lamivudine oral solution 300 mg

lamivudine

AUC ↓ 14 %; 32 %; 35 %

Cmax ↓ 28 %; 52 %; 55 %

When possible, avoid chronic co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products containing sorbitol or other osmotic acting poly-alcohols (e.g., xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV‑1 viral load when chronic co-administration cannot be avoided.

Opioid analgesics

methadone

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

↓ doravirine

AUC 0.74 (0.61, 0.90)

Cmax 0.76 (0.63, 0.91)

C24 0.80 (0.63, 1.03)

↔ R-methadone

AUC 0.95 (0.90, 1.01)

Cmax 0.98 (0.93, 1.03)

C24 0.95 (0.88, 1.03)

↔ S-methadone

AUC 0.98 (0.90, 1.06)

Cmax 0.97 (0.91, 1.04)

C24 0.97 (0.86, 1.10)

No dose adjustment is required.

buprenorphine

naloxone

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ buprenorphine

↔ naloxone

No dose adjustment is required.

Oral contraceptives

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

↔ ethinyl oestradiol

AUC 0.98 (0.94, 1.03)

Cmax 0.83 (0.80, 0.87)

↑ levonorgestrel

AUC 1.21 (1.14, 1.28)

Cmax 0.96 (0.88, 1.05)

No dose adjustment is required.

norgestimate/ethinyl oestradiol

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ norgestimate/ethinyl oestradiol

No dose adjustment is required.

Psychostimulants

modafinil

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↓ doravirine

(Induction of CYP3A)

Co-administration should be avoided. If co-administration cannot be avoided, a 100 mg dose of doravirine should be taken daily, approximately12 h after the dose of doravirine/lamivudine/tenofovir disoproxil.

Sedatives/Hypnotics

midazolam

(2 mg SD, doravirine 120 mg QD)

↓ midazolam

AUC 0.82 (0.70, 0.97)

Cmax 1.02 (0.81, 1.28)

No dose adjustment is required.

Statins

atorvastatin

(20 mg SD, doravirine 100 mg QD)

↔ atorvastatin

AUC 0.98 (0.90, 1.06)

Cmax 0.67 (0.52, 0.85)

No dose adjustment is required.

rosuvastatin

simvastatin

Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.

Expected:

↔ rosuvastatin

↔ simvastatin

No dose adjustment is required.

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

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

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

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

In phase 3 clinical trials with doravirine plus 2 nucleoside 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) and postmarketing experience 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), very rare (< 1/10 000), or not known (cannot be estimated from the available data).

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

Frequency

Adverse reactions

Infections and infestations

Rare

rash pustular

Blood and lymphatic systems disorders

Uncommon

neutropenia*, anaemia*, thrombocytopenia*

Very rare

pure red cell aplasia*

Metabolism and nutrition disorders

Uncommon

hypophosphataemia, hypokalaemia*

Rare

hypomagnesaemia, lactic acidosis*

Psychiatric disorders

Common

abnormal dreams, insomnia1,

Uncommon

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

Rare

aggression, hallucination, adjustment disorder, mood altered, somnambulism

Nervous system disorders

Common

headache, dizziness, somnolence

Uncommon

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

Very rare

peripheral neuropathy (or paraesthesia)*

Vascular disorders

Uncommon

hypertension

Respiratory, thoracic and mediastinal disorders

Common

cough*, nasal symptoms*

Rare

dyspnoea, tonsillar hypertrophy

Gastrointestinal disorders

Common

nausea, diarrhoea, abdominal pain4, vomiting, flatulence

Uncommon

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

Rare

rectal tenesmus

Hepatobiliary disorders

Rare

hepatic steatosis*, hepatitis†

Skin and subcutaneous tissue disorders

Common

alopecia*, rash8

Uncommon

pruritus

Rare

dermatitis allergic, rosacea, angioedema*

Not known

toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Common

muscle disorders*, bone mineral density decreased*

Uncommon

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

Rare

musculoskeletal pain, osteomalacia (manifested as bone pain and infrequently contributing to fractures)*, myopathy*

Renal and urinary disorders

Uncommon

increased creatinine*, proximal renal tubulopathy (including Fanconi syndrome)*

Rare

acute kidney injury, renal disorder, calculus urinary, nephrolithiasis, acute renal failure*, renal failure*, acute tubular necrosis*, nephritis (including acute interstitial)*, nephrogenic diabetes insipidus*

General disorders and administration site conditions

Common

fatigue, fever*

Uncommon

asthenia, malaise

Rare

chest pain, chills, pain, thirst

Investigations

Common

alanine aminotransferase increased9

Uncommon

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

Rare

blood creatine phosphokinase increased

*This adverse reaction was not identified as an adverse reaction associated with doravirine from the Phase 3 clinical studies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but is included in this table as an adverse reaction based on the Summary of Product Characteristics (SmPC) of 3TC and/or TDF. The highest frequency category reported 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 clinical studies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but was seen during post-marketing use of doravirine-containing regimens and is an adverse reaction listed in the SmPC of 3TC and TDF. The highest frequency category 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 causally associated 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, and urticarial.

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

Description of selected adverse reactions

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.

Severe cutaneous adverse reactions (SCARs)

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

Paediatric population

The safety of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically 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 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.

4.9. Overdose

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.