DELSTRIGO®|SELECTED SAFETY INFORMATION – LONG VERSION

from PI last updated May 2025

CONTRAINDICATIONS

Hypersensitivity to the active substances or to any of the excipients. Co-administration with medicinal products that are strong cytochrome P450 (CYP)3A enzyme inducers is contraindicated as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of DELSTRIGO. These medicinal products include, but are not limited to the following: carbamazepine, oxcarbazepine, phenobarbitone, phenytoin, rifampicin, rifapentine and any other tuberculosis medicines which are strong CYP3A enzyme inducers, St. John’s wort (Hypericum perforatum), mitotane, enzalutamide, lumacaftor. Moderate and severe renal impairment (CrCL < 50 mL/minute).

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission of HIV-1, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Patients with HIV and hepatitis B or C virus co-infection:

Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant

package inserts for these medicines. Patients co-infected with HIV and HBV who discontinue DELSTRIGO should be closely monitored with both clinical and laboratory follow-up after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since

post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of DELSTRIGO therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Liver disease:

Use of nucleoside/nucleotide analogues can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of DELSTRIGO has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant package inserts for these medicines. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Mitochondrial dysfunction:

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. Apart from lactic acidosis/hyperlactataemia (see above) other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and

nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant sign and symptoms.

Lipodystrophy and metabolic abnormalities:

Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Lactic acidosis/hyperlactataemia:

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea,

fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/ℓ) and the serum bicarbonate and respond as follows: Lactate 2-5 mmol/ℓ with minimum symptoms: switch to agents that are less likely to cause lactic acidosis. Lactate 5-10 mmol/ℓ with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism. Lactate > 10 mmol/ℓ: STOP all therapy (80 % mortality). The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering DELSTRIGO to patients with known risk factors for liver disease. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medications known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes. Treatment with DELSTRIGO should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Pancreatitis:

Pancreatitis has been observed in some patients receiving nucleoside/nucleotide analogues. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of DELSTRIGO until diagnosis of pancreatitis is excluded.

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. 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.

New onset or worsening renal impairment:

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), 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]). 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 per minute as dose interval adjustment required for lamivudine and tenofovir disoproxil cannot be achieved with the fixed dose combination tablet.

Immune Reconstitution Inflammatory Syndrome:

Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (e.g Graves’ disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can

occur many months after initiation of treatment.

Opportunistic infections:

Patients receiving antiretroviral therapy should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done.

Osteonecrosis:

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Bone loss and mineralisation defects:

Bone mineral density:

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

regimen containing a boosted protease inhibitor. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy. The effects of tenofovir disoproxil associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1 infected adult patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation

with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.

Mineralisation defects:

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

Co-administration with other antiviral medicines:

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. Doravirine/lamivudine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g. with rifabutin).

Use with CYP3A inducers:

Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine.

Lactose:

DELSTRIGO contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g. galactosemia, total lactase deficiency or glucose-galactose malabsorption should not take DELSTRIGO.

INTERACTION WITH OTHER MEDICINES 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 medicines 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, refer to the full prescribing information.

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. 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. Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations. 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. 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. dabrafenib, 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. Co-administration of doravirine/lamivudine/tenofovir disoproxil 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, 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, 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.

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.

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 to 1 000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil. As a precautionary measure, it is preferable to avoid the use of DELSTRIGO during pregnancy.

Breastfeeding:

Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfeeding infants, mother should be instructed not to breastfeed if they are receiving DELSTRIGO.

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.

UNDESIRABLE EFFECTS

The most frequently reported adverse reactions considered possibly or probably related to doravirine were nausea (4 %) and headache (3 %).

Adverse reactions with suspected (at least possible) relationship to treatment with doravirine/lamivudine/tenofovir disoproxil:

Common (≥1/100 to <1/10):

abnormal dreams, insomnia (insomnia includes: insomnia, initial insomnia and sleep disorder), headache, dizziness, somnolence, cough*, nasal symptoms*, nausea, diarrhoea, abdominal pain (abdominal pain includes: abdominal pain and abdominal pain upper), vomiting, flatulence, alopecia*, rash (rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculopapular, rash papular and urticarial), muscle disorders*, fatigue, fever*, alanine aminotransferase increased (alanine aminotransferase increased includes: alanine aminotransferase increased and hepatocellular injury).

Uncommon (≥1/1 000 to <1/100):

neutropenia*, anaemia*, thrombocytopenia*, hypophosphatemia, hypokalaemia*, nightmare, depression (depression includes: depression, depressed mood, major depression and persistent depressive disorder), anxiety (anxiety includes: anxiety and generalised anxiety disorder), irritability, confusional state, suicidal ideation, disturbance in attention, memory impairment, paraesthesia, hypertonia, poor quality sleep, hypertension, constipation, abdominal discomfort (abdominal discomfort includes: abdominal discomfort and epigastric discomfort), abdominal distension, dyspepsia, faeces soft (faeces soft includes: faeces soft and abnormal faeces), gastrointestinal motility disorder (gastrointestinal motility disorder includes: gastrointestinal motility disorder and frequent bowel movements), pancreatitis*, pruritus, myalgia, arthralgia, rhabdomyolysis*,**, muscular weakness*,**, increased creatinine*, proximal renal tubulopathy (including Fanconi syndrome)*, asthenia, malaise, aspartate aminotransferase increased, lipase increased, amylase increased, haemoglobin decreased.

Rare (≥1/10 000 to <1/1 000):

rash pustular, hypomagnesaemia, lactic acidosis*, aggression, hallucination, adjustment disorder, mood altered, somnambulism, dyspnoea, tonsillar hypertrophy, rectal tenesmus, hepatic steatosis*, hepatitis*, dermatitis allergic, rosacea, angioedema*, musculoskeletal pain, osteomalacia (manifested as bone pain and infrequently contributing to fractures)*, myopathy*, acute kidney injury, renal disorder, calculus

urinary, nephrolithiasis, acute renal failure*, renal failure*, acute tubular necrosis*, nephritis (including acute interstitial)*, nephrogenic diabetes insipidus*, chest pain, chills, pain, thirst, blood creatine phosphokinase increased.

Very rare (<1/10 000):

pure red cell aplasia*, peripheral neuropathy (or paraesthesia)*.

Paediatric population:

The safety of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically suppressed or treatment-na.ve paediatric patients 12 to ˂ 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.

*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 of 3TC and/or TDF. The highest frequency category reported in the 3TC or TDF Summary of Product Characteristics 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.

FOR FULL PRESCRIBING INFORMATION REFER TO THE PROFESSIONAL INFORMATION APPROVED BY THE MEDICINES REGULATORY AUTHORITY.

DELSTRIGO® 100 mg/300 mg/245 mg. Each film-coated tablet contains 100 mg of doravirine, 300 mg of lamivudine and 300 mg of tenofovir disoproxil fumarate equivalent to 245 mg of tenofovir disoproxil. Reg. No: 53/20.2.8/0233.

ZA-DOR-00005 Exp: 11/06/2028