PIFELTRO®| SELECTED SAFETY INFORMATION – LONG VERSION
from PI last updated June 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 PIFELTRO. These medicinal products include, but are not limited, to the following: carbamazepine, oxcarbazepine, phenobarbitone, phenytoin, rifampicin, rifapentine, St. John’s wort (Hypericum perforatum), mitotane, enzalutamide, lumacaftor.
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.
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.
Use with CYP3A inducers:
Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine.
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 [PJP] or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reactivation; however, the time to onset is more variable and can occur many months after initiation of treatment.
Lactose:
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take PIFELTRO.
INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTION:
Effects of other medicinal products on doravirine:
Doravirine is primarily metabolised by CYP3A and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine. Doravirine should not be co-administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine.
Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations, refer to the full prescribing information. When doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart). Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g. dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart). Co-administration of doravirine and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors as the plasma levels remain within therapeutically acceptable levels.
Effects of doravirine on other medicinal products:
Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolised by CYP enzymes. However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer. Therefore caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g. tacrolimus and sirolimus).
FERTILITY, PREGNANCY AND LACTATION:
Pregnancy:
There are no or limited amount of data from the use of doravirine in pregnant women. As a precautionary measure, it is preferable to avoid the use of doravirine during pregnancy.
Breastfeeding:
It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk. Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfeeding infants, mothers should be instructed not to breastfeed if they are receiving PIFELTRO.
Fertility:
No human data on the effect of doravirine on fertility are available. Animal studies do not indicate harmful effects of doravirine on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose.
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 used in combination with other antiretrovirals:
Common (≥1/100 to <1/10):
abnormal dreams, insomnia (insomnia includes insomnia, initial insomnia and sleep disorder), headache, dizziness, somnolence, nausea, diarrhoea, flatulence, abdominal pain (abdominal pain includes abdominal pain and abdominal pain upper), vomiting, rash (rash includes rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular and urticarial), fatigue, alanine aminotransferase increased (alanine aminotransferase increased includes alanine aminotransferase increased and hepatocellular injury).
Uncommon (≥1/1 000 to <1/100):
hypophosphatemia, 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), pruritus, myalgia, arthralgia, asthenia, malaise, lipase increased, aspartae aminotransferase increased, amylase increased, haemoglobin decreased.
Rare (≥1/10 000 to <1/1 000):
rash pustular, hypomagnesaemia, aggression, hallucination, adjustment disorder, mood altered, somnambulism, dyspnoea, tonsillar hypertrophy, rectal tenesmus, dermatitis allergic, rosacea, musculoskeletal pain, acute kidney injury, renal disorder, calculus urinary, nephrolithiasis, chest pain, chills, pain, thirst, blood creatine phosphokinase increased.
Paediatric population:
The safety of doravirine as a component of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically suppressed or treatment-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.
FOR FULL PRESCRIBING INFORMATION REFER TO THE PROFESSIONAL INFORMATION APPROVED BY THE MEDICINES REGULATORY AUTHORITY.
PIFELTRO® 100 mg. Each film-coated tablet contains 100 mg of doravirine. Reg. No: 53/20.2.8/0232.
ZA-DOV-00003 | 11/06/2028