Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg. The drug is approved for patients with no prior antiretroviral treatment history or as replacement therapy in patients who are virologically suppressed (i.e., HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen, have no history of treatment failure, and have no known doravirine resistance-associated substitutions. Avoid use of doravirine in patients receiving strong CYP3A inducers, as concurrent therapy may result in an impaired virologic response. Monitor drug recipients for neuropsychiatric adverse events, especially during the first 4 weeks of treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Must be administered in combination with other antiretroviral medications; never administer as monotherapy.
Route-Specific Administration
Oral Administration
-Administer orally with or without food.
Gastrointestinal (GI) and digestive adverse events have occurred in patients receiving treatment with doravirine. During clinical trials, drug recipients reported experiencing symptoms including nausea (5% to 7%), diarrhea (4% to 6%), and abdominal pain (1% to 5%). The majority of these adverse reactions occurred at severity Grade 1 (mild).
During clinical trials, 2% of doravirine recipients developed a rash, defined as generalized rash, erythematous rash, macular rash, maculopapular rash, pruritic rash, and pustular rash. The majority of these adverse reactions occurred at severity Grade 1 (mild).
Neurologic reactions were among the most frequently reported adverse events by recipients of doravirine during clinical trials. Patient treated with doravirine experienced dizziness (3% to 9%), headache (4% to 6%), fatigue (4% to 6%), asthenia (4% to 6%), malaise (4% to 6%), abnormal dreams or nightmares (1% to 5%), insomnia (1% to 4%), and somnolence (up to 3%). The majority of these adverse reactions (97%) were mild to moderate in severity and developed within the first 4 weeks of treatment. When compared to efavirenz-containing regimens, the incidence of dizziness, sleep disturbances, and altered sensorium occurring with doravirine were significantly lower [-28.3 (-34.0, -22.5), -13.5 (-19.1, -7.9), and -3.8 (-7.6, -0.3) respectively]. Neuropsychatric adverse events also occurred less frequently with doravirine as compared to efavirenz. At treatment week 96, the prevalence of neuropsychiatric adverse reactions in doravirine treated patients was 13% (n = 47 of 364) compared to 23% (n = 82 of 364) in the efavirenz treatment group. More severe neuropsychiatric reactions, depression and suicidal ideation (i.e., suicide or self-injury, occurred in 4% of doravirine patients and 7% of efavirenz patients.
During clinical trials, up to 1% of doravirine recipients developed hypercholesterolemia or hypertriglyceridemia, defined as a fasting cholesterol concentration of 300 mg/dL or more and a fasting triglyceride concentration greater than 500 mg/dL. In addition, less than 1% of doravirine treated patients had fasting LDL concentrations of at least 190 mg/dL. When compared with an efavirenz-containing regimen, the change in LDL concentration from baseline was significantly lower for doravirine [-14.4 (-18.0,-10.8)].
During clinical trials of antiretroviral-naive patients, up to 5% of doravirine recipients experienced elevated hepatic enzymes, defined as concentrations of at least 2.5-times upper limit of normal (ULN). In addition, hyperbilirubinemia (i.e., concentrations greater than 2.5-times ULN) was observed in up to 1% of drug recipients. In a clinical trial involving virologically suppressed patients who were switched to a doravirine-containing regimen, elevations in ALT and AST greater than 1.25-times ULN were observed in 22% and 16% of patients, respectively. The ALT and AST elevations in the virologically suppressed population were generally asymptomatic and not associated with hyperbilirubinemia; however, 1% of drug recipients had ALT or AST elevations of more than 5-times ULN. Other laboratory abnormalities observed during doravirine clinical trials included a serum creatinine concentrations of more than 1.8-times ULN or an increase of at least 1.5-times over baseline (3% to 4%), increase in lipase concentrations of at least 3-times ULN (2% to 3%), and an increase in creatine kinase of at least 10-times ULN (4% to 5%).
Doravirine is contraindicated for use in patients receiving strong CYP3A inducers (e.g., rifampin, St. John's wort); concurrent use of strong CYP3A inducers can lead to a significant decrease in plasma concentrations of doravirine, which may result in loss of therapeutic effect and viral resistance. Consider the potential for drug interactions prior to and during therapy; additional monitoring for efficacy and adverse reactions may be needed.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing before initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when doravirine is used either alone or in combination with other agents. Monotherapy is not recommended. Cross-resistance between doravirine and other non-nucleoside reverse transcriptase inhibitors has been observed.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Cases of elevated hepatic enzymes and increased bilirubin concentrations were observed in recipients of doravirine during clinical trials; use of the drug in patients with severe hepatic disease (Child-Pugh C) has not been studied. Patients who present with HIV infection should also be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive ARV regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Furthermore, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. Patients with hepatitis B and HIV coinfection who discontinue emtricitabine or tenofovir may experience severe acute hepatitis B exacerbation with some cases resulting in hepatic decompensation and hepatic failure. Therefore, patients coinfected with HBV and HIV who discontinue emtricitabine or tenofovir-containing regiment should have transaminase concentrations monitored every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. If appropriate, resumption of anti-hepatitis B treatment may be required. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct hepatitis and HIV coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to doravirine therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia, or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. There are insufficient data to recommend the use of doravirine-containing regimens in pregnant patients or patients who are trying to become pregnant. However, for virologically suppressed patients who become pregnant while receiving doravirine, consider whether to change to an alternative treatment option or continue the same regimen. If the decision is made with the patient to continue, viral loads should be monitored more frequently (i.e., every 1 to 2 months). The Antiretroviral Pregnancy Registry (APR) has prospectively monitored 10 patients treated with doravirine during the first trimester and 2 patients treated during the second and third trimesters. One infant with first trimester exposure was noted to have a birth defect. This information is insufficient to make conclusions regarding the safety of doravirine during pregnancy. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to doravirine; information about the registry can be obtained at www.apregistry/com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). It is unknown if doravirine is present in human milk, affects human milk production, or has an effect on the breastfed infant.
Initiation of therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy in all antiretroviral treatment-naive patients and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-In certain clinical situations, doravirine given in combination with 2 NRTIs is a preferred initial regimen for some non-pregnant adults with HIV-1.
-Data regarding administration of doravirine during pregnancy is limited; therefore, use of a doravirine-containing regimens as initial therapy in pregnant patients or patients who are trying to conceive is not recommended. However, it may be appropriate to continue use of the drug in some virologically suppressed pregnant patients.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in antiretroviral-naive and certain treatment-experienced patients:
NOTE: Use in treatment-experienced patients is limited to those who have been virologically-suppressed (i.e., HIV RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and who are without known substitutions associated with resistance to doravirine.
Oral dosage:
Adults: 100 mg PO once daily.
Children and Adolescents weighing 35 kg or more: 100 mg PO once daily.
Maximum Dosage Limits:
-Adults
100 mg/day PO.
-Geriatric
100 mg/day PO.
-Adolescents
weight 35 kg or more: 100 mg/day PO.
weight less than 35 kg: Safety and efficacy have not been established.
-Children
weight 35 kg or more: 100 mg/day PO.
weight less than 35 kg: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed for patients with mild to moderate hepatic impairment (Child-Pugh A and B). Treatment has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adagrasib: (Minor) Coadministration of doravirine and adagrasib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A substrate; adagrasib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Apalutamide: (Contraindicated) Concurrent administration of doravirine and apalutamide is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer.
Armodafinil: (Minor) Concurrent administration of doravirine and armodafinil may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; armodafinil is a weak CYP3A4 inducer.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Atazanavir: (Minor) Coadministration of doravirine and atazanavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; atazanavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Atazanavir; Cobicistat: (Minor) Coadministration of doravirine and atazanavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; atazanavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Belzutifan: (Moderate) Concurrent administration of doravirine and belzutifan may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; belzutifan is a weak CYP3A inducer.
Bexarotene: (Moderate) Concurrent administration of doravirine and bexarotene may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer.
Bosentan: (Moderate) Concurrent administration of doravirine and bosentan may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer.
Brigatinib: (Minor) Concurrent administration of doravirine and brigatinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; brigatinib is a weak CYP3A4 inducer.
Butalbital; Acetaminophen: (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concurrent administration of doravirine and butalbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer.
Carbamazepine: (Contraindicated) Coadministration of carbamazepine and doravirine is contraindicated due to the potential for loss of virologic response and possible resistance to doravirine or the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). If doravirine use is necessary, discontinue carbamazepine at least 4-weeks prior to initiation. Doravirine is a CYP3A4 substrate and carbamazepine is a potent CYP3A4 inducer.
Cenobamate: (Moderate) Concurrent administration of doravirine and cenobamate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Minor) Monitor for an increase in doravirine-related adverse reactions if coadministration with ceritinib is necessary; increased doravirine plasma concentrations may occur. Doravirine is a CYP3A4 substrate; ceritinib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Chloramphenicol: (Minor) Coadministration of doravirine and chloramphenicol may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; chloramphenicol is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Clarithromycin: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Clobazam: (Minor) Concurrent administration of doravirine and clobazam may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; clobazam is a weak CYP3A4 inducer.
Cobicistat: (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Dabrafenib: (Moderate) Concurrent administration of doravirine and dabrafenib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer.
Darunavir: (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Darunavir; Cobicistat: (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Deferasirox: (Minor) Concurrent administration of doravirine and deferasirox may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; deferasirox is a weak CYP3A4 inducer.
Delavirdine: (Minor) Coadministration of doravirine and delavirdine may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; delavirdine is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Dexamethasone: (Moderate) Monitor for a decrease in doravirine efficacy during concurrent use of doravirine and dexamethasone. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may decrease doravirine exposure leading to potential loss of virologic control. Doravirine is a CYP3A substrate and dexamethasone is a weak CYP3A inducer.
Efavirenz: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
Elagolix: (Moderate) Concurrent administration of doravirine and elagolix may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Concurrent administration of doravirine and elagolix may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Enasidenib: (Minor) Concurrent administration of doravirine and enasidenib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; enasidenib is a weak CYP3A inducer.
Encorafenib: (Contraindicated) Concurrent administration of doravirine and encorafenib is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A substrate; encorafenib is a strong CYP3A inducer.
Enzalutamide: (Contraindicated) Concurrent administration of doravirine and enzalutamide is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer.
Eslicarbazepine: (Moderate) Concurrent administration of doravirine and eslicarbazepine may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer.
Etravirine: (Contraindicated) Concurrent treatment with etravirine and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together may result in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; etravirine is a CYP3A4 inducer.
Fosamprenavir: (Minor) Coadministration of doravirine and fosamprenavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; fosamprenavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Fosphenytoin: (Contraindicated) Concurrent administration of doravirine and fosphenytoin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; phenytoin (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer.
Glycerol Phenylbutyrate: (Minor) Concurrent administration of doravirine and glycerol phenylbutyrate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; glycerol phenylbutyrate is a weak CYP3A inducer.
Grapefruit juice: (Minor) Instruct patients that consuming grapefruit or grapefruit juice while taking doravirine may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; grapefruit is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Idelalisib: (Minor) Coadministration of doravirine and idelalisib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; idelalisib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Indinavir: (Minor) Coadministration of doravirine and indinavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; indinavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Concurrent administration of doravirine and rifampin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer.
Isoniazid, INH; Rifampin: (Contraindicated) Concurrent administration of doravirine and rifampin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer.
Itraconazole: (Minor) Coadministration of doravirine and itraconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; itraconazole is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Ketoconazole: (Minor) Coadministration of doravirine and ketoconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ketoconazole is a strong inhibitor. In a drug interaction study, concurrent use of ketoconazole increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Levoketoconazole: (Minor) Coadministration of doravirine and ketoconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ketoconazole is a strong inhibitor. In a drug interaction study, concurrent use of ketoconazole increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Lonafarnib: (Minor) Coadministration of doravirine and lonafarnib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; lonafarnib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Lopinavir; Ritonavir: (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Lorlatinib: (Moderate) Concurrent administration of doravirine and lorlatinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Contraindicated) Concurrent administration of doravirine and lumacaftor; ivacaftor is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Contraindicated) Concurrent administration of doravirine and lumacaftor; ivacaftor is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer.
Mavacamten: (Moderate) Concurrent administration of doravirine and mavacamten may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; mavacamten is a moderate CYP3A inducer.
Meropenem: (Minor) Concurrent administration of doravirine and meropenem may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; meropenem is a weak CYP3A inducer.
Meropenem; Vaborbactam: (Minor) Concurrent administration of doravirine and meropenem may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; meropenem is a weak CYP3A inducer.
Mifepristone: (Minor) Coadministration of doravirine and chronic mifepristone therapy may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; mifepristone is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. The clinical significance of CYP450 inhibition with short-term use of mifepristone for termination of pregnancy is unknown.
Mitapivat: (Moderate) Concurrent administration of doravirine and mitapivat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; mitapivat is a weak CYP3A inducer.
Mitotane: (Contraindicated) Concurrent administration of doravirine and mitotane is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer.
Mobocertinib: (Moderate) Concurrent administration of doravirine and mobocertinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; mobocertinib is a weak CYP3A inducer.
Modafinil: (Moderate) Concurrent administration of doravirine and modafinil may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer.
Nafcillin: (Moderate) Concurrent administration of doravirine and nafcillin may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
Nefazodone: (Minor) Coadministration of doravirine and nefazodone may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; nefazodone is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Nelfinavir: (Minor) Coadministration of doravirine and nelfinavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; nelfinavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Nevirapine: (Major) Coadministration of nevirapine and doravirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. Concomitant use may also cause a significant decrease in doravirine plasma concentrations and, thus, a loss of therapeutic effect. Doravirine is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nirmatrelvir; Ritonavir: (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Odevixibat: (Moderate) Concurrent administration of doravirine and odevixibat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; odevixibat is a weak CYP3A inducer.
Olutasidenib: (Minor) Concurrent administration of doravirine and olutasidenib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; olutasidenib is a weak CYP3A inducer.
Omaveloxolone: (Minor) Concurrent administration of doravirine and omaveloxolone may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; omaveloxolone is a weak CYP3A inducer.
Omeprazole; Amoxicillin; Rifabutin: (Major) Increase the doravirine dose to 100 mg PO twice daily (approximately 12 hours apart) if coadministered with rifabutin. Concurrent use decreases doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Oritavancin: (Minor) Concurrent administration of doravirine and oritavancin may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; oritavancin is a weak CYP3A4 inducer.
Oxcarbazepine: (Contraindicated) Concurrent administration of doravirine and oxcarbazepine is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; oxcarbazepine is a CYP3A4 inducer.
Pexidartinib: (Moderate) Concurrent administration of doravirine and pexidartinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Contraindicated) Concurrent administration of doravirine and phenobarbital is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Concurrent administration of doravirine and phenobarbital is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer.
Phentermine; Topiramate: (Minor) Concurrent administration of doravirine and topiramate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
Phenytoin: (Contraindicated) Concurrent administration of doravirine and phenytoin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer.
Posaconazole: (Minor) Coadministration of doravirine and posaconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; posaconazole is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Primidone: (Contraindicated) Concurrent administration of doravirine and primidone is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer.
Repotrectinib: (Moderate) Concurrent administration of doravirine and repotrectinib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; repotrectinib is a moderate CYP3A inducer.
Ribociclib: (Minor) Coadministration of doravirine and ribociclib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ribociclib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Ribociclib; Letrozole: (Minor) Coadministration of doravirine and ribociclib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ribociclib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Rifabutin: (Major) Increase the doravirine dose to 100 mg PO twice daily (approximately 12 hours apart) if coadministered with rifabutin. Concurrent use decreases doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Rifampin: (Contraindicated) Concurrent administration of doravirine and rifampin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer.
Rifapentine: (Contraindicated) Concurrent administration of doravirine and rifapentine is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer.
Ritonavir: (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Saquinavir: (Minor) Coadministration of doravirine and saquinavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; saquinavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.Coadministration may increase doravirine exposure. Concurrent use of strong inhibitors like saquinavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Secobarbital: (Moderate) Concurrent administration of doravirine and secobarbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer.
Sodium Phenylbutyrate; Taurursodiol: (Minor) Concurrent administration of doravirine and taurursodiol may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; taurursodiol is a weak CYP3A inducer.
Sotorasib: (Moderate) Concurrent administration of doravirine and sotorasib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent administration of doravirine and St. John's Wort is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer.
Tazemetostat: (Minor) Concurrent administration of doravirine and tazemetostat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; tazemetostat is a weak CYP3A4 inducer.
Tecovirimat: (Minor) Concurrent administration of doravirine and tecovirimat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; tecovirimat is a weak CYP3A4 inducer.
Telotristat Ethyl: (Minor) Concurrent administration of doravirine and telotristat may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; telotristat is a weak CYP3A4 inducer.
Tipranavir: (Minor) Coadministration of doravirine and tipranavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; tipranavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Topiramate: (Minor) Concurrent administration of doravirine and topiramate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
Tucatinib: (Minor) Coadministration of doravirine and tucatinib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; tucatinib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Voriconazole: (Minor) Coadministration of doravirine and voriconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; voriconazole is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine inhibits HIV-1 reverse transcriptase. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), it does not compete for binding nor does it require phosphorylation to be active. Doravirine binds directly to a site on reverse transcriptase that is distinct from where NRTIs bind. This binding causes disruption of the enzyme's active site thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. The 50% maximal inhibitory concentrations (EC50) for wild-type laboratory-adapted strains of HIV-1 is approximately 12 nM. Human cellular DNA polymerase alpha, beta, and mitochondrial gamma are not inhibited by doravirine.
Doravirine-resistant strains have been selected in cell cultures, with observed emergent RT amino acid substitutions being V106A, V106I, V106M, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. In clinical trials, 13 of the 36 subjects (36%) in the resistance analysis subset showed doravirine-associated resistance substitutions in RT; which included 1 or more of the following: V90G/I, A98G, V106A, V106I, V106M/T, V108I, E138G, Y188L, H221Y, P225H, P225L, P225P/S, F227C, F227C/R, Y318Y/F, and Y318Y/S. Also, 10 of the 36 subjects (28%) developed genotypic and/or phenotypic resistance to other antiretrovirals (e.g., abacavir, lamivudine, emtricitabine, tenofovir). Cross-resistance to efavirenz, etravirine, rilpivirine, and nevirapine is likely after the development of treatment-emergent doravirine resistance.
Avoid the use of doravirine in patients with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.
Doravirine is administered orally. Following systemic absorption, doravirine has a volume of distribution of 60.5 liters and is 76% bound to plasma proteins. The drug undergoes extensive metabolism in the liver by CYP3A enzymes. Metabolites account for the majority of the drug elimination, with only 6% of the dose being excreted in the urine as unchanged drug. Biliary/fecal excretion is a minor elimination pathway. The elimination half-life is 15 hours.
Affected cytochrome P450 isoenzymes: CYP3A
Doravirine is primarily metabolized CYP3A4. The drug is neither an inducer nor an inhibitor of CYP450 isoenzymes or drug transporters.
-Route-Specific Pharmacokinetics
Oral Route
The absolute oral bioavailability of doravirine is 64%, and the time to reach maximum plasma concentrations (Tmax) is 2 hours. Steady-state concentrations are achieved by treatment day 2, and the drug has an accumulation ratio of 1.2 to 1.4. Although doravirine may be administered with or without food, administration with a high-fat meal (i.e., 1,000 kcal, 50% fat) increases the exposure ratio by 1.16 (1.06, 1.26) and the 24-hour drug concentration by 1.36 (1.19, 1.55).
-Special Populations
Hepatic Impairment
Mild to moderate hepatic dysfunction (Child-Pugh A and B) does not have a clinically significant effect on doravirine pharmacokinetics. Use of the drug in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated.
Renal Impairment
Renal dysfunction was not found to have a clinically relevant effect on doravirine pharmacokinetics; however, use of the drug in patients with end-stage renal disease or patients undergoing dialysis has not been evaluated.
Pediatrics
Mean doravirine exposures were similar in 54 pediatric patients aged 12 to 17 years weighing at least 35 kg who received doravirine or doravirine; lamivudine; tenofovir in IMPAACT 2014 (Protocol 027) compared to adults after administration of doravirine or doravirine; lamivudine; tenofovir. For pediatric patients weighing 35 to 44 kg who received doravirine 100 mg or doravirine; lamivudine; tenofovir, the population pharmacokinetic model-predicted mean C24 of doravirine was comparable to that achieved in adults, whereas mean AUC0 to 24 and Cmax of doravirine were 25% and 36% higher than adult values, respectively. However, the predicted AUC0 to 24 and Cmax increases are not considered clinically significant.
Other
Pregnancy
There are no clinical studies evaluating the pharmacokinetics of doravirine in pregnant patients; however, drug exposure during pregnancy was predicted using full-body, physiologically based pharmacokinetic (PBPK) modeling. The model predicted lower maternal serum exposure (compared to nonpregnant patients) as pregnancy progresses, with decreases in trough plasma concentrations of 65%, 75%, and 84% at 26, 32, and 40 weeks gestation, respectively.