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    Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)s

    DEA CLASS

    Rx

    DESCRIPTION

    Non-nucleoside reverse transcriptase inhibitor (NNRTI)
    Used in combination with other antiretroviral agents to treat HIV-1 infection in adults and pediatric patients weighing at least 35 kg who are treatment-naive or virologically stable on an antiretroviral regimen without history of treatment failure and no known doravirine resistance-associated substitutions
    Contraindicated when co-administered with strong CYP3A inducers which may decrease doravirine effectiveness

    COMMON BRAND NAMES

    PIFELTRO

    HOW SUPPLIED

    PIFELTRO Oral Tab: 100mg

    DOSAGE & INDICATIONS

    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

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Must be administered in combination with other antiretroviral medications; never administer as monotherapy.

    Oral Administration

    Administer orally with or without food.

    STORAGE

    PIFELTRO:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.[63484]
     
    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.
     
    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. Health care 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. [46638] [42452]

    Human immunodeficiency virus (HIV) infection resistance

    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.[46638] [42452] 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.[46638] [63484]

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweigh the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral-naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.[46638]

    Hepatic disease, hepatitis B and HIV coinfection

    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.[63484] 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. [34362] [46638]

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    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.[34362] 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.[63484]

    Pregnancy

    Antiretroviral therapy should be provided to all women 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. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. 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 monitored 4 patients treated with doravirine during the first trimester and 1 patient 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. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 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 women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations more than 500 copies/mL, unless they have already been tested for resistance. 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 women 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 women 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 women 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 woman 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.[23512] [27468] [63484]

    Breast-feeding

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including doravirine. If a mother with HIV opts to breast-feed, the infant 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, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] It is unknown if doravirine is present in human milk, affects human milk production, or has an effect on the breastfed infant.[46675] [63484]

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0-4.0

    Moderate

    elevated hepatic enzymes / Delayed / 0-5.0
    depression / Delayed / 0-4.0
    hypercholesterolemia / Delayed / 0-1.0
    hypertriglyceridemia / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0

    Mild

    dizziness / Early / 3.0-9.0
    nausea / Early / 5.0-7.0
    diarrhea / Early / 4.0-6.0
    asthenia / Delayed / 4.0-6.0
    fatigue / Early / 4.0-6.0
    malaise / Early / 4.0-6.0
    headache / Early / 4.0-6.0
    abdominal pain / Early / 1.0-5.0
    nightmares / Early / 1.0-5.0
    abnormal dreams / Early / 1.0-5.0
    insomnia / Early / 1.0-4.0
    rash / Early / 2.0-2.0
    maculopapular rash / Early / Incidence not known

    DRUG INTERACTIONS

    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.
    Aspirin, ASA; Butalbital; 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.
    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.
    Butabarbital: (Moderate) Concurrent administration of doravirine and butabarbital may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; butabarbital is a moderate 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.
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; 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.
    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) Concurrent administration of doravirine and dexamethasone may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; dexamethasone is a moderate CYP3A4 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.
    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.
    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.
    Lesinurad: (Minor) Concurrent administration of doravirine and lesinurad may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; lesinurad is a weak CYP3A4 inducer.
    Lesinurad; Allopurinol: (Minor) Concurrent administration of doravirine and lesinurad may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; lesinurad is a weak CYP3A4 inducer.
    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.
    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.
    Ombitasvir; Paritaprevir; 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.
    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.
    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.
    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.
    Telithromycin: (Minor) Coadministration of doravirine and telithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; telithromycin 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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Antiretroviral therapy should be provided to all women 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. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. 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 monitored 4 patients treated with doravirine during the first trimester and 1 patient 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. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 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 women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations more than 500 copies/mL, unless they have already been tested for resistance. 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 women 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 women 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 women 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 woman 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.[23512] [27468] [63484]

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including doravirine. If a mother with HIV opts to breast-feed, the infant 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, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] It is unknown if doravirine is present in human milk, affects human milk production, or has an effect on the breastfed infant.[46675] [63484]

    MECHANISM OF ACTION

    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.[63484]
    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.[63484]
    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.[46638]

    PHARMACOKINETICS

    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.[63484]
     
    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.[63484]

    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).