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Efavirenz

Pronunciation

(e FAV e renz)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Sustiva: 50 mg, 200 mg

Tablet, Oral:

Sustiva: 600 mg

Brand Names: U.S.

  • Sustiva

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)

Pharmacology

As a non-nucleoside reverse transcriptase inhibitor, efavirenz has activity against HIV-1 by binding to reverse transcriptase. It consequently blocks the RNA-dependent and DNA-dependent DNA polymerase activities including HIV-1 replication. It does not require intracellular phosphorylation for antiviral activity.

Absorption

Increased by high-fat/high-caloric meals

Distribution

CSF concentrations are 0.69% of plasma (range: 0.26% to 1.2%); however, CSF:plasma concentration ratio is 3 times higher than free fraction in plasma

Metabolism

Hepatic via CYP3A and 2B6 to inactive hydroxylated metabolites which then undergo glucuronidation; induces P450 enzymes and its own metabolism

Excretion

Feces (16% to 61% primarily as unchanged drug); urine (14% to 34% as metabolites; <1% unchanged drug)

Time to Peak

3 to 5 hours

Half-Life Elimination

Single dose: 52 to 76 hours; Multiple doses: 40 to 55 hours

Protein Binding

>99%, primarily to albumin

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infection in combination with other antiretroviral agents in adults and pediatric patients at least 3 months old and weighing at least 3.5 kg

Contraindications

Hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to efavirenz or any component of the formulation

Dosing: Adult

HIV infection: Oral: 600 mg once daily.

Dosage adjustment for concomitant rifampin (only if patient weighs ≥50 kg): Increase efavirenz dose to 800 mg once daily.

Dosage adjustment for concomitant voriconazole: Reduce efavirenz dose to 300 mg once daily and increase voriconazole to 400 mg every 12 hours.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Dosage is based on body weight.

HIV infection (as part of combination therapy): Children ≥3 months and ≥3.5 kg: Oral:

3.5 kg to <5 kg: 100 mg once daily

5 kg to <7.5 kg: 150 mg once daily

7.5 kg to <15 kg: 200 mg once daily

15 kg to <20 kg: 250 mg once daily

20 kg to <25 kg: 300 mg once daily

25 kg to <32.5 kg: 350 mg once daily

32.5 kg to <40 kg: 400 mg once daily

≥40 kg: 600 mg once daily; Note: Dosage adjustments may be necessary if patient receives certain concomitant medications. Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustment provided in manufacturer’s labeling (has not been studied); however, undergoes minimal renal excretion.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary; use with caution.

Moderate-to-severe impairment (Child-Pugh class B or C): No dosage adjustment provided in manufacturer’s labeling (has not been adequately studied); use not recommended.

Administration

Oral: Administer on an empty stomach. Dosing at or before bedtime is recommended to limit central nervous system effects (HHS, [adult] 2014). Tablets must not be broken.

Capsule contents may be sprinkled onto a small amount of soft food (eg, applesauce, grape jelly, yogurt) for pediatric or adult patients who cannot swallow capsules. Place 1-2 teaspoonfuls of food in a small container. Hold capsule horizontally over container and carefully twist in opposite directions to open, sprinkling contents over food. If more than 1 capsule is needed for a dose, add contents of all capsules needed to 1-2 teaspoonfuls of food; do not add more food. Use a small spoon to gently mix capsule contents with food and administer all of mixture to patient. To ensure entire capsule contents are administered, add another 2 teaspoonfuls of food to the container, mix to incorporate any drug residue, and administer.

Capsule contents may also be mixed with infant formula only for pediatric patients who cannot reliably consume solid foods. Combine entire contents of capsule(s) with 10 mL of reconstituted, room temperature infant formula in a 30 mL small container, stir carefully, then draw up mixture in a 10 mL oral syringe for administration. If more than 1 capsule is needed for a dose, add contents of all capsules needed to 10 mL of formula; do not add more formula. To ensure entire capsule contents are administered, add another 10 mL of formula to the cup, stir to incorporate any drug residue, draw up in oral syringe and administer.

Administer within 30 minutes of mixing. Patient should not consume any additional food or administer additional formula for 2 hours after administration.

Dietary Considerations

Should be taken on an empty stomach unless using capsule sprinkle method in patients unable to swallow capsules or tablets. If capsule sprinkle method is used, do not consume additional food for 2 hours after administration.

Storage

Store at 25°C (77°F); excursion permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): Efavirenz may enhance the adverse/toxic effect of Alcohol (Ethyl). Efavirenz may decrease the serum concentration of Alcohol (Ethyl). Monitor therapy

Amodiaquine: Efavirenz may enhance the hepatotoxic effect of Amodiaquine. Efavirenz may increase the serum concentration of Amodiaquine. Avoid combination

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Artemether: Efavirenz may decrease the serum concentration of Artemether. Concentrations of dihydroartemisinin (active metabolite of artemether) may also be decreased by efavirenz Monitor therapy

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Atazanavir: Efavirenz may decrease the serum concentration of Atazanavir. Management: When used with efavirenz, the adult atazanavir dose should be 400 mg daily, boosted with ritonavir 100 mg daily or cobicistat 150 mg daily, for treatment-naive patients only; treatment-experienced patients should not use atazanavir with efavirenz. Consider therapy modification

AtorvaSTATin: Efavirenz may decrease the serum concentration of AtorvaSTATin. Monitor therapy

Atovaquone: Efavirenz may decrease the serum concentration of Atovaquone. Management: Consider alternatives to the use of atovaquone with efavirenz when possible. If this combination must be used, monitor for evidence of reduced atovaquone clinical effectiveness. Consider therapy modification

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: Efavirenz may decrease the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Efavirenz. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: Efavirenz may decrease serum concentrations of the active metabolite(s) of Buprenorphine. Efavirenz may decrease the serum concentration of Buprenorphine. Monitor therapy

BuPROPion: Efavirenz may decrease the serum concentration of BuPROPion. Management: Monitor for decreased response to bupropion in patients treated with efavirenz. Increased bupropion doses may be required. Avoid the use of naltrexone/bupropion for weight management in patients receiving efavirenz. Monitor therapy

Calcium Channel Blockers: Efavirenz may decrease the serum concentration of Calcium Channel Blockers. Monitor therapy

Canagliflozin: Efavirenz may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of CarBAMazepine. Avoid combination

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Consider therapy modification

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clarithromycin: Efavirenz may decrease the serum concentration of Clarithromycin. Management: Consider using an alternative antibiotic, such as azithromycin, for patients taking efavirenz. If concomitant therapy cannot be avoided, monitor for decreased therapeutic effect of clarithromycin and increased incidence of skin rash. Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Contraceptives (Progestins): Efavirenz may decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

CycloSPORINE (Systemic): Efavirenz may decrease the serum concentration of CycloSPORINE (Systemic). Management: Increase monitoring of cyclosporine concentrations when starting, stopping, or adjusting doses of concurrent efavirenz, particularly within the first 2 weeks. Cyclosporine dose adjustment may be required. Consider therapy modification

CYP2B6 Substrates: CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Darunavir: May increase the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of Darunavir. Management: Monitor for decreased concentrations and effects of darunavir and/or increased concentrations and effects of efavirenz when darunavir/ritonavir is combined with efavirenz. The use of darunavir/cobicistat in combination with efavirenz is not recommended. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

DiltiaZEM: Efavirenz may decrease the serum concentration of DiltiaZEM. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dolutegravir: Efavirenz may decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to efavirenz for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Elbasvir: Efavirenz may decrease the serum concentration of Elbasvir. Avoid combination

Elvitegravir: Efavirenz may decrease the serum concentration of Elvitegravir. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Estriol (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Etonogestrel: Efavirenz may diminish the therapeutic effect of Etonogestrel. Management: Use a reliable barrier contraceptive if efavirenz is used in combination with etonogestrel. Continue using barrier contraception for 12 weeks after discontinuation of efavirenz. Consider therapy modification

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Everolimus: Efavirenz may decrease the serum concentration of Everolimus. Management: Closely monitor everolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of everolimus may be required. Consider therapy modification

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosamprenavir: Efavirenz may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Management: For once-daily fosamprenavir/ritonavir with efavirenz, an increased ritonavir dose to 300 mg/day is recommended in adult patients. No ritonavir dose adjustment is required if using twice-daily fosamprenavir/ritonavir. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Fosphenytoin. Consider therapy modification

Ginkgo Biloba: May decrease the serum concentration of Efavirenz. Monitor therapy

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with moderate CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if moderate CYP3A4 inducer therapy is just beginning. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Management: Although moderate CYP3A inducers are not specifically contraindicated with ibrutinib, prescribing information indicates that they may decrease AUC up to 3-fold. If possible, alternatives with less CYP3A induction should be considered. Consider therapy modification

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Indinavir: Efavirenz may decrease the serum concentration of Indinavir. Management: The appropriate dose adjustments for indinavir when used together with efavirenz are unknown. The use of higher unboosted indinavir doses is not likely an adequate approach. Use of a ritonavir-boosted indinavir regimen could be considered. Consider therapy modification

Itraconazole: Efavirenz may decrease the serum concentration of Itraconazole. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Ketoconazole (Systemic): Efavirenz may decrease the serum concentration of Ketoconazole (Systemic). Avoid combination

Lopinavir: Efavirenz may decrease the serum concentration of Lopinavir. Management: Avoid once daily use of lopinavir/ritonavir with efavirenz. Avoid use of this combination in patients less than 6 months of age. See lopinavir/ritonavir prescribing information for specific recommended dose increases in particular patient populations. Consider therapy modification

Lovastatin: Efavirenz may decrease the serum concentration of Lovastatin. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Maraviroc: Efavirenz may decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with efavirenz. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nevirapine: Efavirenz may enhance the adverse/toxic effect of Nevirapine. Nevirapine may enhance the adverse/toxic effect of Efavirenz. Nevirapine may decrease the serum concentration of Efavirenz. Avoid combination

Nilotinib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Norgestimate: Efavirenz may decrease serum concentrations of the active metabolite(s) of Norgestimate. Management: Use a reliable barrier contraceptive if efavirenz is used in combination with norgestimate. Continue using barrier contraception for 12 weeks after discontinuation of efavirenz. Consider therapy modification

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: May decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Phenytoin. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Posaconazole: Efavirenz may decrease the serum concentration of Posaconazole. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Pravastatin: Efavirenz may decrease the serum concentration of Pravastatin. Monitor therapy

Proguanil: Efavirenz may decrease serum concentrations of the active metabolite(s) of Proguanil. Efavirenz may increase the serum concentration of Proguanil. Efavirenz may decrease the serum concentration of Proguanil. Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Rifabutin: Efavirenz may decrease the serum concentration of Rifabutin. Rifabutin may decrease the serum concentration of Efavirenz. Management: If efavirenz is to be used with daily rifabutin, increase the planned rifabutin adult dose by 50%. If used with regimens where rifabutin is administered 2-3 times per week, consider doubling the rifabutin dose. Consider therapy modification

RifAMPin: May decrease the serum concentration of Efavirenz. Management: Increase efavirenz adult dose to 800 mg daily in patients weighing over 50 kg. Consider therapy modification

Rilpivirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Ritonavir: Efavirenz may enhance the adverse/toxic effect of Ritonavir. Efavirenz may increase the serum concentration of Ritonavir. Ritonavir may increase the serum concentration of Efavirenz. Monitor therapy

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Management: Monitor for reduced rolapitant response. Recommended dexamethasone regimens should be used with rolapitant. Higher dexamethasone doses or more prolonged use may increase the potential for a significant interaction. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Saquinavir: May enhance the adverse/toxic effect of Efavirenz. Efavirenz may decrease the serum concentration of Saquinavir. Management: When used together with efavirenz, saquinavir should not be used as the sole protease inhibitor. Appropriate doses of the combination of efavirenz with saquinavir/ritonavir have not been established. Consider therapy modification

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sertraline: Efavirenz may decrease the serum concentration of Sertraline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Simvastatin: Efavirenz may decrease the serum concentration of Simvastatin. Monitor therapy

Sirolimus: Efavirenz may decrease the serum concentration of Sirolimus. Management: Closely monitor sirolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of sirolimus may be required. Consider therapy modification

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

St John's Wort: May decrease the serum concentration of Efavirenz. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tacrolimus (Systemic): Efavirenz may decrease the serum concentration of Tacrolimus (Systemic). Management: Closely monitor tacrolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of tacrolimus may be required. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Telaprevir: Efavirenz may decrease the serum concentration of Telaprevir. Telaprevir may decrease the serum concentration of Efavirenz. Management: Initiate telaprevir at a dose of 1125 mg every 8 hours in patients receiving efavirenz (per adult/adolescent HIV guidelines). Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ulipristal: Efavirenz may decrease the serum concentration of Ulipristal. Avoid combination

Velpatasvir: CYP2B6 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Vitamin K Antagonists (eg, warfarin): Efavirenz may decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Voriconazole: Efavirenz may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Efavirenz. Management: Use of standard doses of these drugs is contraindicated. The voriconazole oral maintenance dose should be increased to 400 mg every 12 hours, and the efavirenz dose should be reduced to 300 mg/day. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

False-positive tests for cannabinoids have been reported when the CEDIA DAU Multilevel THC assay is used. False-positive results with other assays for cannabinoids have not been observed. False-positive tests for benzodiazepines have been reported and are likely due to the 8-hydroxy-efavirenz major metabolite.

Adverse Reactions

Unless otherwise noted, frequency of adverse events is as reported in adults receiving combination antiretroviral therapy.

>10%:

Central nervous system: Dizziness (2% to 28%; children: 16%), fever (children: 21%), depression (≤19%; severe: 1% to 2%), insomnia (≤16%), pain (1% to 13%; children: 14%), anxiety (2% to 13%), headache (2% to 8%; children: 11%)

Dermatologic: Skin rash (5% to 26%, grades 3/4: <1%; children: ≤46%, grades 3/4: 2% to 4%)

Endocrine & metabolic: Increased serum cholesterol (20% to 40%), increased HDL cholesterol (25% to 35%), increased serum triglycerides (≥751 mg/dL: 6% to 11%)

Gastrointestinal: Diarrhea (3% to 14%; children: ≤39%), nausea (2% to 10%; children: 12%), vomiting (3% to 6%; children 12%)

Respiratory: Cough (children: 16%)

1% to 10%:

Central nervous system: Fatigue (≤8%), lack of concentration (≤8%), drowsiness (≤7%), nervousness (2% to 7%), abnormal dreams (1% to 6%), hallucination (1%)

Dermatologic: Pruritus (≤9%)

Endocrine & metabolic: Increased amylase (grades 3/4: ≤6%), hyperglycemia (>250 mg/dL: 2% to 5%)

Gastrointestinal: Dyspepsia (≤4%), abdominal pain (2% to 3%), anorexia (≤2%)

Hematologic & oncologic: Neutropenia (grades 3/4: 2% to 10%)

Hepatic: Increased serum AST (grades 3/4: 5% to 8%; incidence higher with hepatitis B and/or C coinfection), increased serum ALT (grades 3/4: 2% to 8%; incidence higher with hepatitis B and/or C coinfection)

<1% (Limited to important or life-threatening): Ataxia, attempted suicide, cerebellar ataxia, delusions, erythema multiforme, gynecomastia, hepatic failure, hepatitis, hypersensitivity reaction, lipotrophy, malabsorption, mania, neuropathy, palpitations, pancreatitis, paranoia, photodermatitis, psychoneurosis, psychosis, redistribution of body fat, seizure, Stevens-Johnson syndrome, suicidal ideation, visual disturbance

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: May cause CNS effects (eg, abnormal dreams, insomnia, impaired concentration, hallucinations, dizziness or drowsiness); symptoms usually begin within 1 to 2 days after starting efavirenz, and generally resolve within 2 to 4 weeks of continued therapy; dosing at bedtime may improve tolerability; avoid potentially hazardous tasks such as driving or operating machinery.

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hepatotoxicity: Hepatic failure has been reported, including patients with no preexisting hepatic disease or other identifiable risk factors. Monitor liver function tests in patients with underlying hepatic disease (eg, hepatitis B or C, marked transaminase elevations, or taking concomitant medications that may cause hepatotoxicity). Ethanol intake may increase hepatotoxic potential.

• Hypercholesterolemia: Increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Psychiatric effects: Serious psychiatric side effects have been associated with use, including aggressive behavior, severe depression, suicidal ideation, nonfatal suicide attempts, paranoia, and mania; use with caution in patients with a history of mental illness/drug abuse (predisposition to psychological reactions). Patients should be instructed to contact healthcare provider if serious psychiatric effects occur.

• Rash: May cause mild-to-moderate maculopapular rash; usually occurs within 2 weeks of starting therapy; most resolve within 1 month with continued therapy. Discontinue if severe rash (involving blistering, desquamation, mucosal involvement or fever) develops; use is contraindicated in patients with a history of a severe cutaneous reaction (eg, Stevens-Johnson syndrome). Children are more susceptible to development of rash; prophylactic antihistamines/corticosteroids may be used.

Disease-related concerns:

• Hepatic impairment: Not recommended in moderate-to-severe hepatic impairment (Child-Pugh class B or C); use with caution in patients with mild hepatic impairment (Child-Pugh class A), including known or suspected hepatitis B or C infection; monitoring is recommended. Persistent elevations of serum transaminases >5 times the upper limit of normal should prompt evaluation - benefit of continued therapy should be weighed against possible risk of hepatotoxicity.

• HIV-associated dementia: Avoid efavirenz-based regimens if possible in patients with HIV-associated dementia; neuropsychiatric side effects of efavirenz may hinder assessment of the effects of antiretrovirals on the improvement of symptoms associated with HIV-associated dementia (HHS [adult] 2015).

• Seizure disorder: Use with caution in patients with a history of seizure disorder; seizures have been associated with use.

Concurrent drug therapy issues:

• Duplicate therapy: Concomitant use of other efavirenz-containing products should be avoided (unless needed for dosage adjustment with concomitant rifampin treatment).

• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors, moderate or strong CYP3A4 inducers and major CYP3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions. Consult drug interactions database for more detailed information.

• Sedatives: CNS effects may be potentiated when used with other psychoactive drugs or ethanol.

Special populations:

• Pregnancy: Avoid pregnancy; women of childbearing potential should undergo pregnancy testing prior to initiation of therapy.

Other warnings/precautions:

• Appropriate use: Do not use efavirenz plus abacavir and lamivudine (or emtricitabine) in adolescent and adult HIV-1 patients with a pre-ART HIV RNA >100,000 copies/mL (HHS [adult] 2015).

• Resistance: Efavirenz administered as monotherapy or added on to a failing regimen may result in rapid viral resistance to efavirenz. Consider cross-resistance when adding antiretroviral agents on to efavirenz therapy.

Monitoring Parameters

Serum transaminases (discontinuation of treatment should be considered for persistent elevations >5 times the upper limit of normal); cholesterol and triglycerides (prior to therapy and periodically during); signs and symptoms of infection; psychiatric effects

Pregnancy Considerations

Efavirenz has a moderate level of transfer across the human placenta. Based on data from the Antiretroviral Pregnancy Registry, an increased risk of overall birth defects has not been observed following first trimester exposure to efavirenz; however, neural tube and other CNS defects have been reported. Due to the low number of first trimester exposures and the low incidence of neural tube defects in the general population, available data are insufficient to evaluate risk. Other antiretroviral agents should strongly be considered for use in women of childbearing potential who are planning to become pregnant or who are sexually active and not using effective contraception. Nonpregnant women of reproductive age should undergo pregnancy testing prior to initiation of efavirenz. Barrier contraception should be used in combination with other (hormonal) methods of contraception during therapy and for 12 weeks after efavirenz is discontinued. Neural tube defects would occur following exposure during the first 5 to 6 weeks of gestation (most pregnancies are not detected before 4 to 6 weeks gestation). For women who present in the first trimester already on an efavirenz-containing regimen and who have adequate viral suppression, efavirenz may be continued; changing regimens may lead to loss of viral control and increase the risk of perinatal transmission (fetal ultrasound is recommended at 18 to 20 weeks gestation). The HHS Perinatal HIV Guidelines consider efavirenz to be a preferred NNRTI for use in antiretroviral-naive pregnant women after 8 weeks gestation. Hypersensitivity reactions (including hepatic toxicity and rash) are more common in women on NNRTI therapy; it is not known if pregnancy increases this risk. Pharmacokinetic data from available studies do not suggest dose alterations are needed during pregnancy.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance (Note: due to the long half-life of efavirenz, other regimens may need to be substituted to prevent resistance; consult current guidelines). Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, headache, loss of strength and energy, dizziness, fatigue, insomnia, difficulty focusing, or abnormal dreams. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), change in body fat, behavioral changes, hallucinations, memory impairment, confusion, seizures, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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