PREZISTA

Darunavir is a protease inhibitor used with other HIV protease inhibitor drugs as well as ritonavir for the effective management of HIV-1 infection.

As a second-generation protease inhibitor, darunavir is designed to combat resistance to standard HIV therapy. 2, 5 It was initially approved by the FDA in 2006.

Darunavir is being studied as a possible treatment for SARS-CoV-2, the coronavirus responsible for COVID-19, due to in vitro evidence supporting its ability to combat this infection.

Clinical trials are underway and are expected to conclude in August 2020.

Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) in children age 3 or above and adults with HIV-1 infection.

Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease, which prevents HIV viral replication.

When administered with ritonavir in combination antiretroviral therapy, darunavir significantly decreases viral load and increases CD4 cell counts, decreasing the morbidity and mortality of HIV infection. 2, 5, 8.

The absolute oral bioavailability of one single 600 mg dose of darunavir alone and with 100 mg of ritonavir twice a day was 37% and 82%, respectively.

Exposure to darunavir in boosted patients has been found to be 11 times higher than in unboosted patients.

Tmax is achieved approximately 2.4-4 hours after oral administration. 15, 17 When darunavir is taken with food, the Cmax and AUC of darunavir given with ritonavir increase by 30% when compared to the fasted state.

The volume of distribution of darunavir in one pharmacokinetic study in conjunction with ritonavir was 206.5 L (with a range of 161.0–264.9) in healthy young adult volunteers.

Another pharmacokinetic study revealed a volume of distribution of 220 L.

Darunavir is heavily oxidized and metabolized by hepatic cytochrome enzymes, mainly CYP3A.

Darunavir is extensively metabolized in subjects who do not receive a booster, primarily via carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation, as well as both benzylic aromatic hydroxylation and glucuronidation.

A mass balance study in healthy volunteers demonstrated that after single dose administration of 400 mg 14C-darunavir, given with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of radiolabeled darunavir was obtained in the feces and urine, respectively.

Excretion of unchanged drug accounted for 8.0% of the darunavir dose in volunteers who were unboosted.

In boosted darunavir administration, unchanged darunavir made up 48.8% of the excreted dose in boosted subjects due to inhibition of darunavir metabolism by ritonavir.

Unchanged drug in the urine made up 1.2% of the administered dose in volunteers who where unboosted, and 7.7% in boosted volunteers.

The terminal elimination half-life of darunavir is approximately 15 hours when it is combined with ritonavir. 1, 17.

Darunavir has a low renal clearance.

After intravenous administration, the clearance darunavir administered alone and with 100 mg ritonavir twice daily, was 32.8 L/h and 5.9 L/h, respectively.

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LD50 information for darunavir is not readily available in the literature.

One-time doses of up to 3,200 mg of darunavir in an oral solution and up to 1,600 mg of the tablet formulation of darunavir with ritonavir have been given volunteers without significant symptoms.

Information about an overdose with darunavir with ritonavir is limited.

No specific antidote exists for this drug.

Treatment of

In the case of an overdose, employ general supportive measures.

Monitor vital signs and clinical status.

It is unlikely that darunavir not amenable to removal by dialysis due to its high level of protein binding.

Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index).

Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below.

Due to the need for co-administration of darunavir with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.

Alpha 1-adrenoreceptor antagonist: alfuzosin Anti-gout: colchicine, in patients with renal and/or hepatic impairment Antimycobacterial: rifampin Antipsychotics: lurasidone, pimozide Cardiac.

Disorders: dronedarone, ivabradine, ranolazine Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine Herbal product: St.

John's wort (Hypericum perforatum) Hepatitis C direct acting antiviral: elbasvir/grazoprevir Lipid modifying agents: lomitapide, lovastatin, simvastatin Opioid Antagonist: naloxegol PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension Sedatives/hypnotics: orally administered midazolam, triazolam Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index).

In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with darunavir/ritonavir to assess drug susceptibility of the HIV-1 virus Monitor serum liver chemistry tests before and during therapy with darunavir/ritonavir.

Treatment-naïve adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet) taken with ritonavir 100 mg once daily and with food.

Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food.

Pregnant patients: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food.

Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of darunavir and ritonavir is based on body weight and should not exceed the adult dose.

Darunavir should be taken with ritonavir and with food.

Darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment. 2.1 Testing Prior to Initiation of Darunavir/ritonavir In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus.

Refer to Dosage and

Administration, and for dosing recommendations.

Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with darunavir/ritonavir. 2.2 Monitoring During Treatment with Darunavir/ritonavir Patients with underlying chronic hepatitis, cirrhosis or in patients who have pre-treatment elevations of transaminases should be monitored for elevation in serum liver biochemistries, especially during the first several months of darunavir/ritonavir treatment. 2.3 Recommended Dosage in Adult Patients Darunavir must be co-administered with ritonavir to exert its therapeutic effect.

Failure to correctly co-administer darunavir with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

Patients who have difficulty swallowing darunavir tablets can use the 100 mg per mL darunavir oral suspension.

Treatment-Naïve Adult Patients The recommended oral dose of darunavir is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet or capsule or 1.25 mL of a 80 mg per mL ritonavir oral solution) once daily and with food.

An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.

The recommended oral dosage for treatment-experienced adult patients is summarized in Table 1.

Baseline genotypic testing is recommended for dose selection.

However, when genotypic testing is not feasible, darunavir 600 mg taken with ritonavir 100 mg twice daily is recommended.

Table 1 Recommended Darunavir/ritonavir Dosage in Treatment-Experienced Adult Patients a V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V b An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe Baseline Resistance Formulation and Recommended Dosing Darunavir tablets with ritonavir tablets or capsule Darunavir oral suspension (100 mg/mL) with ritonavir oral solution (80 mg/mL) With no darunavir resistance associated substitutions a One 800 mg darunavir tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food 8 mL b darunavir oral suspension with 1.25 mL ritonavir oral solution, taken once daily with food With at least one darunavir resistance associated substitutions a, or with no baseline resistance information One 600 mg darunavir tablet with one 100 mg ritonavir tablet/capsule, taken twice daily with food 6 mL darunavir oral suspension with 1.25 mL ritonavir oral solution, taken twice daily with food 2.4 Recommended Dosage During Pregnancy The recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food.

Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL) and in whom a change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance. 2.5 Recommended Dosage in Pediatric Patients (age to less than 18 years) Healthcare professionals should pay special attention to accurate dose selection of darunavir, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose and underdose.

Prescribers should select the appropriate dose of darunavir/ritonavir for each individual child based on body weight (kg) and should not exceed the recommended dose for adults.

Before prescribing darunavir, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets.

If a child is unable to reliably swallow a tablet, the use of darunavir oral suspension should be considered.

The recommended dose of darunavir/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight and should not exceed the recommended adult dose. Darunavir should be taken with ritonavir and with food. The recommendations for the darunavir/ritonavir dosage regimens were based on pediatric clinical trial data and population pharmacokinetic modeling and simulation. Dosing Recommendations for Treatment-Naïve Pediatric Patients or Antiretroviral Treatment-Experienced Pediatric Patients with No Darunavir Resistance Associated Substitutions Pediatric Patients Weighing At Least 10 kg but Less than 15 kg The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is darunavir 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table: Table 2 Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutions a a darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V b The 350 mg, 385 mg, 455 mg and 490 mg darunavir dose for the specified weight groups were rounded up for suspension dosing convenience to 3.6 mL, 4 mL, 4.6 mL and 5 mL, respectively. Body weight (kg) Formulation: Darunavir oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: once daily with food Greater than or equal to 10 kg to less than 11 kg Darunavir 3.6 mL b (350 mg) with ritonavir 0.8 mL (64 mg) Greater than or equal to 11 kg to less than 12 kg Darunavir 4 mL b (385 mg) with ritonavir 0.8 mL (64 mg) Greater than or equal to 12 kg to less than 13 kg Darunavir 4.2 mL (420 mg) with ritonavir 1 mL (80 mg) Greater than or equal to 13 kg to less than 14 kg Darunavir 4.6 mL b (455 mg) with ritonavir 1 mL (80 mg) Greater than or equal to 14 kg to less than 15 kg Darunavir 5 mL b (490 mg) with ritonavir 1.2 mL (96 mg) Pediatric Patients Weighing At Least 15 kg Pediatric patients weighing at least 15 kg can be dosed with darunavir oral tablet(s) using the following table: Table 3 Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Naïve or Treatment-Experienced with No Darunavir Resistance Associated Substitutions a a darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V b The 675 mg dose using darunavir tablets for this weight group is rounded up to 6.8 mL for suspension dosing convenience. c The 6.8 mL and 8 mL darunavir dose should be taken as two (3.4 mL or 4 mL respectively) administrations with the included oral dosing syringe.

Body weight (kg) Formulation: Darunavir tablet(s) and ritonavir capsules or tablets (100 mg) Formulation: Darunavir oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: once daily with food Dose: once daily with food Greater than or equal to 15 kg to less than 30 kg Darunavir 600 mg with ritonavir 100 mg Darunavir 6 mL (600 mg) with ritonavir 1.25 mL (100 mg) Greater than or equal to 30 kg to less than 40 kg Darunavir 675 mg with ritonavir 100 mg Darunavir 6.8 mL bc (675 mg) with ritonavir 1.25 mL (100 mg) Greater than or equal to 40 kg Darunavir 800 mg with ritonavir 100 mg Darunavir 8 mL c (800 mg) with ritonavir 1.25 mL (100 mg) Dosing Recommendations for Treatment-Experienced Pediatric Patients with At Least One Darunavir Resistance Associated Substitutions Pediatric Patients Weighing At Least 10 kg but Less than 15 kg The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is darunavir 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table: Table 4 Recommended Dose for Pediatric Patients Weighing 10 kg to Less Than 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitution a a darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Body weight (kg) Formulation: Darunavir oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: twice daily with food Greater than or equal to 10 kg to less than 11 kg Darunavir 2 mL (200 mg) with ritonavir 0.4 mL (32 mg) Greater than or equal to 11 kg to less than 12 kg Darunavir 2.2 mL (220 mg) with ritonavir 0.4 mL (32 mg) Greater than or equal to 12 kg to less than 13 kg Darunavir 2.4 mL (240 mg) with ritonavir 0.5 mL (40 mg) Greater than or equal to 13 kg to less than 14 kg Darunavir 2.6 mL (260 mg) with ritonavir 0.5 mL (40 mg) Greater than or equal to 14 kg to less than 15 kg Darunavir 2.8 mL (280 mg) with ritonavir 0.6 mL (48 mg) Pediatric Patients Weighing At Least 15 kg Pediatric patients weighing at least 15 kg can be dosed with darunavir oral tablet(s) or suspension using the following table: Table 5 Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitution a a darunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V b The 375 mg and 450 mg dose using darunavir tablets for this weight group is rounded up to 3.8 mL and 4.6 mL for suspension dosing convenience.

Body weight (kg) Formulation: Darunavir tablet(s) and ritonavir tablets, capsules (100 mg) or oral solution (80 mg/mL) Formulation: Darunavir oral suspension (100 mg/mL) and ritonavir oral solution (80 mg/mL) Dose: twice daily with food Dose: twice daily with food Greater than or equal to 15 kg to less than 30 kg Darunavir 375 mg with ritonavir 0.6 mL (48 mg) Darunavir 3.8 mL (375 mg) b with ritonavir 0.6 mL (48 mg) Greater than or equal to 30 kg to less than 40 kg Darunavir 450 mg with ritonavir 0.75 mL (60 mg) Darunavir 4.6 mL (450 mg) b with ritonavir 0.75 mL (60 mg) Greater than or equal to 40 kg Darunavir 600 mg with ritonavir 100 mg Darunavir 6 mL (600 mg) with ritonavir 1.25 mL (100 mg) The use of darunavir/ritonavir in pediatric patients below 3 years of age is not recommended. 2.6 Not Recommended in Patie.

Darunavir tablets, 600 mg are brown, oval, film-coated tablets debossed "1215" on one side and plain on other side and are supplied as follows: NDC 72578-147-14 in bottles of 60 tablets with child-resistant closure.

NDC 72578-147-28 in bottles of 180 tablets with child-resistant closure.

NDC 72578-147-05 in bottles of 500 tablets.

Darunavir tablets, 800 mg are beige, oval, film coated tablets debossed "1217" on one side and plain on other side and are supplied as follows: NDC 72578-148-06 in bottles of 30 tablets with child-resistant closure.

NDC 72578-148-16 in bottles of 90 tablets with child-resistant closure.

NDC 72578-148-05 in bottles of 500 tablets.

Store at 20 ° C to 25 ° C (68 ° F to 77 ° F); excursions permitted between 15 ° C to 30 ° C (59 ° F to 86 ° F) .

Keep darunavir tablets out of reach of children.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to darunavir during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.

Risk Summary Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage.

Available limited data from the

APR show no statistically significant difference in the overall risk of major birth defects for darunavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) .

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

Studies in animals did not show evidence of developmental toxicity.

Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose.

The recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food.

Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL) and in whom a change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance.

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women during the second and third trimesters and postpartum.

Eighteen subjects were enrolled in each BID and QD treatment arms.

Twenty-nine subjects completed the trial through the postpartum period (6 weeks to 12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.

The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6 weeks to 12 weeks).

Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen.

Virologic response was preserved.

In the

BID arm, the proportion of subjects with HIV-1 RNA < 50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit and 61% (11/18) through the 6 week to 12 week postpartum visit.

Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥ 50 copies/mL for 11% (2/18) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure).

QD arm, the proportion of subjects with HIV-1 RNA < 50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit and 78% (14/18) through the 6 week to 12 week postpartum visit.

Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥ 50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).

Darunavir/ritonavir was well tolerated during pregnancy and postpartum.

There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1-infected adults.

Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum.

All 31 infants received antiretroviral prophylactic treatment containing zidovudine.

Based on prospective reports to the

APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.3% to 5.3.%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens.

Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1,000 mg/kg from gestation day (GD) 6 to with darunavir alone) and rats (doses up to 1,000 mg/kg from GD to 19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1,000 mg/kg/day from GD to 20 with darunavir alone).

In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.

Darunavir/ritonavir is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1,000 mg/kg) up to days to 26 of age.

The safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1-infected pediatric subjects to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age) .

Frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults.

Refer to Dosage and

Administration for twice-daily dosing recommendations for pediatric subjects to less than 18 years of age and weighing at least 10 kg. In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects to less than 18 years of age (12 subjects) .

Once daily dosing recommendations for pediatric patients to less than 12 years of age were derived using population pharmacokinetic modeling and simulation.

Although a darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted darunavir exposures for the dosing recommendations in this.

Please see Dosage and

Administration for once-daily dosing recommendations for pediatric subjects to less than 18 years of age and weighing at least 10 kg. Juvenile Animal Data In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1,000 mg/kg), deaths occurred from post-natal day at plasma exposure levels ranging from 0.1 to of the human exposure levels.

In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.

Clinical studies of darunavir did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

In general, caution should be exercised in the administration and monitoring of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy.