Darunavir

547.66

547.66

1592732-453-0

YO603Y8113

DTXSID0046779

C65364

White, amorphous solid

J05|J05AE10|J - Antiinfectives for systemic use

149

1.8

White Amorphous Solid

1.3±0.1 g/cm3

74 °C

1.620

Approximately 0.15 mg/mL at 20 °C as ethanolate salt

-20°C Freezer

11.43±0.46(Predicted)

Hydroxyl radical reaction rate constant = 1.14X10-10 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

3

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including darunavir ethanolate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Darunavir ethanolate/

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.

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking darunavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (above 5 times the upper limit of normal) are found in 3% to 10% of patients overall, and rates are higher in patients with HIV-HCV coinfection. In clinical trials of darunavir elevations in serum ALT above 5 times ULN occurred in 2% to 3% of patients, but no subject developed clinically apparent liver injury with jaundice. The serum enzyme elevations during therapy are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent acute liver injury due to darunavir has been reported since its approval and more widescale use, but none have been well characterized for clinical features. The liver injury generally arises after 1 to 8 weeks of therapy and the pattern of serum enzyme elevations is usually, but not always, hepatocellular. Signs of hypersensitivity (fever, rash, eosinophilia) are rare, as is autoantibody formation. The acute liver injury is usually self-limited and resolves within a few weeks of stopping darunavir. However, fatal instances have been reported, at least to the sponsor and monitoring of liver enzymes during therapy is recommended.

Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) with ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine). Concomitant use of ritonavir-boosted darunavir and ergot alkaloids is contraindicated. If a woman receiving darunavir or any other PI as part of an antiretroviral regimen experiences uterine atony and excessive postpartum bleeding, methylergonovine maleate (Methergine) should be used for treatment of the hemorrhage only if alternative treatments (e.g., carboprost, misoprostol, oxytocin, dinoprostone) cannot be used and the potential benefits of the ergot alkaloid outweigh the risks.7 In this situation, methylergonovine maleate should be used in the lowest dosage and shortest duration possible.|Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias) with pimozide. Concomitant use of ritonavir-boosted darunavir and pimozide is contraindicated.|Ritonavir-boosted darunavir should be used with particular caution in patients receiving a selective phosphodiesterase (PDE) inhibitor (e.g., sildenafil, tadalafil, vardenafil) since concomitant use of the drugs is expected to result in substantially increased plasma concentrations of the PDE inhibitor and increase the risk of adverse effects (e.g., hypotension, visual changes, priapism) associated with these agents.|Pharmacokinetic interaction with tenofovir disoproxil fumarate (increased tenofovir plasma concentrations and no change in darunavir plasma concentrations). The manufacturer of darunavir states that the usual dosage of ritonavir-boosted darunavir can be used concomitantly with the usual dosage of tenofovir disoproxil fumarate. Some experts state that the clinical importance of this interaction is unknown and patients receiving the drugs concomitantly should be monitored for tenofovir toxicity. Pharmacokinetic interaction not expected with abacavir, emtricitabine, lamivudine, stavudine, or zidovudine. No in vitro evidence of antagonistic antiretroviral effects between darunavir and abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine.|For more Interactions (Complete) data for Darunavir (32 total), please visit the HSDB record page.

Not known whether the drug is distributed into human milk. Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.|Spontaneous bleeding has been reported in patients with hemophilia A or B receiving protease inhibitors; use caution in such patients. Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

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.|FDA Label|Rezolsta, is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus 1 (HIV 1) infection in adults aged 18 years or older.Genotypic testing should guide the use of Rezolsta.|PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adult and paediatric patients from the age of 3 years and at least 15 kg body weight.PREZISTA, co administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg).In deciding to initiate treatment with PREZISTA co administered with cobicistat or low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA.PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV 1) infection.PREZISTA 75 mg, 150 mg, and 600 mg tablets may be used to provide suitable dose regimens:For the treatment of HIV 1 infection in antiretroviral treatment (ART) experienced adult patients, including those that have been highly pre treated.For the treatment of HIV 1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight.In deciding to initiate treatment with PREZISTA co administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA.PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV 1) infection.PREZISTA, co administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg).PREZISTA 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV 1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:antiretroviral therapy (ART) naïve.ART experienced with no darunavir resistance associated mutations (DRV RAMs) and who have plasma HIV 1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/L. In deciding to initiate treatment with PREZISTA in such ART experienced patients, genotypic testing should guide the use of PREZISTA.|400mg and 800 mg Film-coated TabletsDarunavir Krka d.d., co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.Darunavir Krka d.d., co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection in adult patients (see section 4.2).Darunavir Krka d.d. 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:antiretroviral therapy (ART)-naïve (see section 4.2).ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. In deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic testing should guide the use of darunavir (see sections 4.2, 4.3, 4.4 and 5.1).600mg Film-coated TabletsDarunavir Krka d.d., co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.Darunavir Krka d.d. 600 mg tablets may be used to provide suitable dose regimens (see section 4.2):For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated.For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight.In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir.|400 and 800 mgDarunavir Krka, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.Darunavir Krka 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:antiretroviral therapy (ART)-naïve (see section 4.2).ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. In deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic testing should guide the use of darunavir (see sections 4.2, 4.3, 4.4 and 5.1).600 mg Darunavir Krka, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.Darunavir Krka 600 mg tablets may be used to provide suitable dose regimens (see section 4.2):For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated.For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight.In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir.|Darunavir, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.Darunavir Mylan tablets may be used to provide suitable dose regimens:For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated.For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight.In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of daranuvir.Darunavir co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.Darunavir co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.Darunavir Mylan tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:antiretroviral therapy (ART)-naïve.ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. In deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic testing should guide the use of darunavir.|Symtuza is indicated for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults and adolescents (aged 12 years and older with body weight at least 40 kg).Genotypic testing should guide the use of Symtuza.|Treatment of human immunodeficiency virus (HIV-1) infection

Darunavir is an antiretroviral protease inhibitor that is used in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Darunavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent, acute liver injury. In HBV or HCV coinfected patients, highly active antiretroviral therapy with darunavir may result of an exacerbation of the underlying chronic hepatitis B or C.

Antiviral Agents

Darunavir with low-dose ritonavir (ritonavir-boosted darunavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV) infection in treatment-experienced (previously treated) adults, including those infected with HIV-1 strains resistant to multiple HIV protease inhibitors (PIs). This indication is based on surrogate marker data (plasma HIV-1 RNA levels, CD4+ T-cell counts) obtained from two 24-week controlled studies in treatment-experienced adults (previously treated with nucleoside reverse transcriptase inhibitors (NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs), and PIs) with evidence of HIV-1 replication despite ongoing antiretroviral therapy. The manufacturer advises that the following factors be considered when initiating ritonavir-boosted darunavir. Use of ritonavir-boosted darunavir should be guided by results of baseline genotypic and phenotypic viral resistance testing and the individual's prior antiretroviral treatment. Administration of ritonavir-boosted darunavir in conjunction with other active antiretroviral agents is associated with a greater likelihood of treatment response. /Use Included in US product label/|Prezista is a human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV infection in adult patients. Prezista is also indicated for the treatment of HIV infection in pediatric patients 6 years of age and older. Prezista must be co-administered with ritonavir and with other antiretroviral agents. /Use Included in US product label/|Safety and efficacy of darunavir/ritonavir and optimized background regimen in treatment-experienced patients (6-17 years) /was assessed in a/ forty-eight-week, open-label, two-part, phase II study. In part I, 44 patients were randomized (1: 1 ratio) to receive a body weight-adjusted, adult-equivalent dose (group A) or a 20-33% higher darunavir/ritonavir twice daily (b.i.d.) dose (group B). Pharmacokinetics, safety and efficacy were assessed following 2-week dosing (part I), which determined dosing for part II (evaluated 48-week safety and efficacy). In part I, both groups met the protocol-specified criteria for pharmacokinetics and showed favorable tolerability and efficacy. The following body-weight doses were selected: darunavir/ritonavir 375/50 mg b.i.d. (20-<30 kg), 450/60 mg b.i.d. (30-<40 kg) and 600/100 mg b.i.d. (> or =40 kg); these gave an AUC 24 hr, C0 hr and Cmax of 102, 114 and 112%, respectively, versus the corresponding mean adult pharmacokinetic parameter. In part II, 80 patients received darunavir/ritonavir (median age: 14 years, mean baseline HIV-1 RNA: 4.64 log(10)copies/ml). One patient (1%) discontinued (treatment-unrelated grade 3 anxiety). An abnormal mean baseline triglyceride level was normalized at 48 weeks (P < 0.01). At week 48, 65% had at least 1.0 log (10)HIV-1 RNA reduction; 59 and 48% achieved HIV-1 RNA less than 400 and less than 50 copies/mL, respectively (time-to-loss-of-virologic response). Mean age-adjusted weight z-score increased by 0.2 (P = 0.003). In treatment-experienced children and adolescents, darunavir/ritonavir showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. Darunavir/ritonavir is a valuable therapeutic option for this population.

Acute hepatitis has occurred in patients receiving ritonavir-boosted darunavir in clinical studies. Liver injury (in some cases fatal) has been reported during postmarketing surveillance; liver injury generally has occurred in patients with advanced HIV infection who were receiving multiple concomitant drugs, were coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV), and/or were developing immune reconstitution syndrome. Appropriate laboratory tests should be performed to evaluate hepatic function prior to initiating ritonavir-boosted darunavir and periodically during treatment. Increased AST/ALT monitoring should be considered, especially during the first several months of therapy, in patients with hepatitis, cirrhosis, or elevated transaminase values prior to therapy. Interruption or discontinuance of ritonavir-boosted darunavir should be considered in patients who develop manifestations suggestive of hepatic impairment (e.g., fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly, clinically important increases in hepatic enzyme concentrations).|The risks versus benefits of ritonavir-boosted darunavir have not been established in pediatric patients.|Spontaneous bleeding has been reported in patients with hemophilia A or B receiving PIs; use caution in such patients. Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.|Darunavir contains a sulfonamide moiety, which may cause allergic-type reactions in certain susceptible individuals. Use darunavir with caution in patients with known hypersensitivity to sulfonamide-containing drugs.|For more Drug Warnings (Complete) data for Darunavir (19 total), please visit the HSDB record page.

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.

Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly. (See all compounds classified as HIV Protease Inhibitors.)

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 to 4 hours after oral administration. When darunavir is taken with food, the Cmax and AUC of darunavir given with ritonavir increase by 30% when compared to the fasted state.|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 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 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.|Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).|Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5-4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.|Darunavir is distributed into milk in rats; not known whether the drug is distributed into human milk.|A mass balance study in healthy volunteers showed that after single dose administration of 400 mg (14)C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of (14)C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/hr and 5.9 L/hr, respectively.|For more Absorption, Distribution and Excretion (Complete) data for Darunavir (8 total), please visit the HSDB record page.

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.|In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg (14)C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV.|Absorption, metabolism, and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of ((14)C)darunavir given alone (unboosted subjects) or with ritonavir (100 mg b.i.d. 2 days before and 7 days after darunavir administration (boosted subjects)). ... Darunavir was extensively metabolized in unboosted subjects, mainly by carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation and to a lesser extent by benzylic aromatic hydroxylation and glucuronidation. Total excretion of unchanged darunavir accounted for 8.0% of the dose in unboosted subjects. Boosting with ritonavir resulted in significant inhibition of carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation but had no effect on aromatic hydroxylation at the benzylic moiety, whereas excretion of glucuronide metabolites was markedly increased but still represented a minor pathway. Total excretion of unchanged darunavir accounted for 48.8% of the administered dose in boosted subjects as a result of the inhibition of darunavir metabolism by ritonavir. Unchanged darunavir in urine accounted for 1.2% of the administered dose in unboosted subjects and 7.7% in boosted subjects, indicating a low renal clearance.|Darunavir is metabolized by Phase I and Phase II biotransformation mechanisms. A large number of metabolites were detected in vitro using animal and human hepatocytes and microsomal preparations. The metabolic pathway was qualitatively similar in rats, dogs and humans. The most prevalent pathway was the Phase I biotransformation including carbamate hydrolysis, aliphatic hydroxylation at the isobutyl moiety and aromatic hydroxylation at the aniline moiety. Dogs were most representatives of human with carbamate hydrolysis predominating in both species. Darunavir was mainly metabolized by CYP3A. In mice and rats darunavir treatment induced hepatic microsomal CYP3A4. UDP-GT activity was additionally induced in rats. In dogs, no induction effects were observed. Darunavir is presented as a single enantiomer but no chiral inversion occurs in vivo.

The terminal elimination half-life of darunavir is approximately 15 hours when it is combined with ritonavir.|A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg (14)C-darunavir, co-administered with 100 mg ritonavir ... The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir.|The pharmacokinetics of darunavir has been evaluated in vitro and in several species (mice, rats, dogs and rabbits), that were also used in the non-clinical pharmacology and toxicology studies. ... Following oral administration, ... elimination half-life was ... rapid with half-lives generally less than 5 hr.

The HIV-1 protease enzyme is necessary for viral precursor protein processing and viral maturation in preparation for infection, and is therefore a target for antiretroviral therapy for HIV. Protease inhibitors are used as a part of highly active antiretroviral therapy (HAART) in patients diagnosed with HIV infection. It has been shown to effectively suppress the virus, leading to significantly decreased morbidity and mortality rates. Darunavir, a HIV protease inhibitor, prevents HIV replication through binding to the enzyme, stopping the dimerization and the catalytic activity of HIV-1 protease. In particular, it inhibits the cleavage of HIV encoded Gag-Pol proteins in cells that have been infected with the virus, halting the formation of mature virus particles, which spread the infection. The close contact that darunavir makes with the primary chains of the active site amino acids (Asp-29 and Asp-30) on the protease likely contributes to its potency and efficacy against resistant variants of HIV-1. Darunavir is known to bind to different sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer. Darunavir can adapt to changes in the shape of a protease enzyme due to its molecular flexibility.|Darunavir as a protease inhibitor inhibits the cleavage of HIV encoded gag-pol polyproteins in virus infected cells, thereby preventing the formation of mature and infectious new virions. It was selected for its potency against wild type HIV-1 and HIV strains resistant to currently approved protease inhibitors.|Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Treatment of overdose with Prezista consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Prezista is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex (MAC), M. tuberculosis, cytomegalovirus (CMV).|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking.|Darunavir is used in conjunction with low-dose ritonavir (ritonavir-boosted darunavir); the drugs are taken at the same time and with food. Failure to administer darunavir with the recommended ritonavir dosage and with food will result in subtherapeutic darunavir concentrations and inadequate antiviral response. The usual cautions, precautions, and contraindications associated with ritonavir should be considered.|Severe skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have occurred in patients receiving darunavir; fever and increases in serum transaminase concentrations have occurred in some of these patients. Rash (usually maculopapular and of mild to moderate intensity) has occurred in 7% of patients receiving ritonavir-boosted darunavir. Darunavir should be discontinued if severe rash occurs.|For more Human Toxicity Excerpts (Complete) data for Darunavir (6 total), please visit the HSDB record page.

114, TMC

Oral: Tablets, film-coated 300 mg (of darunavir) Prezista (Tibotec); 600 mg (of darunavir) Prezista (Tibotec).

Human drugs -> Rezolsta -> EMA Drug Category|Antivirals for systemic use, Antivirals for treatment of HIV infections, combinations -> Human pharmacotherapeutic group|Human drugs -> Prezista -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Darunavir Krka d.d. -> EMA Drug Category|Human drugs -> Darunavir Krka -> EMA Drug Category|Human drugs -> Darunavir Mylan -> EMA Drug Category|Human drugs -> Symtuza -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients