Darunavir

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.

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. Assigning causality to a specific anti-HIV medication is often difficult because most patients are taking multiple antiviral agents and many have accompanying chronic hepatitis B or C or nonalcoholic steatohepatitis. In reported cases, 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.；Finally, initiation of darunavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Darunavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.；Likelihood score: C (probable, rare cause of clinically apparent liver injury).

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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Darunavir

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Single dose toxicity studies were performed in mice, rats and dogs. ... In mice, treatment related mortality and macroscopic findings (distended or fluid-filled gastro-intestinal tracts) occurred at oral doses > or = 280 mg/kg.

/LABORATORY ANIMALS: Acute Exposure/ Single dose toxicity studies were performed in mice, rats and dogs. ... In rats, there was no treatment mortality or toxicologically relevant observations with oral doses up to 471 mg/kg. In a second study, higher doses were used but the systemic exposure did not really increase to that observed with a dose of approximately 500 mg/kg.

/LABORATORY ANIMALS: Acute Exposure/ Single dose toxicity studies were performed in mice, rats and dogs. ... In dogs, vomiting was the most obvious adverse effect occurring at the doses of 301 mg/kg limiting the maximum tolerated dose to 75 mg/kg. The NOAEL in the IV dog study was 10 mg/kg.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In juvenile rats that were directly dosed on days 12 - 25 of life, mortality was increased already at the lowest dose of 40 mg/kg. Effects included a distended abdomen, an unsteady gait and in some of the animals convulsions.

For more Non-Human Toxicity Excerpts (Complete) data for Darunavir (13 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.

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/

◉ Summary of Use during Lactation；Limited information indicates that maternal doses of darunavir up to 800 mg daily with ritonavir produce low to unmeasurable levels in milk and would not be expected to cause any adverse effects in breastfed infants. The combination of darunavir and cobicistat is expected to produce similar results. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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/

Inhibitor of the HIV-1 protease

THERAPEUTIC CATEGORY: Antiviral

MEDICATION

Use (kg; approx.) in Germany (2009): >750；Consumption (g per capita; approx.) in Germany (2009): 0.00916；Excretion rate: 0.49；Calculated removal (%): 9.2