Delavirdine mesylate

552.67

552.182495

421105KRQE

C28974

White to tan crystalline powder

182

white to tan

118-120°C

732°C at 760 mmHg

396.5ºC

DMSO: >5mg/mL

-20°C Freezer

VP: 2.6X10-15 mm Hg @ 25 °C /Estimated/ /Delavirdine/

Odorless

Henry's Law constant = 4.6X10-25 atm-cu m/mol @ 25 °C /Estimated/ /Delavirdine/

log Kow = 2.34 @ 25 °C /Estimated/ /Delavirdine/|Hydroxyl radical reaction rate constant = 3.1X10-10 cu cm/molec-sec @ 25 °C /Estimated/ /Delavirdine/

Ⅲ

2811

3

6.1

P201, P202, P264, P280, P281, P305+P351+P338, P308+P313, P337+P313, P405, P501

H319

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

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

|Warning|H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]|P201, P202, P264, P280, P281, P305+P351+P338, P308+P313, P337+P313, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Serum aminotransferase elevations occur in 25% or more of patients on delavirdine therapy, but rise above 5 times the upper limit of normal in 4% or less; this rate is higher in patients who have chronic hepatitis C coinfection. Clinically apparent hepatotoxicity due to delavirdine must be rare, as individual case reports of hepatitis or jaundice have not been published. Nevertheless, cases of hepatitis, jaundice and hepatic failure have been reported to the sponsor and are mentioned in the product label. The liver injury may be immunoallergic and similar in pattern to that attributed to nevirapine and efavirenz. In immunoallergic hepatitis due to nonnucleoside reverse transcriptase inhibitors, injury usually arises within 1 to 8 weeks of starting therapy. Signs of hypersensitivity are common including rash, fever, and eosinophilia and sometimes facial edema, lymphadenoapthy and lymphocytosis. The serum enzyme pattern can be cholestatic, hepatocellular or mixed. Recovery is rapid upon stopping therapy.

Concurrent administration of amphetamines, astemizole, benzodiazepines, calcium channel blocking agents, cisapride, ergot derivatives, or terfenadine with delavirdine may result in potentially serious and/or life-threatening adverse events as a result of the inhibitory effect of delavirdine on CYP isoenzymes 3A and 2C9; it is recommended that dosage adjustments be made for these medications, or that alternative medications be used, while patients are taking delavirdine.|Concurrent administration of delavirdine 300 mg with aluminum and magnesium oral suspension decreases AUC for delavirdine by 41 + or - 19%; patients should be advised not to take antacids within 1 hour of taking delavirdine.|Concurrent use of delavirdine with carbamazepine, phenobarbital, or phenytoin substantially decreases the trough plasma concentration of delavirdine; concurrent use is not recommended.|Cimetidine, famotidine, nizatidine, and ranitidine increase gastric pH and may reduce absorption of delavirdine; long-term use of these medications with delavirdine is not recommended.|For more Interactions (Complete) data for DELAVIRDINE MESYLATE (17 total), please visit the HSDB record page.

Although it is not known whether delavirdine is distributed into human milk, the drug is distributed into milk in rats.

Delavirdine is a nonnucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Delavirdine is associated with a low rate of transient serum aminotransferase elevations during therapy and is a rare cause of clinically apparent acute liver injury.

Antiviral Agents

Delavirdine is indicated in the treatment of HIV-1 infection in combination with other appropriate antiretroviral therapy. /Included in US product labeling/

Plasma lipid and lipoprotein levels were measured at baseline and after 8 weeks of highly active antiretroviral therapy among patients receiving delavirdine with or without a protease inhibitor (PI). In patients receiving nucleoside reverse transcriptase inhibitors (NRTI) plus delavirdine, there was a statistically significant increase in cholesterol and HDL levels, whereas those receiving NRTI plus a PI had no significant change in their HDL levels. When delavirdine was combined with a PI, there was a more dramatic increase in both cholesterol and HDL concentrations.|Rash is the most frequently reported adverse effect of delavirdine. In 2 clinical studies..., rash was reported in 32-35% of adults who received the usual dosage of delavirdine in conjunction with nucleoside reverse transcriptase inhibitors compared with 16-21% of adults who received the nucleoside reverse transcriptase inhibitors alone. In these studies, grade 1 rash (erythema, pruritus), grade 2 rash (diffuse maculopapular rash, dry desquamation), or grade 3 rash (vesiculation, moist desquamation, ulceration) occurred in about 17, 14, and 4%, respectively, of patients receiving delavirdine in conjunction with nucleoside reverse transcriptase inhibitors compared with 12, 6, and 0%, respectively, of patients receiving the nucleoside reverse transcriptase inhibitors alone.There were no cases of grade 4 rash (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis requiring surgery, exfoliative dermatitis) in either patient group. About 3-4% of patients receiving delavirdine in conjunction with nucleoside reverse transcriptase inhibitors discontinued treatment because of rash compared with 0-1% of patients who received the nucleoside reverse transcriptase inhibitors alone.|Delavirdine-associated rash occurs mainly on the upper body and proximal arms with decreasing intensity of the lesions on the neck and face and progressively less on the rest of the trunk and limbs. Rash usually is evident within the first few weeks following initiation of delavirdine therapy; occurrence of rash after 1 month of therapy is uncommon. Because there is no evidence that the incidence of rash is decreased by initiating delavirdine therapy using a low dose and then titrating dosage, dosage titration is not recommended.|Severe and life-threatening skin reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported rarely in patients receiving delavirdine; 2 cases of Stevens-Johnson syndrome were reported during postmarketing surveillance. These severe reactions resolved after the drug was discontinued..|For more Drug Warnings (Complete) data for DELAVIRDINE MESYLATE (26 total), please visit the HSDB record page.

As with other nonnucleoside reverse transcriptase inhibitors, high-level resistance to delavirdine can emerge rapidly. In vitro passage of HIV-1 in the presence of delavirdine selects for a mutation at reverse transcriptase codon 236, which does not confer cross-resistance to other compounds in this class. However, in vivo resistance rarely is associated with the 236 mutation. Most clinically derived resistant strains have mutations at reverse transcriptase codons 181 and/or 103. Resistance also has been associated with mutations at codons 100, 101, 106, and 188. There is evidence that resistance to delavirdine may restore zidovudine susceptibility to zidovudine-resistant HIV.

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)|Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)

Elimination: Fecal: 44% following multiple doses of 330 mg three times a day in healthy volunteers. Renal: 51%, following multiple doses of 330 mg three times a day in healthy volunteers. Less than 5% of the dose is recovered unchanged in urine.|Delavirdine is distributed predominantly into blood plasma.|Delavirdine is well absorbed, especially at pH less than 2.0.|Delavirdine mesylate is rapidly absorbed following oral administration, and peak plasma concentrations of the drug are attained approximately 1 hour after the dose. Following oral administration of 400 mg of delavirdine mesylate 3 times daily in HIV-infected adults, mean steady-state peak plasma concentrations of the drug are 15.98 ug/ml (range: 0.91-45.66 ug/ml), mean trough plasma concentrations are 6.85 ug/ml (range: 0.05-20.55 ug/ml), and mean AUC is 82.19 ughour/ml.|For more Absorption, Distribution and Excretion (Complete) data for DELAVIRDINE MESYLATE (8 total), please visit the HSDB record page.

Delavirdine binds extensively to plasma proteins and primarily is metabolized by CYP3A4. The major metabolic pathway results in N-dealkylation. There is considerable intersubject variability in plasma delavirdine concentrations related to differences in CYP3A activity. The CSF-to-plasma ratio is 0.02.|The metabolism of delavirdine in the mouse was extensive and involved amide bond cleavage, N-desalkylation, hydroxylation at the C-6' position of the pyridine ring, and pyridine ring-cleavage as determined by MS and/or 1H and 13C NMR spectroscopies. N-desalkylation and amide bond cleavage were the primary metabolic pathways at low drug doses and, as the biotransformation of delavirdine to desalkyl delavirdine reached saturation or inhibition, amide bond cleavage became the predominant pathway at higher doses and after multiple doses.

The apparent plasma half-life of delavirdine increases with dose. The mean plasma half-life of delavirdine is 5.8 hours (range: 2-11 hours) in adults receiving a dosage of 400 mg 3 times daily.|Elimination from plasma: Mean, 5.8 hours (range, 2 to 11 hours) following treatment with 400 mg three times a day. The apparent half-life increases with dose.

After entering the cell, delavirdine binds to a hydrophobic pocket in the p66 subunit of reverse transcriptase. This causes a conformational change to a stable, inactive form of the enzyme. The delavirdine-reverse transcriptase complex is stabilized by hydrogen bonds at residue Lys-103 and strong hydrophobic interactions with residue Pro-236. Much higher concentrations of delavirdine are required to inhibit cellular polymerase than reverse transcriptase.|While the complete mechanism of antiviral activity of delavirdine has not been fully elucidated, the drug inhibits replication of human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. HIV reverse transcriptase is essential for viral replication, and its activities occur in the host cell cytoplasm after the viral particle penetrates the cell membrane and releases the viral core, but before nuclear entry and chromosomal integration of proviral DNA. The enzyme is multifunctional, with 3 principal activities (ie., RNA-directed DNA polymerase, RNase H, and DNA-directed DNA polymerase functions). Using viral RNA as a template, reverse transcriptase forms a minus strand of viral DNA, creating a double-stranded RNA:DNA hybrid (i.e., RNA-directed DNA polymerase function). The RNase H function of reverse transcriptase facilitates copying of viral RNA by degrading the RNA component of the RNA:DNA hybrid after the RNA is copied, leaving a single minus strand of viral DNA. Using the newly formed minus strand of viral DNA as a template, reverse transcriptase forms the plus strand of viral DNA, converting single-stranded viral DNA to the double-stranded proviral DNA form (i.e, DNA-directed DNA polymerase function). BHAP derivatives, including delavirdine, inhibit the polymerase functions, but not the RNase H function, of reverse transcriptase. The drugs bind directly to heterodimeric HIV-1 reverse transcriptase and exert a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.|Nonnucleoside reverse transcriptase inhibitors affect reverse transcriptase at a different site than nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), and the drugs have different mechanisms of action. Unlike currently available nonnucleoside reverse transcriptase inhibitors, dideoxynucleoside antiretroviral agents require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5 to 3 phosphodiester linkages.

Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Treatment of overdose: To decrease absorption: Patients may benefit from treatment with activated charcoal. Monitoring: Patient's vital signs should be monitored. Supportive care: Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.|Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. There are no specific antidotes for these agents. Administer activated charcoal.

/HUMAN EXPOSURE STUDIES/ Concurrent administration of amphetamines, astemizole, benzodiazepines, calcium channel blocking agents, cisapride, ergot derivatives, or terfenadine with delavirdine may result in potentially serious and/or life-threatening adverse events as a result of the inhibitory effect of delavirdine on CYP isoenzymes 3A and 2C9; it is recommended that dosage adjustments be made for these medications, or that alternative medications be used, while patients are taking delavirdine.|/HUMAN EXPOSURE STUDIES/ Severe and life-threatening skin reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported rarely in patients receiving delavirdine; 2 cases of Stevens-Johnson syndrome were reported during postmarketing surveillance. These severe reactions resolved after the drug was discontinued..|/HUMAN EXPOSURE STUDIES/ Substantially increased (>5 times the upper limit of normal) serum concentrations of ALT (SGPT), AST (SGOT), or Gamma-glutamyltransferase (GGT, Gamma-glutamyl transpeptidase, GGPT) occurred in 4.1-5.1, 2.3-3.4, or 1.8%, respectively, of patients receiving delavirdine in conjunction with nucleoside reverse transcriptase inhibitors in clinical studies...; these adverse effects were reported in 1.6-4.1% of patients receiving nucleoside reverse transcriptase inhibitors alone. Additionally, increases in serum amylase (>2 times the upper limit of normal) and bilirubin (>2.5 times the upper limit of normal) occurred in 2.5-2.9 and 1.7-2.5%, respectively. Other adverse hepatic effects reported in <5% of patients receiving delavirdine in conjunction with nucleoside reverse transcriptase inhibitors in studies... include increased serum lipase and increased serum alkaline phosphatase. Hepatic failure has been reported during postmarketing surveillance.|/SIGNS AND SYMPTOMS/ Adverse GI effects reported in <5% of patients receiving delavirdine in conjunction with nucleoside reverse transcriptase inhibitors in clinical studies... include abdominal cramps, abdominal distention, abdominal pain (localized), anorexia, bloody stool, colitis, constipation, decreased appetite, diarrhea (Clostridium difficile), diverticulitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, fecal incontinence, flatulence, gagging, gastritis, gastroesophageal reflux, GI bleeding, GI disorder, gingivitis, gum hemorrhage, hepatomegaly, increased appetite, increased saliva, increased thirst, jaundice, mouth inflammation or ulcer, nonspecific hepatitis, oral or enteric moniliasis, pancreatitis, rectal disorder, sialadenitis, stomatitis, taste perversion, tongue edema or ulceration, tooth abscess, and toothache.|For more Human Toxicity Excerpts (Complete) data for DELAVIRDINE MESYLATE (6 total), please visit the HSDB record page.

Delavirdine

Oral: Tablets: 100 mg, Rescriptor, Agouron, 200 mg, Rescriptor, Agouron

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients