Amprenavir

505.63

505.63

1806241-263-5

5S0W860XNR

DTXSID5046061

C28824

J05AE05|J - Antiinfectives for systemic use

29350090

140

2.2 @ 25 deg C /Estimated/

white to beige

1.30±0.1 g/cm3(Predicted)

72-74°C

722.5±70.0 °C at 760 mmHg

390.8±35.7 °C

1.602

DMSO: soluble20mg/mL, clear

-20°C Freezer

9.9X10-18 mm Hg @ 25 deg C /Estimated/

Henry's Law constant = 1.6X10-23 atm-cu m/mol @ 25 °C /Estimated/

Hydroxyl radical reaction rate constant = 1.1X10-10 cu cm/molec sec @ 25 °C /Estimated/

3077

3

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 amprenavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H351 (100%): Suspected of causing cancer [Warning Carcinogenicity]|P201, P202, P273, P281, P308+P313, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking amprenavir or fosamprenavir containing antiretroviral regimens. In large, multicenter trials of fosamprenavir based antiretroviral therapy, moderate-to-severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) were found in 3% to 10% of patients. Rates of enzyme elevations are higher in patients with HIV-HCV coinfection then in those with monoinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Furthermore, similar rates of enzyme elevations were found in comparator arms (using other HIV protease inhibitors).

Because amprenavir oral solution contains a large amount of propylene glycol, concurrent use /with alcohol, disulfiram, or metronidazole/ is not recommended.|Although these medications /alprazolam, clorazepate, diazepam, or flurazepam/ have not been specifically studied with amprenavir, amprenavir may increase the serum concentrations of these medications.|Although these medications /amiodarone, lidocaine (systemic), tricyclic antidepressants, or quinidine/ have not been specifically studied with amprenavir, amprenavir may interfere in the metabolism of these medications and cause serious or life threatening adverse events; monitoring of serum concentrations for these medications is recommended if amprenavir is used concurrently.|Although antacids have not been specifically studied with amprenavir, based on data from other protease inhibitors, antacids (and didanosine due to the antacid content present in didanosine formulations) may interfere with the absorption of amprenavir; it is recommended that antacid and didanosine administration be separated from amprenavir administration by at least one hour.|For more Interactions (Complete) data for AMPRENAVIR (21 total), please visit the HSDB record page.

The usually recommended dosage of amprenavir oral solution (22.5 mg/kg twice daily) provides a propylene glycol intake of 1650 mg/kg daily; however, an acceptable intake of propylene glycol used as an excipient in pharmaceuticals has not been established to date. Propylene glycol is metabolized in the liver by the alcohol and aldehyde dehydrogenase enzyme pathway, and the possibility exists that young infants, patients with renal or hepatic impairment, and certain patient groups (females, Asians, Native Alaskans, Native Americans) may be at increased risk of propylene glycol-associated adverse effects if they receive amprenavir oral solution because of diminished ability to metabolize propylene glycol /SRP: due to alcohol dehydrogenase polymorphism/.

Very high (90%). Amprenavir has the highest affinity for alpha(1)-acid glycoprotein.

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

For the treatment of HIV-1 infection in combination with other antiretroviral agents.|FDA Label|Agenerase, in combination with other antiretroviral agents, is indicated for the treatment of protease inhibitor (PI) experienced HIV-1 infected adults and children above the age of 4 years. Agenerase capsules should normally be administered with low dose ritonavir as a pharmacokinetic enhancer of amprenavir (see sections 4.2 and 4.5). The choice of amprenavir should be based on individual viral resistance testing and treatment history of patients (see section 5.1).The benefit of Agenerase boosted with ritonavir has not been demonstrated in PI nave patients (see section 5.1)

Amprenavir is an antiretroviral protease inhibitor used in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Fosamprenavir is a prodrug of amprenavir that has better oral bioavailability and that has largely replaced amprenavir in clinical use. Both amprenavir and fosamprenavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and are rare causes of clinically apparent, acute liver injury. In coinfected patients, hepatic injury during highly active antiretroviral therapy may be a result of exacerbation of the underlying chronic hepatitis B or C rather than a direct toxic effect of the medication.

Antiviral Agents

Amprenavir is indicated in combination with other antiretroviral agents in the treatment of HIV-1 infection. /Included in US product labeling/|Amprenavir is a human immunodeficiency virus (HIV)-protease inhibitor. The use of amprenavir for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretrovirals is based on analyses of plasma HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks duration. Results from controlled trials evaluating the long-term suppression of HIV-RNA or disease progression with amprenavir have not yet been obtained.|Amprenavir is a viral protease inhibitor with specificity for the HIV protease enzyme. The resistance profile of amprenavir appears to differ from that of other protease inhibitors such as saquinavir and indinavir. Twelve hours after single-dose administration of amprenavir 1200 mg to HIV-infected individuals, the mean plasma concentration of the drug was more than 10-fold greater than the 50% inhibitory concentration for HIV-1IIIB in peripheral blood lymphocytes. In a small nonblind study, amprenavir monotherapy increased CD4+ cell count and decreased viral load in 37 patients with HIV infection and no previous exposure to protease inhibitor therapy. Combination therapy comprising amprenavir and other antiretroviral agents (abacavir, zidovudine, lamivudine, indinavir, saquinavir or nelfinavir) decreased viral load and increased CD4+ cell counts in patients with HIV infection. Antiviral efficacy was maintained during up to 24 weeks' follow-up.

The usually recommended dosage of amprenavir oral solution (22.5 mg/kg twice daily) provides a propylene glycol intake of 1650 mg/kg daily; however, an acceptable intake of propylene glycol used as an excipient in pharmaceuticals has not been established to date. Propylene glycol is metabolized in the liver by the alcohol and aldehyde dehydrogenase enzyme pathway, and the possibility exists that young infants, patients with renal or hepatic impairment, and certain patient groups (females, Asians, Native Alaskans, Native Americans) may be at increased risk of propylene glycol-associated adverse effects if they receive amprenavir oral solution because of diminished ability to metabolize propylene glycol. Therefore, amprenavir oral solution is contraindicated during pregnancy; in infants younger than 4 years of age; in patients with renal or hepatic failure; and in patients receiving disulfiram or metronidazole. In addition, although metabolism of propylene glycol has not been specifically studied in these patient groups, the possibility that females may have lower concentrations of alcohol dehydrogenase compared with males and that certain ethnic populations (Asians, Native Alaskans, Native Americans) may have alcohol dehydrogenase polymorphism should be considered.|Because amprenavir oral solution contains large amounts of propylene glycol and because young infants may be at increased risk of propylene glycol-associated adverse effects, the oral solution is contraindicated in pediatric patients younger than 4 years of age. Propylene glycol is metabolized in the liver by the alcohol and aldehyde dehydrogenase enzyme pathway. Although alcohol dehydrogenase is present in human fetal liver at 2 months of gestational age, this represent only about 3% of the activity reported in adults. Limited data indicate that alcohol dehydrogenase activity in infants 12-30 months of age is equal to or greater than that reported in adults. Oral or IV administration of various drugs (e.g., multivitamins) containing high concentrations of propylene glycol in pediatric patients has resulted in various propylene glycol-associated adverse effects, including hyperosmolality, lactic acidosis, respiratory depression, and seizures.|Patients being treated with amprenavir oral solution should be closely monitored for propylene glycol associated side effects including hemolysis, hyperosmolality, lactic acidosis, renal toxicity, seizures, stupor, and tachycardia.|The pharmacokinetics of amprenavir do not differ between females and males or between Blacks and non-Blacks. However, amprenavir oral solution contains a large amount of propylene glycol and because Asians, Eskimos, Native Americans, and women have a decreased ability to metabolize this compound, they may have an increased risk of developing propylene glycol-associated side effects.|For more Drug Warnings (Complete) data for AMPRENAVIR (18 total), please visit the HSDB record page.

Amprenavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Amprenavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

Substances obtained from various species of microorganisms that are, alone or in combination with other agents, of use in treating various forms of tuberculosis; most of these agents are merely bacteriostatic, induce resistance in the organisms, and may be toxic. (See all compounds classified as Antibiotics, Antitubercular.)|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 HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly. (See all compounds classified as HIV Protease Inhibitors.)

Rapidly absorbed after oral administration in HIV-1-infected patients with a time to peak concentration (T_max) typically between 1 and 2 hours after a single oral dose. The absolute oral bioavailability of amprenavir in humans has not been established.|Amprenavir is absorbed rapidly after oral administration. Taking amprenavir with a standard meal reduces the plasma AUC by only about 13%, but high-fat meals may have greater effects and should be avoided.|Only minimal amounts of amprenavir are eliminated unchanged in urine or feces; less than 3% of a dose is eliminated unchanged in urine. Following a single oral dose of radiolabeled amprenavir, approximately 14% of the dose is eliminated in urine and 75% is eliminated in feces; 2 metabolites account for more than 90% of radioactivity in feces.|Distribution of amprenavir into body tissues and fluids has not been fully characterized. Studies in rats indicate that amprenavir is distributed to a variety of tissues following oral administration. The apparent volume of distribution of amprenavir in healthy adults is approximately 430 L.|It is not known whether amprenavir crosses the human placenta; however, the drug crosses the placenta in rats. Information from an ex vivo human placental model for transplacental passage indicates that amprenavir crosses the human placenta. Although it is not known whether amprenavir is distributed in human milk, the drug is distributed into milk in rats.|In patients with hepatic impairment, the peak plasma concentration and AUC of amprenavir may be increased. In adults with moderate cirrhosis who received a single 600-mg oral dose of amprenavir given as liquid-filled capsules, the AUC (0-4 hours) of the drug averaged 25.76 ug hour/mL compared with 12 ug hour/ml in healthy adults. In adults with severe cirrhosis who received the same dose, peak plasma concentrations averaged 9.43 ug/ml and the AUC (0-4 hours) averaged 38.66 ug hour/ml compared with 4.9 ug/ml or 12 ug hour/ml, respectively, in healthy adults.

Hepatic. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system. The 2 major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.|The metabolic fate of amprenavir has not been fully determined, but the drug is metabolized in the liver. Amprenavir is metabolized principally by the cytochrome P450 (CYP) isoenzyme 3A4. The 2 major metabolites of the drug result from oxidation of the tetrahydrofuran and aniline moieties; glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces.

7.1-10.6 hours|The plasma elimination half-life of amprenavir in HIV-infected adults with normal renal and hepatic function ranges from 7.1-10.6 hours.

Amprenavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.|Amprenavir acts by reversibly binding to the active site of HIV protease. This prevents polypeptide processing and subsequent viral maturation.|Although the complete mechanism(s) of antiviral activity of amprenavir has not been fully elucidated, amprenavir apparently inhibits replication of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) by interfering with HIV protease. The drug, therefore, exerts a virustatic effect against retroviruses by acting as an HIV protease inhibitor.|Amprenavir is a selective, competitive, reversible inhibitor of HIV protease. HIV protease, an aspartic endopeptidase that functions as a homodimer, plays an essential role in the HIV replication cycle and the formation of infectious virus. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes (i.e., p55 and p160) to form structural proteins of the virion core (i.e., p17, p24, p9, and p7) and essential viral enzymes (i.e., reverse transcriptase, integrase, protease). By interfering with the formation of these essential proteins and enzymes, amprenavir blocks maturation of the virus and causes the formation of nonfunctional, immature, noninfectious virions. Amprenavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly. Thus, the drug is active in a subset of chronically infected cells (e.g., monocytes, macrophages) that generally are not affected by nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Amprenavir does not affect early stages of the HIV replication cycle; however, the drug interferes with the production of infectious HIV and limits further infectious spread of the virus.|Unlike nucleoside reverse transcriptase inhibitors, the antiretroviral activity of amprenavir does not depend on intracellular conversion to an active metabolite. Amprenavir and other HIV protease inhibitors (e.g., indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) act at a different stage of the HIV replication cycle than other currently available antiretroviral agents, including nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors.|Amprenavir is a highly specific inhibitor of HIV protease. Amprenavir has low affinity for human aspartic endopeptidases such as pepsin, renin, gastricin, cathepsin D, and cathepsin E. Results of in vitro studies using MT-4 cells indicate that amprenavir is not cytotoxic at concentrations up to 100 um.

There is no known specific antidote for amprenavir overdose. It has not been determined whether amprenavir can be removed from the circulation by peritoneal dialysis or hemodialysis. Amprenavir oral solution contains large amounts of propylene glycol, and propylene glycol can be removed by hemodialysis. Monitoring: Amprenavir capsules: Patients should be monitored for signs of toxicity. Amprenavir oral solution: Because of the propylene glycol content, patients should be additionally monitored for signs and symptoms of acid-base abnormalities, with appropriate management. Supportive care: Standard supportive treatment should be provided as necessary. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.|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/ Although these medications /amiodarone, lidocaine (systemic), tricyclic antidepressants, or quinidine/ have not been specifically studied with amprenavir, amprenavir may interfere in the metabolism of these medications and cause serious or life threatening adverse events; monitoring of serum concentrations for these medications is recommended if amprenavir is used concurrently.|/HUMAN EXPOSURE STUDIES/ Although these medications /astemizole, bepridil, cisapride, dihydroergotamine, ergotamine, midazolam, or triazolam/ have not been specifically studied with amprenavir, amprenavir may interfere in the metabolism of these medications and cause serious or life threatening adverse events; concurrent use is not recommended.

(3S-(3R*(1R*,2S*)))-(3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1-(phenylmethyl)propyl) tetrahydro-3-furanyl carbamate

Oral: Capsules, liquid-filled, 50 mg, Agenerase (with propylene glycol 19 mg and vitamin E 36 units), GlaxoSmithKline; 150 mg, Agenerase (with propylene glycol and vitamin E 109 units), GlaxoSmithKline.Solution: 15 mg/ml, Agenerase (with propylene glycol 550 mg/ml, and vitamin E 46 units/ml), GlaxoSmithKline

Human drugs -> Agenerase -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients