Fosamprenavir

585.6 g/mol

585.61

607-123-4

WOU1621EEG

DTXSID2048296

C83720

J05AE07|J - Antiinfectives for systemic use

186 Ų

log Kow = 2.2 (est)

White to cream colored solid. Solubility in water is approximately 0.31 mg/mL at 25 °C /Calcium salt/|In water, 2.8 mg/L at 25 °C (est)|6.85e-01 g/L

Store at 25 °C (77 °F), excursions permitted to 15 to 30deg C (59 to 86 °F ).

6.1X10-11 mm Hg at 25 °C (est)

Henry's Law constant = 1.4X10-29 atm-cu m/mole at 25 °C (est)

pKa = 1.7 (est)

Hydroxyl radical reaction rate constant = 1.6X10-10 cu cm/molec-sec at 25 °C (est)

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 fosamprenavir calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fosamprenavir Calcium/

Chapman TM et al; Fosamprenavir: A Review of its Use in the Management of Antiretroviral Therapy-Naive Patients with HIV Infection; Drugs 64 (18): 2101-24 (2004)

|Warning|H315 (33.33%): Causes skin irritation [Warning Skin corrosion/irritation]|P201, P202, P260, P263, P264, P270, P280, P281, P302+P352, P308+P313, P314, P321, P332+P313, P362, P405, and P501|Aggregated GHS information provided by 3 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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).

Amprenavir inhibits and induces cytochrome P-450 (CYP) isoenzyme 3A4; potential pharmacokinetic interactions (altered metabolism of the other drug). Caution is advised if fosamprenavir is used concomitantly with substrates, inhibitors, or inducers of CYP3A4. Concomitant use with drugs with a narrow therapeutic index that are CYP3A4 substrates is not recommended. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, or CYP2E1.|Pharmacokinetic interaction with antacids (decreased amprenavir peak concentrations and AUC). ... This pharmacokinetic interaction is not clinically important and there are no restrictions for concomitant use of fosamprenavir and antacids.|Pharmacokinetic interaction following concomitant use of ritonavir-boosted fosamprenavir with flecainide or propafenone (increased plasma concentrations of the antiarrhythmic agent). Potential for serious and/or life-threatening adverse effects (eg, cardiac arrhythmias). Concomitant use of ritonavir-boosted fosamprenavir with flecainide or propafenone is contraindicated.|Pharmacokinetic interaction with amiodarone, bepridil (no longer commercially available in US), systemic lidocaine, or quinidine (increased concentrations of the antiarrhythmic). Potential for serious and/or life-threatening adverse effects. Use concomitantly with caution and, if possible, monitor plasma concentrations of the antiarrhythmic agents.|For more Interactions (Complete) data for FOSAMPRENAVIR (37 total), please visit the HSDB record page.

Spontaneous bleeding has been reported in patients with hemophilia A or B receiving HIV protease inhibitors; use caution in such patients. Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.

Very high (approximately 90%); primarily bound to alpha 1 -acid glycoprotein. Higher amounts of unbound amprenavir present as amprenavir serum concentrations increase.

Fosamprenavir's production and use as the free acid of fosamprenavir calcium which is used in the treatment of AIDS(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,400(SRC), determined from a structure estimation method(2), indicates that fosamprenavir is expected to have low mobility in soil(SRC). The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7 (3), indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from moist soil surfaces. Fosamprenavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-11 mm Hg(SRC), determined from a fragment constant method(4). No biodegradation data were available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,400(SRC), determined from a structure estimation method(2), indicates that fosamprenavir is expected to adsorb to suspended solids and sediment(SRC). The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7(3), indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from water surfaces and generally do not adsorb as strongly to organic carbon and clay than their neutral counterparts(4). According to a classification scheme(5), an estimated BCF of 9.4(SRC), from an estimated log Kow of 2.2(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(8). No biodegradation data were available(SRC, 2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fosamprenavir, which has an estimated vapor pressure of 6.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase fosamprenavir may be removed from the air by wet and dry deposition(SRC). Fosamprenavir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(1). Fosamprenavir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 9.4 was calculated for fosamprenavir(SRC), using an estimated log Kow of 2.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for fosamprenavir can be estimated to be 1,400(SRC). According to a classification scheme(2), this estimated Koc value suggests that fosamprenavir is expected to have low mobility in soil. The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7(3), indicating that this compound will primarily be an anion under environmental conditions and anions generally do not adsorb as strongly to organic carbon and clay as their neutral counterparts(4).

The pKa of the phosphoric acid moiety of fosamprenavir is estimated to be 1.7(1), indicating that this compound will primarily be an anion under environmental conditions and anions do not volatilize from water or moist soil surfaces. Fosamprenavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-11 mm Hg(SRC), determined from a fragment constant method(2).

Occupational exposure to fosamprenavir may occur through dermal contact with this compound at workplaces where fosamprenavir is produced or used. Exposure to the drug among the general population may be limited to those administered the Lexiva (an HIV drug) which contains fosamprenavir calcium as its active component. (SRC)

Indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission. The use of fosamprenavir is pending revision due to a potential association between the drug and myocardial infarction and dyslipidemia in HIV infected adults.|FDA Label|Telzir in combination with low-dose ritonavir is indicated for the treatment of human-immunodeficiency-virus-type-1-infected adults, adolescents and children of six years and above in combination with other antiretroviral medicinal products.In moderately antiretroviral-experienced adults, Telzir in combination with low-dose ritonavir has not been shown to be as effective as lopinavir / ritonavir. No comparative studies have been undertaken in children or adolescents.In heavily pretreated patients, the use of Telzir in combination with low-dose ritonavir has not been sufficiently studied.In protease-inhibitor-experienced patients, the choice of Telzir should be based on individual viral resistance testing and treatment history.

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

Fosamprenavir is indicated in combination with other antiretroviral agents for the treatment of HIV infections in adults. /Included in US product labeling/

Rash (usually maculopapular and of mild or moderate intensity, with or without pruritus) has been reported in about 19% of patients receiving fosamprenavir in clinical studies; manifestations occurred approximately 11 days after initiation of fosamprenavir and persisted for a median of 13 days. Severe or life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of patients receiving fosamprenavir in clinical studies.|Fosamprenavir contains a sulfonamide moiety, which may cause allergic-type reactions (e.g., rash) in certain susceptible individuals. The potential for cross-sensitivity between drugs with sulfonamide moieties and fosamprenavir is unknown. Use fosamprenavir with caution in patients with known hypersensitivity to sulfonamide-containing drugs.|Patients with chronic hepatitis B or C virus infection and those with marked increases in AST or ALT concentrations prior to fosamprenavir therapy may be at increased risk for further elevations in hepatic enzyme concentrations. Liver function tests should be performed prior to initiating therapy with fosamprenavir, and patients should be monitored closely during treatment. ... Increases in serum AST (SGOT) and/or ALT (SGPT) concentrations (more than 5 times the upper limit of normal) have been reported in approximately 4-8% of patients receiving fosamprenavir in clinical studies.|Possible amprenavir resistance. The possible effect of fosamprenavir therapy on subsequent therapy with other HIV protease inhibitors in unknown.|For more Drug Warnings (Complete) data for FOSAMPRENAVIR (14 total), please visit the HSDB record page.

HIV-1 isolates with a decreased susceptibility to amprenavir have been selected in vitro and obtained from patients treated with fosamprenavir. Genotypic analysis of isolates from amprenavir-treated patients showed mutations in the HIV-1 protease gene resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as mutations in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites.

Fosamprenavir is hydrolyzed by cellular phosphatases to the antiretroviral protease inhibitor amprenavir. This hydrolysis allows for the slow release of amprenavir, reducing the number of pills a patient must take.

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.)

The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established. After administration of a single 1,400 mg dose in the fasted state, fosamprenavir oral suspension (50 mg/mL) and fosamprenavir tablets (700 mg) provided similar amprenavir exposures (AUC), however, the C_max of amprenavir after administration of the suspension formulation was 14.5 % higher compared with the tablet.|Excretion of unchanged amprenavir in urine and feces is minimal. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir. Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system.|Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by enzymes in the gut epithelium as it is absorbed. After administration of a single dose of fosamprenavir to HIV-1-infected patients, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and 4 hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established.|Administration of a single 1400 mg dose of fosamprenavir in the fed state compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax or AUC.|The following are areas under the curve (AUC) values of amprenavir based on the drug therapy regimen administered: Fosamprenavir 1400 mg twice per day: 27.6 to 39.2 ug/hr/mL (median 33 ug/hr/mL; Fosamprenavir 1400 mg once per day plus ritonavir 200 mg once per day: 59.7 to 80.8 ug/hr/mL (median 69.4 ug/hr/mL);Fosamprenavir 700 mg twice per day plus ritonavir 100 mg twice per day: 69 to 90.6 ug/hr/mL (median 79.2 ug/hr/mL). Fosamprenavir may be taken with or without food.|Peak plasma concentration (Cmax): The following Cmax values of amprenavir based on the drug therapy regimen administered: Fosamprenavir 1400 mg once per day plus ritonavir 200 mg once per day: 6.32 to 8.28 ug/mL (median 7.24 ug/mL); Fosamprenavir 1400 mg twice per day: 4.06 to 5.72 ug/mL (median 4.82 ug/mL); Fosamprenavir 700 mg twice per day plus ritonavir 100 mg twice per day: 5.38 to 6.86 ug/mL (median 6.08 ug/mL)...|For more Absorption, Distribution and Excretion (Complete) data for FOSAMPRENAVIR (10 total), please visit the HSDB record page.

In the gut epithelium during absorption, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system.|After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the cytochrome P450 and 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 plasma elimination half-life of amprenavir (the active metabolite) is approximately 7.7 hours.|The plasma elimination half-life of amprenavir is approximately 7.7 hours.

Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. During HIV replication, HIV protease cleaves viral polypeptide products of the Gag and Gag-Pol genes to form structural proteins of the virion core and essential viral enzymes. Amprenavir interferes with this process by binding to the active site of HIV-1 protease, thereby preventing the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.|Fosamprenavir is a prodrug of amprenavir, an inhibitor of HIV protease. ...Fosamprenavir is rapidly converted to amprenavir by cellular phosphatases in vivo. Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature noninfectious viral particles.

There is no known antidote for /fosamprenavir/. It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary.|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/

/SIGNS AND SYMPTOMS/ ... Severe or life-threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of patients receiving fosamprenavir in clinical studies.

(3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-1-(phenylmethyl)-2-(phosphonooxy)propyl)carbamic acid C-(tetrahydro-3-furanyl) ester

Oral: Tablets, film-coated: 700 mg (of fosamprenavir) Lexiva, (GlaxoSmithKline). /Fosamprenavir calcium/

While data specific to fosamprenavir were not available(SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).

Human drugs -> Telzir -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group