Capsules amprenavir

Amprenavir is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name of amprenavir is (3 S)-tetrahydro-3-furyl N-[(1 S,2 R)-3-(4-amino-N-isobu-tylbenzenesulfonamido)-1 -benzyl-2-hydroxypropyl]car-bamate. Amprenavir is a single stereoisomer with the (3 

S)(l S,2 R) configuration. It has a molecular formula of C 25 H 35 N 3 6 S. The capsules are available for oral administration in strengths of 50 and 150 mg. Each 50-mg capsule contains the inactive ingredients D-alpha toco-pheryl polyethylene glycol 1000 succinate (TPGS), poly- 

00 2 D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) 400.00 

Charge item 2 in a suitable stainless steel-jacketed vessel and heat to 50°C until liquefied. 

Add item 4 and balance of item 2, cool to room temperature, apply vacuum to remove air entrapped. 

---

Use amprenavir oral solution only when amprenavir capsules or other protease inhibitor formulations are not therapeutic options. 

Amprenavir may be taken with or without food however, a high-fat meal decreases the absorption of amprenavir and should be avoided. Advise adult and pediatric patients not to take supplemental vitamin E since the vitamin E content of amprenavir capsules and oral solution exceeds the Reference Daily Intake (adults, 30 units pediatrics, approximately 10 units). 

Amprenavir capsules and oral solution are not interchangeable on a mg per mg basis. 

Adults The recommended oral dose of amprenavir capsules for adults is 1200 mg (eight 150 mg capsules) twice daily in combination with other antiretroviral agents. 

Capsules - Use with caution in patients with moderate or severe hepatic impairment. Patients with Child-Pugh scores ranging from 5 to 8 should receive a reduced dose of amprenavir capsules of 450 mg twice daily, and patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of amprenavir capsules of 300 mg twice daily. 

Oral solution Because of the possible toxicity associated with the large amount of propylene glycol and the lack of information on chronic exposure to large amounts of propylene glycol, use amprenavir oral solution only when amprenavir capsules or P.1078... 

Children Two hundred fifty-one patients 4 years of age and above have received amprenavir as single or multiple doses in studies. An adverse event profile similar to that seen in adults was seen in pediatric patients. The safety, efficacy, and pharmacokinetics of amprenavir capsules have not been evaluated in pediatric patients below 4 years of age. 

Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. Fosamprenavir is most often administered in combination with low-dose ritonavir. 

In attempts to lower the amprenavir capsule burden, low-dose ritonavir has been used as a pharmacokinetic booster. When ritonavir was added to amprenavir, the amprenavir AUC increased 3-4 times (13), which should allow the total daily capsule burden to be reduced. Adverse effects included diarrhea, nausea, paresthesia, rash, increased cholesterol, and increased triglycerides. The frequency of adverse events correlated with the dose of ritonavir. 

Capsules If amprenavir and ritonavir are used in combination, the recommended dosage regimens are the following amprenavir 1,200 mg with ritonavir 200 mg once daily or amprenavir 600 mg with ritonavir 100 mg twice daily. 

Amprenavir oral solution was 14% less bioavailable compared to the capsules. 

Pregnancy Category C. Amprenavir oral solution is contraindicated during pregnancy because of the potential risk of toxicity to the fetus from the high propylene glycol content. Therefore, if amprenavir is used in pregnant women, use the capsule formulation. 

If patients require treatment with amprenavir oral solution, monitor them closely for propylene glycol-associated adverse reactions, including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Switch patients from amprenavir oral solution to capsules as soon as they are able to take the capsule formulation. 

Concomitant therapy with efavirenz, nevirapine, fosamprenavir, or nelfinavir-Consider a dose increase to 533/133 mg lopinavir/ritonavir (4 capsules or 6.5 mL) twice daily taken with food when used in combination with efavirenz, nevirapine, amprenavir, or nelfinavir, or 600/150 mg (3 tablets) twice daily with or without food when used in combination with efavirenz, nevirapine, fosamprenavir without ritonavir, or nelfinavir in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). 

In 1995 the FDA approved saquinavir, the first protease inhibitor, for use in combination with other nucleoside analogue medications. In 1999 a soft gel capsule formulation of saquinavir with considerably improved absorption characteristics was developed. Ritonavir and indinavir have been approved for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Nelfinavir is the first protease inhibitor labeled for use in children. Amprenavir is the newest of the protease inhibitors. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because the fat content may decrease the absorption of the drug. The most disturbing adverse reactions to protease inhibitors consist of the lipodystrophy syndrome with severe hyperlipidemia and unpredictable fat redistributions over the body... 

Oral 100 mg capsules, tablets 50 mg/5 ml syrup Amprenavir (Agenerase)... 

Drug-specific toxicities ritonavir, gastrointestinal distress saquinavir, hard gel capsules indinavir, renal colic nelfinavir, diarrhea amprenavir, nausea and vomiting. Increased risk of poor adherence with long-term treatment, leading to resistance... 

Amprenavir [am PREN a veer] Like other protease inhibitors, amprenavir is used in combination with a least two nucleoside reverse transcriptase inhibitors. Its long plasma half-life permits twice daily dosing, but the large size and number of capsules per day (16) day may reduce patient compliance. The drug may be less well tolerated than some other protease inhibitors and it is unclear whether amprenavir offers any clinical advantages over other protease inhibitors. 

Protease inhibitors HfV protease is essential for virus infectivity because protease is needed for viral replication. Protease inhibitors bind reversibly to the active site of HfV protease preventing protease from cleaving the viral precursor polypeptide and blocking viral maturation. Immature viral particles are noninfectious. Amprenavir (APV) Agenerase 50 mg capsule 15 mg/ml solutions Itraconazole, fluconazole, ketoconazole, voriconazole,... 

The use of amprenavir has been hmited to patients who are highly motivated, because of the high capsule burden (16/day). 

Amprenavir is rapidly absorbed following oral administration and may be taken with or without food. High-fat meals decrease the absorption of the drug and, therefore, should be avoided. The product is available in capsule and liquid form. The recommended adult and adolescent dose of 1,200 mg twice... 

Food increases the bioavailability of atazanavir, darunavir, lopinavir/ritonavir soft capsules and solution, nelfinavir, saquinavir (all formulations) and tipranavir, but decreases that of indinavir. Food only minimally affects the bioavailability of amprenavir, fosamprenavir, lopinavir/ritonavir tablets and ritonavir. Mixing ritonavir with enteral feeds does not affect the pharmacokinetics of ritonavir. 

The steady-state AUC of amprenavir was reduced by 32% when amprenavir 750 or 800 mg three times daily was given with saquinavir (soft gel capsule) 800 mg three times daily, and the maximum plasma level was reduced by 37%. In this study, the pharmacokinetics of saquinavir were not changed when compared with historical control data. In a model-based pharmacokinetic analysis of data from a clinical study, amprenavir intrinsic clearance was not altered by saquinavir, which agrees with in vitro data. It was suggested that, as amprenavir was given with food , (p.818), in the first study, this may have accounted for the reduced amprenavir levels. ... 

---