2010/06/24

Agenerase

Composition, structure and packing

1 capsule Capsules. amprenavir 50 mg - 150 mg.

A solution for oral use 5 ml amprenavir 75 mg.

Excipients: propylene glycol, macrogol 400, D-α-tocopheryl polyethylene glycol 1000 succinate, potassium acesulfame, sodium saccharin, sodium chloride, artificial flavors grape, natural flavor peppermint, menthol, citric acid anhydrous, sodium citrate, dihydrate, purified water.

Clinico-pharmacological group: antiviral activity against HIV.

Pharmacological action

Nepeptidny competitive inhibitor of HIV protease. Blocks the ability of viral proteases to cleave precursor polyproteins necessary for viral replication. In vitro protease inhibitors may be more active in relation to HIV than known nucleoside analogues that inhibit the activity of reverse transcriptase of HIV. Amprenavir is a highly selective inhibitor of the replication of HIV-1 and HIV-2. In vitro synergy of amprenavira noted in its combination with nucleoside analogues (including didanosine, zidovudine, abacavir), and with the protease inhibitor saquinavir. In combination with indinavir, ritonavir and nelfinavir amprenavir has an additive effect.

In vitro were isolated strains of HIV resistant to amprenaviru. It is shown that it is necessary for at least 3 mutations in 46, 47 and 50 amino acid positions of HIV-protease to suppress the strain with more than 10-fold increase in IC50. The main mutation 150V, associated with resistance to amprenaviru, was not observed in vivo, as well as strains isolated from patients receiving protease inhibitor. Cross-resistance to other protease inhibitors have strains resistant to amprenaviru, raised slightly, which allows you to continue therapy protease inhibitors. Other mutations associated with resistance to amprenaviru (154V and 184V), rarely observed in the treatment of amprenavirom. In clinical practice profile of resistance to amprenaviru differs from the profile of resistance to another protease inhibitor. Resistant to amprenaviru strains in vitro are highly sensitive to indinavir, saquinavir and nelfinavir, and low sensitivity to ritonavir.

Of the 55 clinical strains with mutations that cause resistance to protease inhibitors in vivo, 55% were susceptible to amprenaviru. The development of cross-resistance between amprenavirom and reverse transcriptase inhibitors is unlikely because these drugs act on different enzymes of HIV. In clinical studies it was demonstrated that Ageneraza in combination with other antiretroviral drugs, including nucleoside analogues, non-nucleoside analogues and protease inhibitors, is effective treatment for HIV infection in adults.

In clinical studies in patients not previously treated with antiretroviral therapy, efficacy amprenavira in conjunction with tsidovudinom and lamivudine was higher than that of the combination of zidovudine and lamivudine. Antiviral effect amprenavira similar in adults and children. Was confirmed Agenerazy efficiency in all phases of HIV infection (including early and late stages of the disease) as patients who have not previously received antiretroviral drugs, and patients already receiving antiviral therapy.

Pharmacokinetics

Absorption

After oral amprenavir quickly and is well absorbed from the digestive tract. In the absence of dosage forms in / introduction of the absolute bioavailability amprenavira humans is unknown, but estimated that it could be about 90%. After oral administration the average time required to reach Cmax amprenavira in serum are 1-2 h for capsules and approximately 0.75 h for the solution. The second peak concentration was observed after 10-12 h and may be associated with delayed absorption or enterohepatic recirculation. When you receive amprenavira at intervals of 12 hr AUC averaged 18.46 (3.02-32.95) mg / h / ml. Capsules containing 50 mg and 150 mg amprenavira, bioequivalent.

Solution for oral administration of equivalent doses has a lower bioavailability than capsules; solution for AUC and Cmax of less than about 14 and 19%, respectively. Receiving amprenavira simultaneously with the food has a moderate effect on its concentration in plasma, ie reduces the AUC by 14-25%, and Cmax - approximately 33%. These changes are not clinically significant, so Agenerazu can be taken with food or fasting.

Distribution

When you receive Agenerazy capsules at therapeutic doses (1.2 g, 2 times / day) average Cssmax 5.36 (0.92-0.81) ug / ml, Cssmin - 0.28 (0.12-0.51) ug / ml. The apparent Vd amprenavira is about 430 l (6 l / kg for a person weighing 70 kg), indicating that a large Vd and free penetration amprenavira of the bloodstream into the tissues. Amprenavira concentration in the cerebrospinal fluid is less than 1% of its concentration in plasma. About 90% amprenavira binds to plasma proteins, primarily to α1-acid glycoprotein (ACS), and to a lesser extent - with albumin.

During antiretroviral therapy reduced the concentration of ACS. This change reduces the total concentration amprenavira in plasma, however, the number of unbound amprenavira, which is the active compound, apparently remains unchanged. Drugs that bind primarily with ACS usually not involved in clinically significant drug interactions, caused by displacement from binding sites of plasma proteins. Therefore, drug interactions with amprenavirom due to displacement from binding sites with proteins, it is unlikely. After a long reception amprenavira oral dose of 1.2 g 2 times / day a significant accumulation of the drug was not observed.

Metabolism

Amprenavira Metabolism occurs mainly in the liver with the involvement of CYP3A4 isoenzyme of cytochrome P450. Amprenavir is a substrate and inhibitor of CYP3A4. Metabolism of propylene glycol (filler) also occurs mainly in the liver.

Putting T1 / 2 amprenavira ranges from 7.1 to 10.6 h. The main mechanism for removing amprenavira is its metabolism in the liver. With urine as unchanged allocated less than 3% of the applied dose of the drug. Metabolites and unchanged amprenavir excreted in the urine (about 14%) and feces (about 75%).

Pharmacokinetics in special clinical situations

In children, pharmacokinetic parameters amprenavira are similar to those in adults. When assigning children Agenerazy in capsules at a dose of 20 mg / kg 2 times per day or 15 mg / kg 3 times / day amprenavira concentrations in plasma were similar to concentrations in adults taking the drug at 1.2 g 2 times / day.

Special studies of pharmacokinetics in patients with impaired renal function was conducted. As with the urine in unchanged form is displayed less than 3% of the therapeutic dose amprenavira, renal failure, apparently, has minimal effect on the excretion of the drug. In patients with moderate hepatic impairment increased AUC amprenavira approximately 3 times, with severely impaired liver function - 4-fold. Clearance amprenavira decreases with the increase of AUC. Pharmacokinetics amprenavira in patients older than 65 years is not known.

Statement
treatment of HIV infection in adults and children (as part of combination antiretroviral therapy).

Dosage regimen

Drugs are taken by mouth, regardless of the meal. A solution for oral administration is recommended for children and adult patients who have difficulty swallowing capsules. In applying the solution for oral bioavailability amprenavira 14% lower than when taking capsules. Therefore recommended doses amprenavira same for capsules and solution for oral administration.

Capsules

For adults and adolescents aged 13 and over (with a body weight over 50 kg): the recommended dose - to 1.2 g 2 times / day.

For children aged 4-12 years, and patients weighing less than 50 kg: the recommended dose - 20 mg / kg 2 times per day or 15 mg / kg 3 times / day, maximum daily dose - 2.4, the patients with moderate hepatic impairment dose Agenerazy capsules should be reduced to 450 mg 2 times / day, and when expressed disorders of liver function - up to 300 mg 2 times / day.

Solution for oral

For adults and adolescents aged 13 years and older (body weight over 50 kg) who can not swallow capsules, the recommended dose of the solution - at 1.4 g (93.3 ml), 2 times per day.

For children aged 4-12 years, and patients weighing less than 50 kg who can not swallow capsules, the recommended dose - to 22 mg (1.5 ml) / kg body weight 2 times per day or 17 mg (1.1 ml) / kg 3 times / day, maximum daily dose - 2.8 PM

In adults with moderate abnormal liver function Agenerazy dose in the form of the solution should reduce to 513 mg (34 mL) 2 times / day, and with the expressed abnormal liver function - up to 342 mg (23 mL) 2 times / day.

Side effect

On the part of the digestive system: frequent - nausea, diarrhea, flatulence and vomiting. On the part of CNS: possible oral / perioral paresthesia, headaches, fatigue. Allergic reactions: possible skin rash (most often appears in the 2 weeks of treatment and usually gets to go on for 2 weeks without discontinuation of the drug), and in some cases, the rash can be expressed, in 3% of the patients required removal of the drug, and in some cases - a syndrome, Stevens- Johnson.

Other: rare - changes in laboratory parameters (mainly in patients with baseline abnormalities of indicators may increase in the activity of transaminases, higher level of triglycerides). In most cases, side effects associated with therapy amprenavirom were light to moderate, developed at the beginning of treatment and rarely led to the abolition of the drug. In children, the safety profile amprenavira similar to that in adults. For many of the side effects is not clear whether they are caused by amprenavirom, other drugs used to treat HIV infection, or are the complications of the disease itself.

Contraindications
joint application with terfenadinom, tsizapridom, astemizolom and rifampicin;
Children younger than 4 years (for a solution for oral administration);
Hypersensitivity to amprenaviru or to other components of the drug.

Pregnancy and lactation

Health & Safety Agenerazy during pregnancy has not been established. Purpose of the drug in capsule form may, in cases where the expected benefit of therapy for the mother exceeds potential risk to the fetus. Agenerazu in the form of a solution for oral administration should not be given during pregnancy because of possible toxic effects of propylene glycol on the fetus.

If necessary, use during lactation should stop breastfeeding. This is consistent with general recommendations for HIV-infected women about the undesirability of breastfeeding in relation to the possibility of infection of the newborn. In experimental studies on animals showed that amprenavir and / or its metabolites can cross the placental barrier. During treatment for women of childbearing age should use an additional non-hormonal methods of contraception (as the therapy may decrease the effectiveness of Agenerazoy hormonal contraceptives).

Cautions

Appoint Agenerazu have specialists experienced in treating HIV infection. Precautions should be prescribed to patients with hepatic impairment. Given the presence of propylene glycol (550 mg / ml) in solution for oral administration, when applying Agenerazy in this dosage form should monitor the status of children (4 years and older) and adults, especially when abnormal liver function or renal disease and genetically determined low levels of the enzyme alcohol dehydrogenase (for example, in patients belonging to ethnic groups of China and Japan) to identify possible adverse effects associated with propylene glycol (convulsions, stupor, tachycardia, hyperosmolarity, lactic acidosis, toxic to the kidneys, hemolysis). In the capsules and solution for oral administration contains vitamin E (46 IU / ml for the solution), so there is no necessity for the admission of this vitamin. There are reports that patients with hemophilia type A and B, taking protease inhibitors, intensified hemorrhagic complications, including spontaneous skin hematomas and Hemarthrosis. Some of these patients additionally injected factor VIII. More than half of the cases described, treatment of protease inhibitors was continued or resumed after a temporary withdrawal. There was found a causal relationship with the reception Agenerazy, but the mechanism of bleeding disorders is not installed.

Patients with hemophilia should be made aware of the possible strengthening of bleeding in patients receiving protease inhibitors. Patients should be informed that Ageneraza as other antiretroviral drugs, does not cure HIV infection. Therefore, despite ongoing therapy, may develop infections caused by opportunistic pathogens, and other complications of HIV infection. Treatment with antiretroviral drugs, including amprenavirom, does not prevent the risk of transmitting HIV to others through sexual contact or blood transfusion, so patients must comply with appropriate precautions.

In applying the drug in patients over 65 years of age should take account of possible violations of the liver, kidney or heart failure, concomitant diseases and concomitant drug therapy.

Patients with impaired renal function do not need to adjust the initial dose Agenerazy capsules. Agenerazu in the form of solution for oral administration of this category of patients should be prescribed with caution. Precautions should be appointed Agenerazu simultaneously with drugs that are inducers, inhibitors or substrates of isoenzyme CYP3A4. Agenerazu should not be used simultaneously with terfenadinom, tsizapridom, astemizolom, and rifampicin, with the drugs that are substrates of isoenzyme CYP3A4 and have a small range of therapeutic doses. Avoid the simultaneous application of Agenerazy with strong sedatives, metabolism which occurs with the participation of isoenzyme CYP3A4 (eg, triazolam, midazolam). Amprenavir should not be used simultaneously with derivatives of ergot alkaloids.

Propylene glycol, contained in a solution for oral administration, is metabolized with the participation of the enzyme alcohol dehydrogenase. In this regard, it is not recommended simultaneous appointment Agenerazy in solution for oral and disulfiram or other drugs that reduce the activity of alcohol dehydrogenase (eg metronidazole) and preparations containing ethanol or propylene glycol. If necessary, the simultaneous application of rifabutin and amprenavira, rifabutin dose should be reduced by at least 2 times as compared with the recommended. At the same time appointing amprenavira and zidovudine, lamivudine, abacavir, indinavir, saquinavir, nelfinavir, ketoconazole, clarithromycin is not necessary to adjust the dose of drugs.

Use in Pediatrics

Children under 4 years old the ability to metabolize propylene glycol may be insufficiently developed, so Ageneraza in the form of solution for oral use is contraindicated for use in this patient. Safety and efficacy Agenerazy in the form of capsules in children under 4 years are not installed. Children with liver problems should not appoint Agenerazu in solution for oral use.

Effects on ability to drive vehicles and management mechanisms

Specific studies on the effect amprenavira on ability to drive a car and work with moving machinery and sophisticated equipment not carried out.

Results of experimental study researches are ongoing carcinogenicity studies amprenavira rats and mice. In tests in vitro and in vivo showed that amprenavir did not have mutagenic and genotoxic activity. Sexually mature animals are usually well tolerated amprenavir. Clinically significant changes were observed only in the liver.

Signs of toxic liver damage include increase in liver enzymes, enlarged liver, and the changes revealed by the morphological study, including necrosis of hepatocytes. In the course of toxicological studies in immature animals, which amprenavir was administered from 4 days of life, have a high mortality in the control group, and in the group treated with amprenavir. These results suggest that immature animals are not fully developed metabolic mechanisms, and they can not metabolize or remove amprenavir or other components Agenerazy. In clinical studies did not have severe symptoms of toxic liver injury or during treatment Agenerazoy or after therapy.

Overdose

Data on overdose amprenavira few. Treatment: In case of overdose should monitor the general condition of the patient to identify possible signs of intoxication and, if necessary to carry out standard supportive therapy. Amprenavir extensively bound to plasma proteins, so it is unlikely that dialysis may reduce its concentration in the blood.

Drug Interactions

With simultaneous application Agenerazy with hormonal contraceptives may decrease the effectiveness of the latter due to metabolic interactions. Preparations, metabolism, which occurs with the participation of isoenzyme CYP3A4, or drugs that affect the activity of this enzyme may alter the pharmacokinetics amprenavira. In turn, amprenavir may modify pharmacokinetics, metabolism of which is under the influence of isoenzyme CYP3A4. At simultaneous application with amprenavirom terfenadina, tsizaprida and astemizola possible competitive inhibition of metabolism of these drugs and the development of life-threatening cardiac arrhythmias.

Special studies on the interaction amprenavira with strong sedatives, metabolism which occurs with the participation of isoenzyme CYP3A4 (eg, triazolam, midazolam), were not conducted.

With simultaneous application Agenerazy with these treatments there is a risk of prolonged sedative effect. Amprenavir has the ability to cause clinically significant drug interactions caused by displacement from binding sites of plasma proteins. Amprenavir binds preferentially to α1-acid glycoprotein, but this protein is rarely involved in this interaction. In cases when the observed changes in pharmacokinetics, such as a combination of two protease inhibitors, clinical trials have confirmed that the antiviral effect is maintained. Rifampicin reduces plasma concentrations amprenavira approximately 80%.

The simultaneous use of amprenavira and rifabutin increases the AUC rifabutin at 200% and to increase the side effects of the latter. Agents listed below are examples of substrates, inhibitors or inducers of the enzyme CYP3A4, that can interact with amprenavirom.

Clinical significance of these possible interactions has not been studied, and the need to monitor the state of patients for early detection of toxic effects of these drugs in case of their simultaneous application with amprenavirom. Amprenavir may increase the plasma concentrations of dapsone, erythromycin, itraconazole. Erythromycin and itraconazole may increase serum concentrations amprenavira.

Amprenavir may increase serum concentrations of alprazolam, klorazepama, diazepam, flurazepama, diltiazem, nicardipine, nifedipine and nimodipine and thereby increase their activity. Amprenavir may increase serum concentrations of atorvastatin, Fluvastatin, lovastatin, pravastatin and simvastatin and thereby enhance their activity or toxic effects. Based on data on the interaction with other drugs of the group of inhibitors of HIV protease can be assumed that Efavirenz and nevirapine can reduce the serum concentration amprenavira. Delavirdine may increase serum concentrations amprenavira.

Estrogens, progestogens, and some of the SCS can interact with amprenavirom, but available data are insufficient to determine the nature of this interaction. The effectiveness of hormonal contraceptives may decrease due to possible metabolic interactions with amprenavirom. It is not recommended at the same time appoint amprenavir and preparations containing Hypericum perforatum. These pharmacokinetic studies using indinavir suggest that Hypericum perforatum may reduce serum concentrations amprenavira at their simultaneous application. Amprenavir may increase the plasma concentrations of other drugs such as clozapine, carbamazepine, cimetidine, loratadine, pimozida, warfarin and others. Cimetidine and ritonavir may increase the concentration amprenavira in plasma. Interaction of antacids (and didanosine because of the content therein antacid) with amprenavirom not specifically investigated.

Based on the data of other protease inhibitors is not recommended to take antacids at the same time Agenerazoy, because they can disrupt the absorption amprenavira. The interval between doses Agenerazy and antacids should be at least 1 h.

Terms and Conditions of storage

The drug should be stored at temperatures not above 30 ° C, the lid tightly closed bottle. Shelf life - 2 years.