Medicinal Products

AGENERASE 150 mg

Generic drug of the therapeutic class: Infectiology - Parasitology
active ingredients: Amprenavir
laboratory: Glaxo Group Ltd

Soft capsule
Bottle of 240
All forms

Indication

Agenerase is indicated in combination with other antiretrovirals in the treatment of adult patients and children over 4 years of age infected with HIV-1 who have already received protease inhibitor (PI) therapy. In general, Agenerase capsules should be given in combination with low doses of ritonavir, which improves the pharmacokinetics of amprenavir (see section on dosage and administration and interactions). The choice of a treatment with amprenavir should take into account the results of the tests of viral resistance of the patient and the previous treatments (see heading pharmacodynamic properties).
- The benefit of Agenerase boosted with ritonavir has not been demonstrated in patients not previously treated with protease inhibitors (see section on pharmacodynamic properties).

Dosage AGENERASE 150 mg Soft Capsule Bottle of 240

- Treatment should be initiated by a physician experienced in the management of HIV infection.
- Patients should be informed of the importance of adhering to the recommended dosage.
- Agenerase is administered orally and can be taken during or without meals.
- Agenerase is also available as an oral solution for children or adults who can not swallow capsules. The oral solution of amprenavir has a bioavailability 14% lower than that of soft capsules. Therefore, the dosage of Agenerase soft capsule and oral solution are not transferable to the equivalent mg ​​(see section pharmacokinetic properties).
- Adults and adolescents aged 12 years and older (body weight> 50 kg): The recommended dosage for Agenerase soft capsules is 600 mg twice daily in combination with 100 mg ritonavir twice daily, in combination with other antiretrovirals.
If Agenerase Soft Capsules is administered without ritonavir, Agenerase dosages should be increased (1200 mg twice daily).
- Children (4 to 12 years) and patients weighing less than 50 kg: The recommended dosage of Agenerase soft capsules is 20 mg / kg body weight twice daily, without exceeding the maximum dose of 2400 mg per day, in combination with other antiretrovirals.
To date, the pharmacokinetics, efficacy and safety of Agenerase in combination with low doses of ritonavir or other protease inhibitors have not been studied in children. Therefore, such associations should be avoided in children.
- Children under 4 years of age: Agenerase is not recommended for children under 4 years of age (see preclinical safety data).
- Elderly: The pharmacokinetics, efficacy and safety of amprenavir have not been studied in patients over 65 years of age (see section 5.2).
- Renal impairment: No dose adjustment is deemed necessary in patients with renal impairment (see section 5.2).
- Hepatic insufficiency: Amprenavir is metabolised mainly in the liver. Agenerase capsules should be administered with caution in patients with hepatic impairment. The clinical efficacy and safety of Agenerase have not been established in this group of patients. Pharmacokinetic data on the use of Agenerase Capsules without the boosting effect of ritonavir is available for patients with hepatic impairment. Based on pharmacokinetic data, the dosage of Agenerase soft capsules should be reduced to 450 mg twice daily in adult patients with moderate hepatic impairment, and to 300 mg twice daily in adult patients with impaired severe hepatic No dosage recommendation can be made for children with hepatic impairment (see section 5.2).
The use of amprenavir with ritonavir has not been studied in patients with hepatic impairment. No dosage recommendation can be made for this combination. Co-administration of these two drugs will be cautious in patients with mild to moderate hepatic impairment; it is contraindicated in cases of severe hepatic impairment (see section contraindications).

Against indications

CONTRAINDICATED:
- Known hypersensitivity to amprenavir or to any of the excipients of Agenerase soft capsules.
- Agenerase should not be co-administered with cytochrome P450 3A4 (CYP3A4) substrates that have a narrow therapeutic index. This type of combination can lead to a competitive inhibition of the metabolism of these drugs, and induce a risk of serious or potentially life-threatening adverse effects, such as cardiac arrhythmias (eg terfenadine, astemizole, cisapride, pimozide ), a prolonged sedative effect or respiratory depression (eg triazolam, diazepam, flurazepam, midazolam), or peripheral spasmodic vasoconstriction or ischemia and ischemia of other tissues, including cerebral ischemia or myocardial 'ergot).
- Administration of Agenerase with ritonavir is contraindicated in patients with severe hepatic impairment.
- Rifampicin should not be co-administered with Agenerase because it decreases the residual plasma concentrations of amprenavir by approximately 92% (see section interactions).
- Herbal preparations containing St. John's wort ( Hypericum perforatum ) should not be used during treatment with amprenavir due to the potential for decreased plasma concentrations and clinical activity of amprenavir (see section 5.2). interactions).
NOT RECOMMENDED :
- Children under 4 years: Agenerase is not recommended for children under 4 years.
Pregnancy: The safety of use of amprenavir during pregnancy has not been established in humans. In animals, amprenavir and / or its metabolites cross the placenta. Administration of this drug during pregnancy should be considered only if the expected benefits outweigh the potential risks to the fetus.
- Breast-feeding: Products derived from amprenavir have been found in the milk of the spleen, but it is not known whether or not amprenavir is excreted in human milk. A reproductive study in pregnant rats treated from the time of uterine implantation to breastfeeding showed a decrease in litter weight gain during the lactation period. The systemic impregnation of the females at the origin of this result was similar to that of the human being after administration of the recommended dose. Subsequent development of the litter, including fertility and reproductive capacity, was not affected by the maternal administration of amprenavir. It is therefore recommended that Agenerase-treated mothers do not breastfeed. In addition, HIV-infected women are not advised to breastfeed their infants to prevent post-natal transmission of the virus.

Agenerase side effects

- The safety profile of Agenerase has been studied in adults and children aged 4 years or older, in controlled clinical trials, in combination with various other antiretroviral drugs. Adverse reactions that are considered to be related to Agenerase are: gastrointestinal disturbances, rashes and oral or perioral paresthesia. The majority of adverse events associated with Agenerase treatment were mild to moderate, early onset, and rarely required treatment modification. For many of them, the causality study could not formally distinguish between responsibility for treatment and that of the evolution of HIV infection and associated treatments.
- In children, the nature of the safety profile is similar to that observed in adults.
- The undesirable effects are listed below by organ class and by frequency (MedDRA classification). Frequencies are defined according to the following categories:
Very common> = 1/10.
Frequent> = 1/100 and <1/10.
Uncommon> = 1/1000 and <1/100.
Rare> = 1/10000 and <1/1000.
- The following events were ranked according to their frequency, based on clinical trial and post-marketing data.
- Most of the events listed below are from two clinical studies (PROAB3001, PROAB3006) in patients not previously treated with protease inhibitors and receiving 1200 mg Agenerase twice daily. This includes the events (grade 2-4) reported by the investigators as attributable to the treatments in these trials, as well as grade 3-4 laboratory abnormalities that occurred during treatment. It should be noted that the frequencies of the events reported in the comparator arms are not mentioned.
- Metabolism and nutrition disorders:
. Frequency : elevation of triglycerides, elevation of amylase, abnormal redistribution of fat mass, anorexia.
. Uncommon : Hyperglycemia, hypercholesterolemia.
Triglyceride and amylase elevations, and hyperglycemia (grade 3-4) were mainly reported in patients with abnormal baseline values.
The elevations of cholesterol level were of grade 3-4 intensity.
Combination antiretroviral therapy has been associated with a redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of subcutaneous peripheral and facial adipose tissue, increased body fat intra-abdominal and visceral, breast hypertrophy and retrocervical fat mass accumulation (buffalo hump).
With amprenavir, symptoms associated with abnormal redistribution of body fat have been uncommon in PROAB3001. Only one case (buffalo hump) was reported in 113 subjects (<1%) who had never received antiretroviral therapy and who received amprenavir in combination with lamivudine and zidovudine for a median of 36 weeks. In the PROAB3006 study, 7 cases (3%) of 245 patients previously treated with reverse transcriptase inhibitor nucleoside analogues were reported in the amprenavir group and 27 (11%) cases out of 241 in the indinavir group, for a median duration. 56 weeks (p <0.001).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactataemia (see section 4.4).
- Psychiatric disorders:
Common : Mood disorders, depressive episodes.
- disorders of the nervous system:
. Very common : Headache.
. Common : Oral / perioral paresthesia, tremors, sleep disturbances.
- Gastrointestinal disorders:
. Very common : Diarrhea, nausea, flatulence, vomiting.
. Common : Abdominal pain and discomfort, dyspeptic symptoms, loose stools.
- Hepatobiliary disorders:
. Frequency : Elevation of transaminases.
. Uncommon : Hyperbilirubinemia.
Elevation of transaminases and hyperbilirubinemia (grade 3-4) were mainly reported in patients with abnormal baseline values. Virtually all subjects with abnormal liver function tests were infected with hepatitis B or C.
- Skin and subcutaneous tissue disorders:
. Very common : Rash.
. Rare : Stevens-Johnson Syndrome.
In general, rashes were mild to moderate, erythematous or maculopapular, with or without pruritus, occurring during the second week of treatment and disappearing spontaneously within two weeks, without the need to stop treatment with amprenavir. A higher rate of rash has been reported in subjects treated with amprenavir in combination with efavirenz. Severe or potentially life-threatening rash has occurred in patients taking amprenavir (see section 4.4).
- Musculoskeletal and systemic disorders:
CPK elevations, myalgia, myositis and, rarely, rhabdomyolysis have been reported with protease inhibitor therapy, particularly in combination with nucleoside analogues.
- General disorders and anomalies at the site of administration:
Very common : Fatigue.
- In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral combination therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur (see section 4.4). examples: cytomegalovirus retinitis, generalized and / or localized mycobacterial infections, and Pneumocystis carinii pneumonia ).
- In patients previously treated with protease inhibitors and receiving 600 mg of Agenerase capsules twice daily with low doses of ritonavir (100 mg twice daily), the nature and frequency of adverse reactions (Grade 2 -4) and grade 3/4 laboratory abnormalities were similar to those observed after administration of Agenerase alone, with the exception of elevated triglyceride levels and CPK levels, which was very common in patients receiving Agenerase combined with low doses of ritonavir.

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