Medicinal Products

AGENERASE 15 mg / mL

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

Drinkable solution
Box of 1 bottle of 240 ml
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. 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 potentiated by ritonavir has not been demonstrated in patients who have never received antiprotease or in patients who have already received it.

Dosage AGENERASE 15 mg / mL Oral solution Box of 1 bottle of 240 ml

- 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 oral solution is administered orally and can be taken during or without meals.
- Agenerase is also available in capsule form. Agenerase oral solution has a 14% lower bioavailability than soft capsules. Therefore, the dosage of Agenerase soft capsule and oral solution are not transferable to the equivalent mg ​​(see section pharmacokinetic properties).
- Patients should stop treatment with Agenerase oral solution as soon as they are able to swallow Agenerase capsules (see section on warnings and precautions for use).
- Patients 4 years of age and over unable to swallow capsules: The recommended dose of Agenerase oral solution is 17 mg (1.1 ml) / kg three times daily, not exceeding the maximum dose of 2800 mg per day, in combination with other antiretrovirals (see section on pharmacodynamic properties). The pharmacokinetic interactions between amprenavir and low doses of ritonavir or other protease inhibitors have not been evaluated in children. In addition, since no dosage recommendation can be made about the concomitant use of Agenerase oral solution and low doses of ritonavir, the use of this combination should be avoided in these patients. - Children under 4 years: Agenerase oral solution is contraindicated in children under 4 years (see sections contraindications and preclinical safety data).
- Elderly patients: The pharmacokinetics, efficacy and safety of amprenavir have not been studied in patients over 65 years of age (see section 5.2). Renal Insufficiency: Although no dose adjustment of amprenavir is considered necessary in patients with renal impairment, Agenerase oral solution is contraindicated in patients with renal failure (see section 4.3). - Hepatic impairment: Agenerase oral solution is contraindicated in patients with hepatic insufficiency or failure (see section contraindications) (see Summary of Features of Agenerase Soft Capsules).

Against indications

CONTRAINDICATED:
- Hypersensitivity to the active substance or to any of the excipients.
- Due to the potential risk of toxicity due to the large amount of propylene glycol (excipient) in the oral solution, Agenerase oral solution is contraindicated in neonates and children under 4 years, pregnant women, patients with hepatic insufficiency or failure and patients with renal failure. Agenerase oral solution is also contraindicated in patients treated with disulfiram, or any other drug that reduces the metabolism of alcohol (eg metronidazole), or with preparations containing alcohol (eg, ritonavir oral solution) or propylene glycol (see warnings and precautions for use and pharmacodynamic properties). - Agenerase should not be co-administered with cytochrome P450 3A4 (CYP3A4) substrates and having a narrow therapeutic index. This type of combination may result in a competitive inhibition of the metabolism of these drugs, and may lead to a risk of serious or potentially life-threatening adverse effects, such as cardiac arrhythmias (eg amiodarone, bepridil, quinidine, terfenadine, astemizole, cisapride, pimozide), respiratory depression and / or prolonged sedation [eg: triazolam and midazolam administered orally (for precautions for midazolam administered parenterally, see section interactions)], vasoconstriction peripheral spasmodic or ischemia and ischemia of other tissues, including cerebral ischemia or myocardium (eg ergot derivatives). - Concomitant administration of rifampicin with Agenerase combined with low doses of ritonavir is contraindicated (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: - Pregnancy: There is insufficient data on the use of amprenavir in pregnant women. Studies in animals have shown reproductive toxicity. The potiential risk to humans is unknown.
- 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.
- The concomitant use of Agenerase / ritonavir and fluticasone, or other glucocorticoids metabolized by CYP3A4, is not recommended unless the expected benefit to the patient outweighs the risk of systemic effects. corticosteroid therapy, such as Cushing's syndrome or adrenal suppression (see section on interactions).
- Concomitant administration of Agenerase with simvastatin or lovastatin is not recommended because of the increased risk of myopathy or even rhabdomyolysis.
- The concomitant use of Agenerase with halofantrine or lidocaine (systemically) is not recommended (see section interactions).
- The effectiveness of hormonal contraceptives may be affected by possible metabolic interactions with amprenavir. However, the available data are insufficient to predict the nature of these interactions. It is therefore recommended that women of childbearing potential use other effective methods of contraception (see section on interactions).
- Co-administration of efavirenz with amprenavir and saquinavir is not recommended as systemic exposure to both protease inhibitors may be decreased. - Agenerase oral solution contains vitamin E (46 IU / ml). Extra vitamin E is not recommended.

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. Included are events (Grade 2-4) reported by the investigators as attributable to the treatments of 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.
Elevation of triglycerides and amylase, and hyperglycemia (Grade 3-4) were mainly reported in patients with abnormal baseline values.
Elevations in cholesterol levels were Grade 3-4 in 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.
Elevated transaminases and hyperbilirubinemia (Grade 3-4) have been reported mainly 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. . Uncommon : Angioedema.
. 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.
. Cases of osteonecrosis have been reported, particularly in patients with known risk factors, advanced HIV-related disease, or combination therapy with long-term antiretrovirals. Their frequency of occurrence is not known (see section warnings and precautions for use: pain, arthralgia, joint stiffness, difficulty in moving).
- 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 ).
- Although limited, the experience related to the use of Agenerase oral solution shows a tolerance profile similar to that of capsules.
- 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 commonly seen in patients receiving Agenerase combined with low doses of ritonavir.

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