HTB

Safety warning on amprenavir oral liquid

15 June 2000. Related: Treatment alerts.

Glaxo Wellcome (U.S.A) has issued an important drug warning in a letter sent to health professionals regarding potential safety concerns with the large amount of propylene glycol contained in the oral solution of amprenavir (AgeneraseTM). As a result of these safety concerns, the company has revised information about the drug in the product insert.

Amprenavir is an HIV protease inhibitor drug manufactured by Glaxo Wellcome which is FDA-approved in the United States for the treatment of HIV infection in combination with other anti-HIV drugs in patients four years of age and older. This drug has not been approved in Europe, but is available in expanded access and named patient programs pending a decision on approval by the EMEA.

Propylene glycol is added to the liquid formulation of Agenerase to achieve adequate solubility of Agenerase. There have been no reports of deaths or serious injury attributed to propylene glycol in Agenerase oral solution, but ‘there are potential safety concerns,’ according to Glaxo Wellcome. Following are excerpts from a letter sent by the company to health professionals concerning changes to the labelling for Agenerase oral solution: ÔBecause of the potential risk of toxicity from the large amount of the excipient [component that is not active drug] propylene glycol, AGENERASE Oral Solution is contraindicated [should not be used] in infants and children below the age of 4 years, pregnant women, patients with hepatic [liver] or renal [kidney] failure, and patients treated with disulfiram [Antabuse] or metronidazole [Flagyl].”

“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, AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not therapeutic options. Certain ethnic populations (Asians, Eskimos, Native Americans) and women may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolise propylene glycol; no data are available on propylene glycol metabolism in these groups.

“If patients require treatment with AGENERASE Oral Solution, they should be monitored closely for propylene glycol-associated adverse events, including seizures [convulsions], stupor [dazed, near coma], tachycardia [rapid heart beat], hyperosmolality [excess ‘ion’ concentration in blood], lactic acidosis [acid state of blood due to excess lactate], renal [kidney] toxicity, and haemolysis [bursting of red cells]. Patients should be switched from AGENERASE Oral Solution to AGENERASE Capsules as soon as they are able to take the capsule formulation. Use of alcoholic beverages is not recommended in patients treated with AGENERASE Oral Solution.2

The following new statements have been added to the Boxed Warning of the package insert for Agenerase:

“Because of the potential risk of toxicity from the large amount of the excipient [see above] propylene glycol, AGENERASE Oral Solution is contraindicated in infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole (see CONTRAINDICATIONS and WARNINGS). AGENERASE Oral Solution should be used only when AGENERASE Capsules or other protease inhibitor formulations are not therapeutic options.”

In addition to the above changes to the package insert for Agenerase oral solution, Glaxo Wellcome has revised the Patient Information leaflet to address the safety concerns outlined in the letter. 2This patient information is supplied to pharmacies with each bottle of the product for dispensing to the patient,2 according to the company.

The complete text of the letter (in PDF format) to health professionals from Glaxo Wellcome,is at:
http://www.fda.gov/medwatch/safety/2000/agener.pdf.

Source: Letter from Glaxo Wellcome to Health Professionals. ‘Potential safety concerns with the large amount of propylene glycol in AGENERASE (amprenavir) Oral Solution.’ May 2000.

Comment

Amprenavir is rarely (if ever) prescribed as a single PI. Addition of ritonavir to an amprenavir containing combination allows reduction in the total daily amount of amprenavir (and propylene glycol).

Additionally a reduced dose of amprenavir should be used for people with liver disease.1 The standard dose of amprenavir is 1,200mg taken twice daily. Liver damage is assessed using a special scoring system called the Child-Pugh score. For people whose liver damage measures between 5 to 8 on the Child-Pugh score, the researchers recommend that the dose of amprenavir should be reduced to 450mg twice daily. For people with more severe liver damage that falls between 9 and 15 on the Child-Pugh score, the researchers recommend an amprenavir dose of 300mg twice daily. The reason for the dose reduction is that liver damage slows down the processing of amprenavir, leading to higher levels of the drug in the body than normal. Therapeutic drug monitoring would appear useful in establishing appropriate drug levels in the setting of impaired liver function.

Reference:

  1. Veronese L, et al. Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function. Antimicrob Agents Chemother. 2000 Apr;44(4):821-6.

Links to other websites are current at date of posting but not maintained.