Potential safety concerns with the large amount of propylene glycol in AGENERASEÆ (amprenavir) Oral Solution
From Glaxo Wellcome: Important
Drug Warning
May 2000
Re: Potential safety concerns with the large amount of propylene glycol in AGENERASEÆ (amprenavir) Oral Solution.
Dear Health Care Professional:
Glaxo Wellcome Inc., is writing
to inform you of important changes to the labeling for AGENERASE (amprenavir)
Oral Solution, a protease inhibitor indicated for the treatment of HIV-1
infection in combination with other antiretroviral agents in patients 4 years of
age and older.
Propylene glycol is metabolized
by the alcohol and aldehyde dehydrogenase enzyme pathway. This enzyme pathway
does not attain full adult activity until 12 to 30 months of age. Some patients
(infants and children below the age of 4 years, pregnant women, patients with
hepatic or renal failure, and patients treated with disulfiram or metronidazole)
are not able to adequately metabolize and eliminate propylene glycol, thereby
leading to its accumulation and potential adverse events.
Additionally, other patient
subgroups as described below may also be at risk. Although, we have received no
reports of death or serious injury that have been attributed to propylene gylcol
in AGENERASE Oral Solution, there are potential safety concerns regarding
AGENERASE Oral Solution due to its high propylene glycol content.
To communicate this important
information to health care professionals, the prescribing information for
AGENERASE Oral Solution has been revised. The revised boxed warning and the
additions to the sections DESCRIPTION, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS,
OVERDOSAGE, and DOSAGE AND ADMINISTRATION
are as follows.
The following paragraphs show the
complete text of the change to labeling for each section of the package insert
for AGENERASE Oral Solution:
BOXED
WARNING (new statements in the box are underlined):
DESCRIPTION:
Propylene glycol is in the
formulation to achieve adequate solubility of amprenavir. The recommended daily
dose of AGENERASE Oral Solution of 22.5 mg/kg twice daily corresponds to a
propylene glycol intake of 1650 mg/kg per day. Acceptable intake of propylene
glycol for pharmaceuticals has not been established.
INDICATIONS AND USAGE:
AGENERASE Oral Solution should be
used only when AGENERASE Capsules or other protease inhibitor formulations are
not therapeutic options.
CONTRAINDICATIONS:
Because of the potential risk of
toxicity from the large amount of the excipient 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 WARNINGS and PRECAUTIONS).
WARNINGS:
Because of the potential risk of
toxicity from the large amount of the excipient 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 CLINICAL PHARMACOLOGY, CONTRAINDICATIONS,
and PRECAUTIONS).
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 metabolize propylene glycol; no data
are available on propylene glycol metabolism in these groups (see CLINICAL
PHARMACOLOGY: Special Populations: Gender and Race). If patients require
treatment with AGENERASE Oral Solution, they should be monitored closely for
propylene glycol-associated adverse events, including seizures, stupor,
tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis.
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.
PRECAUTIONS:
Information for Patients:
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 AGENERASE Oral Solution should be used
only when AGENERASE Capsule or other protease inhibitor formulations are not
therapeutic options.
Patients treated with
AGENERASE Capsules should be cautioned against switching to AGENERASE Oral
Solution because of the increased risk of adverse events from the large amount
of propylene glycol in AGENERASE Oral Solution.
Women, Asians, Eskimos, or Native
Americans, as well as patients who have hepatic or renal insufficiency, should
be informed that they may be at increased risk of adverse events from the large
amount propylene glycol in AGENERASE Oral Solution.
Patients should be advised that drinking alcoholic beverages is not recommended while taking AGENERASE Oral Solution.
Pediatric Use: AGENERASE Oral
Solution is contraindicated in infants and children below the age of 4 years due
to the potential risk of toxicity from the excipient propylene glycol (see
CONTRAINDICATIONS and WARNINGS).Although the data are limited, it appears that
by 12 to 30 months of postnatal age, ADH activity is equal to or greater than
that observed in adults.
OVERDOSAGE:
AGENERASE Oral Solution contains
large amounts of propylene glycol. In the event of overdosage, monitoring and
management of acid-base abnormalities is recommended. Propylene glycol can be
removed by hemodialysis.
DOSAGE AND ADMINISTRATION:
Consideration should be given to switching patients from AGENERASE Oral Solution to AGENERASE Capsules as soon as they are able to take the capsule formulation (see WARNINGS).
In addition to the above changes
in the prescribing information, the Patient Information leaflet has been amended
to address the information provided in this letter. A copy of this Patient
Information is printed at the end of the enclosed package insert. This Patient
Information is supplied to pharmacies with each bottle of the product for
dispensing to the patient.
Glaxo Wellcome is committed
to providing you with the most current product information for the management of
your patients being treated with AGENERASE. You can assist us in monitoring the
safety of AGENERASE by reporting adverse reactions to the Glaxo Wellcome Product
Surveillance Department at 1-888-825-5249 or to the FDA MedWatch program by
telephone at 1-800-332-1088, by FAX at 1-800-332-0178, via
Please refer to the enclosed revised prescribing information for AGENERASE Oral Solution. If you have questions about the new information or want additional medical information about AGENERASE Oral Solution, please contact the Glaxo Wellcome Customer Response Center at 1-888-TALK2GW (1-888-825-5249).
Sincerely,
Marc Rubin, M.D.
Vice President, Therapeutic Development and Product Strategy
HIV, Infectious Disease and Hepatitis
Glaxo Wellcome, Inc.
Five Moore Drive
P.O. Box 13398
Research Triangle Park, North Carolina 27709-3398
Telephone: 919 483-2100