Tibotec
and FDA Warn of Liver Toxicity Linked to Ritonavir-boosted Darunavir (Prezista)  | Prezista
Tablet |
On
March 11, Tibotec Therapeutics issued a letter to healthcare providers informing
them of previously unrecognized drug-associated hepatotoxicity in patients taking
ritonavir-boosted darunavir (Prezista).This
liver toxicity has primarily been observed among patients with advanced HIV disease
taking multiple medications, some of whom had other conditions such as chronic
hepatitis B or C, or who developed immune reconstitution syndrome after starting
darunavir. Based
on these observations, the company, in cooperation with the U.S. Food and Drug
Administration (FDA), revised the darunavir prescribing information to reflect
the new findings. Below
is the text of Tibotec's letter to clinicians, a summary of the product label
updates from the FDA, and a link to the revised product label in PDF format: | Tibotec
Letter IMPORTANT
DRUG WARNING March
2008 Dear Healthcare
Professional: Tibotec
Therapeutics, in cooperation with the U.S. Food and Drug Administration, would
like to inform you of an important update to the prescribing information for PREZISTA
(darunavir) tablets regarding addition of a Warning on Hepatotoxicity. In
clinical trials and post-marketing experience, drug-induced hepatitis (e.g., acute
hepatitis, cytolytic hepatitis) has been reported in patients receiving combination
therapy with PREZISTA/ritonavir. Given the clinical relevance of this adverse
reaction, the following information on hepatotoxicity has been added to the WARNINGS
section of the PREZISTA Prescribing Information: WARNINGS: Hepatotoxicity Drug-induced
hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with
PREZISTA/ritonavir. During the clinical development program (N=3063), hepatitis
has been reported in 0.5% of patients receiving combination therapy with PREZISTA/ritonavir.
Patients with pre-existing liver dysfunction, including chronic active hepatitis
B or C, have an increased risk for liver function abnormalities including severe
hepatic adverse events. Post-marketing
cases of liver injury, including some fatalities, have been reported. These have
generally occurred in patients with advanced HIV-1 disease taking multiple concomitant
medications, having co-morbidities including hepatitis B or C coinfection, and/or
developing immune reconstitution syndrome. A causal relationship with PREZISTA/ritonavir
therapy has not been established. Appropriate
laboratory testing should be conducted prior to initiating therapy with PREZISTA/ritonavir
and patients should be monitored during treatment. Increased AST/ALT monitoring
should be considered in patients with underlying chronic hepatitis, cirrhosis,
or in patients who have pretreatment elevations of transaminases, especially during
the first several months of PREZISTA/ritonavir treatment. If
there is evidence of new or worsening liver dysfunction (including clinically
significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia,
nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on PREZISTA/ritonavir,
interruption or discontinuation of treatment must be considered.
In
addition, the Adverse Reaction section of the PREZISTA Prescribing Information
and the Patient Package Insert have been updated to include this new information. Enclosed
[SEE LINK BELOW], please find the updated Prescribing Information as well
as the Patient Package Insert. Please
see PREZISTA Indication and Additional Important Safety Information included on
page 3 and page 4 of this letter [SEE TEXT BELOW]. Tibotec
Therapeutics is committed to ensuring that PREZISTA is used safely and effectively
and providing you with the most current information for our products. Should
you have any questions, require further information on product safety, or wish
to report adverse patient experiences, please contact Tibotec Therapeutics Medical
Information at 1-877-REACH TT (1-877-732-2488). Alternatively,
adverse events may be reported to FDA's MedWatch reporting system
•
By phone (1-800-FDA-1088), by facsimile (1-800-FDA-0178),
•
Online
(https://www.accessdata.fda.gov/scripts/medwatch/) or
•
Mailed, using the MedWatch for FDA 3500 postage paid form,
to the FDA Medical Products Reporting Program, 5600 Fishers Lane, Rockville, MD
20852-9787
Sincerely,
Alan
Tennenberg, MD, MPH
Vice President, Clinical Affairs |
About
PREZISTA PREZISTA,
co-administered with 100 mg ritonavir (PREZISTA/r), and with other antiretroviral
agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection
in antiretroviral treatment-experienced adult patients, such as those with HIV-1
strains resistant to more than one protease inhibitor. This
indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell
counts from 2 controlled trials of PREZISTA/r in combination with other antiretroviral
drugs. Both studies were conducted in clinically advanced, treatment-experienced
(NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite
ongoing antiretroviral therapy. The
following points should be considered when initiating therapy with PREZISTA/r: •
Treatment history and, when available, genotypic or phenotypic
testing, should guide the use of PREZISTA/r.
•
The use of other active agents with PREZISTA/r is associated
with a greater likelihood of treatment response.
•
The risks and benefits of PREZISTA/r have not been established
in treatment-naive adult patients or pediatric patients.
Additional
Important Safety Information •
Co-administration of PREZISTA/r is contraindicated with
drugs that are highly dependent on CYP3A for clearance and have a narrow therapeutic
index (e.g., astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine,
methylergonovine, cisapride, pimozide, midazolam, or triazolam) and for which
elevated plasma concentrations are associated with serious and/or life-threatening
events.
•
Co-administration is not recommended with carbamazepine,
phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin,
pravastatin, simvastatin, or products containing St. John's wort (Hypericum perforatum).
•
Caution should be used when prescribing agents such as
sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers
of CYP3A in patients receiving PREZISTA/r. This list of potential drug interactions
is not complete.
•
PREZISTA is contraindicated in patients with known hypersensitivity
to any of its ingredients. •
PREZISTA must be co-administered with 100 mg ritonavir
and food to exert its therapeutic effect. Failure to correctly administer PREZISTA
with ritonavir and food will result in reduced plasma concentration of darunavir
that will be insufficient to achieve the desired antiviral effect. Please refer
to ritonavir prescribing information for additional information on precautionary
measures.
•
Severe skin rash, including erythema multiforme and Stevens-Johnson
Syndrome has been reported in subjects receiving PREZISTA during the clinical
development program. In some cases, fever and elevations of transaminases have
also been reported. In clinical trials (n=924), rash (all grades, regardless of
causality) occurred in 7% of subjects treated with PREZISTA? discontinuation due
to rash was 0.3%. Rashes were generally mild-to-moderate, self-limiting &
maculopapular. PREZISTA should be discontinued if severe rash develops.
•
PREZISTA should be used with caution in patients with
known sulfonamide allergy.
•
New-onset or exacerbations of preexisting diabetes mellitus
and hyperglycemia, and increased bleeding in hemophiliacs have been reported in
patients receiving protease inhibitors. A causal relationship between protease
inhibitors and these events has not been established.
•
PREZISTA/r is not recommended for use in patients with
severe hepatic impairment. There are no pharmacokinetic or safety data available
regarding the use of PREZISTA/r in patients with severe hepatic impairment.
•
Redistribution and/or accumulation of body fat have been
observed in patients receiving [antiretroviral] therapy. The casual relationship,
mechanism, and long-term consequences of these events have not been established.
•
Immune reconstitution syndrome has been reported in patients
treated with [antiretroviral] therapy.
•
The potential for HIV-cross-resistance among protease
inhibitors has not been fully explored in PREZISTA/r treated patients.
•
In the pooled analysis of POWER 1 & 2 studies, the
most frequently reported drug-related adverse events of at least moderate to severe
intensity in patients receiving PREZISTA/r-containing regimen were headache (3.8%),
diarrhea (2.3%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%).
FDA
Announcement
Updates
have been made to Prezista (darunavir) tablets labeling to reflect significant
new risk information. Changes have been made to the CLINICAL PHARMACOLOGY section
to include data from 6 pharmacokinetic, drug interaction Phase 1 trials, and to
the WARNINGS, PRECAUTIONS AND ADVERSE REACTIONS sections of the package insert
to include hepatotoxicity information. Other updates include those made to PRECAUTIONS,
updates to DOSAGE AND ADMINISTRATION, and changes to Table 11 to include information
regarding a potential drug-drug interaction with rosuvastatin [Crestor]. [Changes
to WARNINGS section are detailed above, in the Tibotec letter]
The
PRECAUTIONS section has been changed to read as follows: Patients
with co-existing conditions
"Hepatic Impairment: No dose adjustment
of PREZISTA/ritonavir is necessary for patients with either mild or moderate hepatic
impairment. There are no pharmacokinetic or safety data available for subjects
with severe hepatic impairment, therefore, PREZISTA/ritonavir is not recommended
for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY,
Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and DOSAGE
AND ADMINISTRATION)." Table
11, Established and Other Potentially Significant Drug Interactions, has
been modified, under HMG-CoA Reductase Inhibitors, to include rosuvastatin, indicating
increased concentration of rosuvastatin, with the following clinical comment:
"Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin
with careful monitoring, or consider other HMG-CoA reductase inhibitors such as
fluvastatin in combination with PREZISTA/ritonavir." The
following sentence has been added to the CLINICAL PHARMACOLOGY section, under
Absorption and Bioavailabilty: "In vivo data suggests that darunavir/ritonavir
is an inhibitor of the p-glycoprotein (p-gp) transporters." The
following has been added under: Special Populations
"Hepatic
Impairment: Darunavir is primarily metabolized by the liver. The steady-state
pharmacokinetic parameters of darunavir were similar after multiple dose co-administration
of PREZISTA/ritonavir 600/100 mg b.i.d. to subjects with normal hepatic function
(n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic
impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment
on the pharmacokinetics of darunavir has not been evaluated (see PRECAUTIONS,
Patients with co-existing conditions, Hepatic Impairment and DOSAGE AND ADMINISTRATION)."
In addition,
there are updates to Table 4: Drug Interactions Pharmacokinetic Parameters
for Darunavir in the Presence of Co-administered Drugs, and Table 5: Drug
Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence
of Darunavir/Ritonavir. The
last paragraph of the ADVERSE REACTIONS section now reads:
"Patients
co-infected with hepatitis B and/or hepatitis C virus: In subjects coinfected
with hepatitis B or C virus receiving PREZISTA/ritonavir, the incidence of adverse
events and clinical chemistry abnormalities was not higher than in subjects receiving
PREZISTA/ritonavir who were not coinfected, except for increased hepatic enzymes
(see WARNINGS, Hepatotoxicity). The pharmacokinetic exposure in coinfected subjects
was comparable to that in subjects without co-infection." In
addition, the following has been added:
"Additional adverse reactions
identified in clinical studies, occurring in less than 1% of the patients, are
listed below by body system: Hepatobiliary
System: acute hepatitis, cytolytic hepatitis, hepatotoxicity, hyperbilirubinemia. Skin
and Appendages: erythema multiforme, Stevens-Johnson Syndrome
[this duplicate
information was deleted from the Skin and Appendages section under the treatment-emergent
adverse events occurring in less than 2% of de novo subjects]." Changes
were also made to DOSAGE AND ADMINISTRATION, to include the following:
"Hepatic
Impairment: No dose adjustment is required in patients with mild or moderate hepatic
impairment. There are no data regarding the use of PREZISTA/ritonavir when co-administered
to subjects with severe hepatic impairment; therefore, PREZISTA/ritonavir is not
recommended for use in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY,
Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS,
Patients with co-existing conditions, Hepatic Impairment)."
The new
label will be posted soon at DailyMed to replace the 08/2007 version.
Richard
Klein
Office of Special Health Issues
Food and Drug Administration Kimberly
Struble
Division of Antiviral Drug Products
Food and Drug Administration
Complete Prezista prescribing information The
full, revised Prezista package insert is available at:
http://www.prezista.com/prezista/documents/us_package_insert.pdf 3/12/08 Sources A
Tennenberg (Tibotec). "Dear Healthcare Professional" letter. March 11,
2008. R Klein
and K Struble (FDA). Updates to Prezista (darunavir) tablets labeling. Community
announcement. March 11, 2008. |
| |
