Additional clinically relevant adverse reactions that were reported in
< 10% of the patients with adenocarcinoma of the pancreas who received
Infections & infestations: oral candidiasis, pneumonia
Vascular disorders: hypertension
Cardiac disorders: tachycardia, congestive cardiac failure
Eye disorders: cystoid macular edema
Grade 3 peripheral neuropathy occurred in 17% of patients who received
ABRAXANE/gemcitabine compared to 1% of patients who received
gemcitabine only; no patients developed grade 4 peripheral neuropathy.
The median time to first occurrence of Grade 3 peripheral neuropathy in
the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE
dosing, the median time to improvement from Grade 3 peripheral
neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients
with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a
Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine
compared to 2% of patients who received gemcitabine alone. Sepsis
occurred both in patients with and without neutropenia. Risk factors for
sepsis included biliary obstruction or presence of biliary stent.
Pneumonitis occurred in 4% of patients who received ABRAXANE/
gemcitabine compared to 1% of patients who received gemcitabine alone.
Two of 17 patients in the ABRAXANE arm with pneumonitis died.
6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel
Unless otherwise noted, the following discussion refers to the adverse
reactions that have been identified during post-approval use of ABRAXANE.
Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure. In some instances,
severe events observed with paclitaxel injection may be expected to occur
Severe and sometimes fatal hypersensitivity reactions have been reported
with ABRAXANE. The use of ABRAXANE in patients previously exhibiting
hypersensitivity to paclitaxel injection or human albumin has not been
There have been reports of congestive heart failure, left ventricular
dysfunction, and atrioventricular block with ABRAXANE. Most of the
individuals were previously exposed to cardiotoxic drugs, such as
anthracyclines, or had underlying cardiac history.
There have been reports of pneumonitis, interstitial pneumonia and
pulmonary embolism in patients receiving ABRAXANE and reports of
radiation pneumonitis in patients receiving concurrent radiotherapy. Reports
of lung fibrosis have been received as part of the continuing surveillance of
paclitaxel injection safety and may also be observed with ABRAXANE.
Cranial nerve palsies and vocal cord paresis have been reported, as well
as autonomic neuropathy resulting in paralytic ileus.
Reports in the literature of abnormal visual evoked potentials in patients
treated with paclitaxel injection suggest persistent optic nerve damage.
These may also be observed with ABRAXANE.
Reduced visual acuity due to cystoid macular edema (CME) has been
reported during treatment with ABRAXANE as well as with other taxanes.
After cessation of treatment, CME improves and visual acuity may return
Reports of hepatic necrosis and hepatic encephalopathy leading to death
have been received as part of the continuing surveillance of paclitaxel
injection safety and may occur following ABRAXANE treatment.
There have been reports of intestinal obstruction, intestinal perforation,
pancreatitis, and ischemic colitis following ABRAXANE treatment. There
have been reports of neutropenic enterocolitis (typhlitis), despite the
coadministration of G-CSF, occurring in patients treated with paclitaxel
injection alone and in combination with other chemotherapeutic agents.
Injection Site Reaction
There have been reports of extravasation of ABRAXANE. Given the possibility
of extravasation, it is advisable to monitor closely the ABRAXANE infusion
site for possible infiltration during drug administration.
Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis
have been reported as part of the continuing surveillance of paclitaxel
injection safety. In some cases the onset of the injection site reaction in
paclitaxel injection patients either occurred during a prolonged infusion
or was delayed by a week to ten days. Recurrence of skin reactions at a
site of previous extravasation following administration of paclitaxel injection
at a different site, i.e., “recall”, has been reported.
Other Clinical Events
Skin reactions including generalized or maculopapular rash, erythema,
and pruritus have been observed with ABRAXANE. There have been case
reports of photosensitivity reactions, radiation recall phenomenon, and in
some patients previously exposed to capecitabine, reports of palmar-plantar
erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal
necrolysis have been reported.
There have been reports of conjunctivitis, cellulitis, and increased lacrimation
with paclitaxel injection.
6.5 Accidental Exposure
No reports of accidental exposure to ABRAXANE have been received.
However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes,
sore throat, and nausea have been reported. Following topical exposure,
events have included tingling, burning, and redness.
7 DRUG INTERACTIONS
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4.
Caution should be exercised when administering ABRAXANE concomitantly
with medicines known to inhibit (e.g., ketoconazole and other imidazole
antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir,
saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin,
carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category D [see Warnings and Precautions (5.8)].
There are no adequate and well-controlled studies in pregnant women using
ABRAXANE. Based on its mechanism of action and findings in animals,
ABRAXANE can cause fetal harm when administered to a pregnant woman.
If this drug is used during pregnancy, or if the patient becomes pregnant
while receiving this drug, the patient should be apprised of the potential
hazard to the fetus. Women of childbearing potential should be advised
to avoid becoming pregnant while receiving ABRAXANE.
Administration of paclitaxel formulated as albumin-bound particles to rats
during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2
(approximately 2% of the daily maximum recommended human dose on
a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine
mortality, increased resorptions (up to 5-fold), reduced numbers of litters
and live fetuses, reduction in fetal body weight and increase in fetal
anomalies. Fetal anomalies included soft tissue and skeletal malformations,
such as eye bulge, folded retina, microphthalmia, and dilation of brain
ventricles. A lower incidence of soft tissue and skeletal malformations
were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum
recommended human dose on a mg/m2 basis).
8.3 Nursing Mothers
It is not known whether paclitaxel is excreted in human milk. Paclitaxel
and/or its metabolites were excreted into the milk of lactating rats. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants, a decision should be made
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.