A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Taxol Side Effects, and Drug Interactions - Paclitaxel
Taxol Side Effects, and Drug Interactions - Paclitaxel
SIDE EFFECTS
Data in the following table
are based on the experience
of 812 patients (493 with ovarian
carcinoma and 319
with breast carcinoma)
enrolled in 10 studies. Two hundred and seventy-five patients were
treated in 8 Phase 2 studies with TAXOL doses ranging from 135 to
300 mg/m2 administered over 24 hours (in 4 of these studies,
G-CSF was administered as hematopoietic support). Three hundred
and one patients were treated in the randomized Phase 3 ovarian
carcinoma study which
compared two doses (135 or 175 mg/m2) and two schedules
(3 or 24 hours) of TAXOL. Two hundred and thirty-six patients with
breast carcinoma
received TAXOL (135 or 175 mg/m2) administered over 3
hours in a controlled study.
|
Summary of Adverse Events in 812 Patients With Solid
Tumors
|
|
Receiving Single-Agent TAXOL
|
| |
|
% Incidence
|
| • Bone Marrow |
|
|
| -
Neutropenia |
<
2,000/mm3 |
90
|
| |
< 500/mm3 |
52
|
| - Leukopenia |
< 4,000/mm3 |
90
|
| |
< 1,000/mm3 |
17
|
| - Thrombocytopenia |
< 100,000/mm3 |
20
|
| |
< 50,000/mm3 |
7
|
| - Anemia |
< 11 g/dL |
78
|
| |
< 8 g/dL |
16
|
| - Infections |
|
30
|
| - Bleeding |
|
14
|
| - Red Cell Transfusions |
|
25
|
| - Platelet Transfusions |
|
2
|
| • Hypersensitivity
Reaction1 |
|
|
| - All |
|
41
|
| - Severe |
|
2
|
| • Cardiovascular |
|
|
| - Vital Sign Changes2 |
|
|
| --- Bradycardia (N=537) |
|
3
|
| --- Hypotension (N=532) |
|
12
|
| - Significant Cardiovascular
Events |
|
1
|
| • Abnormal ECG
|
|
|
| - All Pts |
|
23
|
| - Pts with normal
baseline (N=559) |
|
14
|
| • Peripheral Neuropathy |
|
|
| - Any symptoms |
|
60
|
| - Severe symptoms |
|
3
|
| • Myalgia/ Arthralgia |
|
|
| - Any symptoms |
|
60
|
| - Severe symptoms
|
|
8
|
| • Gastrointestinal
|
|
|
| - Nausea and vomiting |
|
52
|
| - Diarrhea |
|
38
|
| - Mucositis |
|
31
|
| • Alopecia |
|
87
|
| • Hepatic (Pts
with normal baseline and on study data) |
| - Bilirubin elevations
(N=765) |
|
7
|
| - Alkaline phosphatase
elevations (N=575) |
|
22
|
| - AST
(SGOT) elevations (N=591) |
|
19
|
| • Injection Site
Reaction |
|
13
|
| 1
All patients received premedication
2 During the first 3- hours of infusion
|
None of the observed toxicities were clearly influenced by age.
The following table shows
the frequency of important
adverse events in the 85 patients with KS treated with two different
TAXOL (paclitaxel) Injection regimens.
|
Frequency* of Important Adverse Events
|
|
in the AIDS- Related Kaposi’s Sarcoma Studies
|
| |
|
Percent of Patients
|
| |
|
Study CA139-174
|
Study CA139-281
|
| |
|
135 mg/m2q 3 wk
|
100 mg/m2 q 2 wk
|
| |
|
(n=29)
|
(n=56)
|
| • Bone Marrow
|
|
|
|
| - Neutropenia |
< 2,000/mm3
|
100
|
95
|
| |
< 500/mm3
|
76
|
35
|
| - Thrombocytopenia
|
< 100,000/mm3
|
52
|
27
|
| |
< 50,000/mm3
|
17
|
5
|
| - Anemia |
< 11 g/dL |
86
|
73
|
| |
< 8 g/dL |
34
|
25
|
| - Febrile Neutropenia
|
|
55
|
9
|
| • Opportunistic
Infection |
|
|
|
| - Any |
|
76
|
54
|
| - Cytomegalovirus
|
|
45
|
27
|
| - Herpes Simplex
|
|
38
|
11
|
| - Pneumocystis
carinii |
|
14
|
21
|
| - M. avium intracellulare
|
|
24
|
4
|
| - Candidiasis, esophageal
|
|
7
|
9
|
| - Cryptosporidiosis
|
|
7
|
7
|
| - Cryptococcal meningitis
|
|
3
|
2
|
| - Leukoencephalopathy
|
|
–
|
2
|
| • Hypersensitivity
Reaction** |
|
|
|
| - All |
|
14
|
9
|
| • Cardiovascular |
|
|
|
| - Hypotension |
|
17
|
9
|
| - Bradycardia |
|
3
|
–
|
| • Peripheral Neuropathy |
|
|
|
| - Any |
|
79
|
46
|
| - Severe |
|
10
|
2
|
| • Myalgia/ Arthralgia |
|
|
|
| - Any |
|
93
|
48
|
| - Severe |
|
14
|
16
|
| • Gastrointestinal |
|
|
|
| - Nausea and Vomiting |
|
69
|
70
|
| - Diarrhea |
|
90
|
73
|
| - Mucositis |
|
45
|
20
|
| • Renal (creatinine
elevation) |
|
|
|
| - Any |
|
34
|
18
|
| - Severe (grade III/
IV) |
|
7
|
5
|
| • Discontinuation
for drug toxicity |
|
7
|
16
|
| * Based on worst
course analysis |
| ** All patients
received premedication |
As demonstrated in this table, toxicity
was more pronounced in the study utilizing TAXOL at a dose
of 135 mg/m2 every 3 weeks than in the study utilizing
TAXOL at a dose of 100
mg/m2 every 2 weeks. Notably, severe neutropenia
(76% versus 35%), febrile
neutropenia (55%
versus 9%), and opportunistic infections (76% versus 54%) were more
common with the former dose
and schedule. The differences between the two studies with respect
to dose escalation and
use of hematopoietic
growth factors, as described
above, should be taken into account. (See CLINICAL
PHARMACOLOGY, CLINICAL STUDIES: AIDS-Related Kaposi’s
Sarcoma section.) Note also that only 26% of the 85 patients
in these studies received concomitant treatment
with protease inhibitors, whose effect
on paclitaxel metabolism has not yet been studied.
The following discussion refers to the overall safety database
of 812 patients with solid
tumors treated in clinical
studies. The frequency
and severity of adverse events have been generally similar for patients
receiving TAXOL for the treatment
of ovarian or breast
carcinoma or for Kaposi’s
sarcoma, but patients with AIDS-related Kaposi’s sarcoma
may have more frequent and severe hematologic toxicity,
infections, and febrile
neutropenia. These patients require a lower dose
intensity and supportive
care. (See CLINICAL PHARMACOLOGY,
CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma section.) In
addition, rare events have been reported from the postmarketing
experience or from
other clinical studies; toxicities that were observed only in the
population with Kaposi’s
sarcoma or that occurred with greater severity in this population
are also described. The frequency
and severity of important adverse events for the Phase 3 ovarian
and breast carcinoma
studies are presented in tabular
form by treatment
arm in the CLINICAL
PHARMACOLOGY - CLINICAL STUDIES section.
Hematologic: Bone marrow
suppression was
the major dose-limiting toxicity of TAXOL. Neutropenia, the most
important hematologic toxicity, was dose
and schedule dependent
and was generally rapidly reversible. Among patients treated in
the Phase 3 ovarian
study with a 3-hour infusion,
neutrophil counts declined below 500 cells/mm3 in 13%
of the patients treated with a dose
of 135 mg/m2 compared to 27% at a dose
of 175 mg/m2 (p= 0.05). In
the same study, severe neutropenia
(<500 cells/mm3) was more frequent with the 24-hour
than with the 3-hour infusion; infusion duration had a greater impact
on myelosuppression
than dose. Neutropenia did not appear to increase with cumulative
exposure and did not
appear to be more frequent nor more severe for patients previously
treated with radiation therapy.
Fever was frequent (12% of all treatment
courses). Infectious episodes occurred in 30% of all patients and
9% of all courses; these episodes were fatal in 1% of all patients,
and included sepsis,
pneumonia and peritonitis.
In the Phase 3 ovarian
study, infectious
episodes were reported in 19% of the patients given either 135 or
175 mg/m2 dose
by a 3-hour infusion. Urinary tract
infections and upper respiratory
tract infections were
the most frequently reported infectious
complications. In the immunosuppressed
patient population
with advanced HIV disease
and poor-risk AIDS-related Kaposi’s sarcoma, 61% of the patients
reported at least one opportunistic infection. (See CLINICAL
PHARMACOLOGY, CLINICAL STUDIES: AIDS- Related Kaposi’s
Sarcoma section.) The use of supportive therapy,
including G-CSF, is recommended for patients who have experienced
severe neutropenia. (See DOSAGE
AND ADMINISTRATION section.)
Thrombocytopenia was uncommon, and almost never severe (< 50,000
cells/mm3 ). Twenty percent
of the patients experienced a drop in their platelet
count below 100,000 cells/mm3
at least once while on treatment; 7% had a platelet
count <50,000 cells/mm3
at the time of their worst
nadir. Among the 812 patients, bleeding
episodes were reported in 4% of all courses and by 14% of all patients
but most of the hemorrhagic
episodes were localized
and the frequency
of these events was unrelated to the TAXOL dose
and schedule. In the Phase
3 ovarian study, bleeding
episodes were reported in 10% of the patients receiving either the135
or 175 mg/m2 dose
given by a 3-hour infusion; no
patients treated with the 3-hour infusion
received platelet transfusions.
Anemia (Hb <11 g/dL) was observed in 78% of all patients and
was severe (Hb <8 g/dL) in 16% of the cases. No
consistent relationship between dose
or schedule and the
frequency of anemia
was observed. Among all patients with normal
baseline hemoglobin,
69% became anemic on
study but only 7% had severe anemia. Red cell
transfusions were required in 25% of all patients and in 12% of
those with normal baseline
hemoglobin levels.
Hypersensitivity Reactions (HSRs): All patients received
premedication prior to TAXOL (see WARNINGS
and PRECAUTIONS: Hypersensitivity
REACTIONSsections). The frequency
and severity of HSRs were not affected by the dose
or schedule of TAXOL
(paclitaxel) Injection administration. In the Phase 3 ovarian
study the 3-hour infusion
was not associated with a greater increase in HSRs when compared
to the 24-hour infusion. Hypersensitivity reactions were observed
in 20% of all courses and in 41% of all patients. These reactions
were severe in less than 2% of the patients and 1% of the courses.
No severe reactions were
observed after course 3 and severe symptoms occurred generally within
the first hour of TAXOL infusion. The most frequent symptoms observed
during these severe reactions were dyspnea,
flushing, chest pain and
tachycardia.
The minor hypersensitivity
reactions consisted mostly of flushing (28%), rash (12%), hypotension
(4%), dyspnea (2%),
tachycardia (2%)
and hypertension (1%). The frequency
of hypersensitivity
reactions remained relatively stable during the entire
treatment period.
Rare reports of chills and reports of back
pain in association
with hypersensitivity reactions have been received as proof
of the continuing surveillance of TAXOL safety.
Cardiovascular: Hypotension, during the first 3 hours of
infusion, occurred in 12% of all patients and 3% of all courses
administered. Bradycardia, during the first 3 hours of infusion,
occurred in 3% of all patients and 1% of all courses. In
the Phase 3 ovarian
study, neither dose nor
schedule had an effect
on the frequency of
hypotension and
bradycardia. These vital sign changes most often caused no
symptoms and required neither specific therapy nor treatment
discontinuation. The frequency
of hypotension and
bradycardia were not influenced by prior anthracycline
therapy.
Significant cardiovascular
events possibly related to TAXOL occurred in approximately 1% of
all patients. These events included syncope,
rhythm abnormalities, hypertension
and venous thrombosis.
One of the patients with syncope
treated with TAXOL at 175 mg/m2 over 24 hours had progressive
hypotension and
died. The arrhythmias included asymptomatic ventricular tachycardia,
bigeminy and complete
AV block requiring pacemaker
placement.
Electrocardiogram (ECG) abnormalities were common among patients
at baseline. ECG abnormalities
on study did not usually result in symptoms, were not dose-limiting,
and required no intervention.
ECG abnormalities were noted
in 23% of all patients. Among patients with a normal
ECG prior to study entry,
14% of all patients developed an abnormal
tracing while on study.
The most frequently reported ECG
modifications were non-specific repolarization abnormalities, sinus
bradycardia, sinus
tachycardia and
premature beats. Among patients with normal
ECGs at baseline, prior
therapy with anthracyclines did not influence the frequency
of ECG abnormalities.
Cases of myocardial
infarction have been
reported rarely. Congestive heart failure
has been reported typically in patients who have received other
chemotherapy, notably
anthracyclines. (See DRUG INTERACTIONS
section.)
Rare reports of atrial
fibrillation and
supraventricular
tachycardia have been received as proof
of the continuing surveillance
of TAXOL safety.
Respiratory: Rare reports of interstitial
pneumonia, lung
fibrosis and pulmonary
embolism have been
received as proof of the
continuing surveillance of TAXOL safety. Rare reports of radiation
pneumonitis have
been received in patients receiving concurrent radiotherapy.
Neurologic: The frequency
and severity of neurologic manifestations were dose-dependent, but
were not influenced by infusion
duration. Peripheral neuropathy was observed in 60% of all patients
(3% severe) and in 52% (2% severe) of the patients without pre-existing
neuropathy.
The frequency of
peripheral neuropathy
increased with cumulative
dose. Neurologic symptoms were observed in 27% of the patients after
the first course of treatment
and in 34-51% from course 2 to 10.
Peripheral neuropathy
was the cause of TAXOL
discontinuation in 1% of all patients. Sensory symptoms have usually
improved or resolved within several months of TAXOL discontinuation.
The incidence of neurologic
symptoms did not increase in the subset of patients previously treated
with cisplatin. Pre-existing neuropathies resulting from prior therapies
are not a contraindication for TAXOL therapy.
Other than peripheral
neuropathy, serious
neurologic events following TAXOL administration
have been rare (< 1%) and have included grand mal seizures, syncope,
ataxia and neuroencephalopathy.
Rare reports of autonomic
neuropathy resulting
in paralytic ileus
have been received as proof
of the continuing surveillance
of TAXOL safety. Optic nerve and
or visual disturbances
(scintillating scotomata) have also been reported, particularly
in patients who have received higher doses than those recommended.
These effects generally have been reversible. However, rare reports
in the literature of abnormal
visual evoked potentials
in patients have suggested persistent optic
nerve damage.
Arthralgia/ Myalgia: There was no
consistent relationship between dose or schedule
of TAXOL and the frequency
or severity of arthralgia/ myalgia. Sixty percent
of all patients treated experienced arthralgia/myalgia; 8% experienced
severe symptoms. The symptoms were usually transient, occurred two
or three days after TAXOL administration, and resolved within a
few days. The frequency
and severity of musculoskeletal
symptoms remained unchanged throughout the treatment
period.
Hepatic: No relationship
was observed between liver
function abnormalities and either dose
or schedule of TAXOL
administration. Among patients with normal
baseline liver
function 7%, 22% and
19% had elevations in bilirubin,
alkaline phosphatase
and AST (SGOT), respectively.
Prolonged exposure to TAXOL was not associated with cumulative
hepatic toxicity.
Rare reports of hepatic
necrosis and hepatic
encephalopathy
leading to death have
been received as proof of
the continuing surveillance
of TAXOL safety.
Renal: Among the patients treated for Kaposi’s sarcoma
with TAXOL, five patients had renal
toxicity of grade
III or IV severity. One patient
with suspected HIV nephropathy
of grade IV
severity had to discontinue therapy. The other four patients had
renal insufficiency
with reversible elevations of serum
creatinine.
Gastrointestinal (GI): Nausea/ vomiting,
diarrhea and mucositis
were reported by 52%, 38% and 31% of all patients, respectively.
These manifestations were usually mild to moderate. Mucositis was
schedule dependent
and occurred more frequently with the 24-hour than with the 3-hour
infusion.
In patients with poor-risk AIDS-related Kaposi’s sarcoma, nausea/vomiting,
diarrhea, and mucositis
were reported by 69%, 79%, and 28% of patients, respectively. One
third of patients with Kaposi’s sarcoma
complained of diarrhea prior to study start. (See CLINICAL
PHARMACOLOGY, CLINICAL STUDIES: AIDS- Related Kaposi’s
Sarcoma section.)
Rare reports of intestinal
obstruction, intestinal
perforation, pancreatitis,
ischemic colitis, and
dehydration have
been received as proof of
the continuing surveillance of TAXOL safety. Rare reports of neutropenic
enterocolitis (typhlitis), despite the coadministration
of G-CSF, were observed in patients treated with TAXOL alone and
in combination with other chemotherapeutic agents.
Injection Site Reaction: Injection site
reactions, including reactions secondary
to extravasation, were usually mild and consisted of erythema, tenderness,
skin discoloration, or
swelling at the injection
site. These reactions have been observed more frequently with the
24-hour infusion than with the 3-hour infusion. Recurrence of skin
reactions at a site of
previous extravasation
following administration
of TAXOL at a different site, i.e., "recall", has been
reported rarely.
Rare reports of more severe events such
as phlebitis, cellulitis,
induration, skin exfoliation, necrosis
and fibrosis have been
received as proof of the
continuing surveillance
of TAXOL safety. In some
cases the onset of the injection site
reaction either occurred
during a prolonged infusion
or was delayed by a week to ten days.
A specific treatment
for extravasation
reactions is unknown at this time. Given the possibility of extravasation,
it is advisable to closely monitor the infusion
site for possible infiltration
during drug administration.
Other Clinical Events: Alopecia was observed in almost all
(87%) of the patients. Transient skin
changes due to TAXOL- related hypersensitivity reactions have been
observed, but no other skin
toxicities were significantly associated with TAXOL (paclitaxel)
Injection administration. Nail changes (changes in pigmentation
or discoloration of nail
body were uncommon (2%).
Edema was reported in 21% of all patients (17% of those without
baseline edema); only 1% had severe edema
and none of these patients required treatment discontinuation. Edema
was most commonly focal
and disease-related. Edema was observed in 5% of all courses for
patients with normal
baseline and did not
increase with time on study.
Rare reports of skin abnormalities
related to radiation
recall as well as reports
of maculopapular
rash and pruritus
have been received as part of the continuing surveillance
of TAXOL safety.
Reports of asthenia
and malaise have been
received as proof of the
continuing surveillance of TAXOL safety.
Accidental Exposure: Upon inhalation, dyspnea,
chest pain,
burning eyes, sore throat
and nausea have been
reported. Following topical
exposure, events have included tingling, burning and redness.
DRUG INTERACTIONS
In a Phase I trial using escalating doses of TAXOL (110-200 mg/m2
) and cisplatin (50
or 75 mg/m2) given as sequential
infusions, myelosuppression was more profound when TAXOL was given
after cisplatin than with the alternate sequence
(i.e., TAXOL before cisplatin). Pharmacokinetic data from these
patients demonstrated a decrease in paclitaxel clearance of approximately
33% when TAXOL was administered following cisplatin.
The metabolism of
TAXOL is catalyzed by cytochrome
P450 isoenzymes CYP2C8 and CYP3A4. In
the absence of formal
clinical drug
interaction studies, caution should be exercised when administering
TAXOL concomitantly with known substrates or inhibitors of the cytochrome
P450 isoenzymes CYP2C8 and CYP3A4. (See CLINICAL
PHARMACOLOGY section.)
Potential interactions between paclitaxel, a substrate
of C.P.A. and protease
inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which
are substrates and/or inhibitors of C.P.A.
have not been evaluated in clinical
trials.
Reports in the literature suggest that plasma
levels of doxorubicin (and its active metabolite
doxorubicinol) may be increased when paclitaxel and doxorubicin
are used in combination.
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