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
Doxil Side Effects, and Drug Interactions - Doxorubicin
Doxil Side Effects, and Drug Interactions - Doxorubicin
SIDE EFFECTS
Ovarian Cancer Patients
Safety data are available from 373 ovarian
cancer patients treated
with Doxil in 4 clinical
studies. The patient
population was predominantly
white (93.6%) with a median
age of 60 years. Patients
received a median cycle
dose of 50 mg/m2 administered with a median
cycle length
of 29.5 days. They remained on study drug
for a median of 56 days
and received a median
cumulative dose
of 137.5 mg/m2. Patients received a median of 3-cycles
of Doxil , although some patients remained on study drug for a prolonged
period, with 46 patients (12.3%) receiving more than 10 cycles of
treatment.
Adverse events (AEs) were reported in all but 2 of the 361 patients
who had at least one AE form
collected. A total of 3,124 AEs were reported, an average
of 8.6 AEs per patient.
Most (91.7%) patients had AEs that were considered related to study
drug.
Drug-Related Adverse Events Reported in ³
5% of Ovarian Cancer Patients
|
Adverse Effect
|
% Ovarian Patients
|
|
Hematologic
|
(n= 373)
|
|
Leukopenia
|
|
< 4,000/ mm3
|
42.2
|
|
< 1,000/ mm3
|
8.3
|
|
G-CSF or GM-CSF support*
|
3.3
|
|
Neutropenia
|
|
<2000/ mm3
|
51.7
|
|
<500/ mm3
|
8.3
|
|
Febrile neutropenia
|
0.3
|
|
Anemia
|
|
<10 g/dL
|
52.6
|
|
<8 g/dL
|
25.0
|
|
RBC transfusions
|
12.9
|
|
Epoetin alpha
support*
|
2.1
|
|
Thrombocytopenia
|
|
<150,000/ mm3
|
24.2
|
|
<25,000/ mm3
|
1.1
|
|
Platelet transfusions*
|
1.4
|
|
Non-Hematologic
|
(n= 361)
|
|
Palmar-plantar erythrodysesthesia
|
|
All Grades
|
37.4
|
|
Grade 3 & 4
|
16.4
|
|
Stomatitis
|
|
All Grades
|
37.4
|
|
Grade 3 & 4
|
7.7
|
|
Nausea
|
|
All Grades
|
37.7
|
|
Grade 3 & 4
|
4.2
|
|
Asthenia
|
33.0
|
|
Vomiting
|
22.4
|
|
Rash
|
21.6
|
|
Alopecia
|
15.2
|
|
Constipation
|
12.7
|
|
Anorexia
|
11.9
|
|
Mucous Membrane Disorder
|
11.6
|
|
Diarrhea
|
10.0
|
|
Abdominal Pain
|
8.0
|
|
Paresthesia
|
7.8
|
|
Pain
|
7.2
|
|
Fever
|
6.9
|
|
Pharyngitis
|
5.5
|
|
Dry Skin
|
5.5
|
|
Headache
|
5.3
|
*From concomitant
medication or transfusion
logs, not reported as AEs.
The following additional (not in table) adverse events were
observed in ovarian
cancer patients with
doses administered every four weeks; only events considered at least
possibly drug-related by investigators are included.
Incidence 1% to 5%
- Body as a Whole: allergic
reaction, chills,
infection, chest pain,
back pain,
abdomen enlarged,
malaise.
- Digestive System: dyspepsia, oral
moniliasis, mouth ulceration,
esophagitis, dysphagia.
- Metabolic and Nutritional System: peripheral
edema, dehydration.
- Musculoskeletal System: myalgia.
- Nervous System: somnolence,
dizziness, depression,
insomnia, anxiety.
- Respiratory System: dyspnea,
cough increased, rhinitis.
- Cutaneous: pruritus,
skin discoloration, skin
disorder, vesiculobullous rash,
maculopapular
rash, exfoliative dermatitis,
herpes zoster, sweating.
- Special Senses: conjunctivitis, taste
perversion.
Incidence Less Than 1%
- Body As A Whole:
cellulitis, anaphylactoid reaction, ascites, flu
syndrome, neck
pain, moniliasis, injection
site pain,
face edema, chills and fever,
pelvic pain,
chest pain
substernal, injection site inflammation.
- Cardiovascular System: hypertension,
angina pectoris, pericardial
effusion, postural
hypotension, hypotension,
palpitation, syncope,
shock, bradycardia,
arrhythmia, phlebitis,
tachycardia, cardiomegaly,
heart failure, hemorrhage.
- Digestive System: gingivitis,
eructation, increased
salivation, melena, gastrointestinal
hemorrhage, proctitis,
jaundice, ileus,
periodontal abscess, flatulence,
aphthous stomatitis,
gastritis, glossitis,
gum hemorrhage.
- Hemic and Lymphatic System: hypochromic anemia,
lymphadenopathy, eccymosis, petechia.
- Metabolic/Nutritional Disorders: SGOT increase,
creatinine increase, hypocalcemia, hyperglycemia,
hypokalemia, hypermagnesemia,
hyponatremia, weight gain, bilirubinemia, generalized edema,
cachexia, hypochloremia.
- Musculoskeletal System: arthralgia,
bone pain,
myasthenia.
- Nervous System: peripheral neuritis,
incoordination, thinking abnormal, confusion,
hypertonia, nervousness,
hyperesthesia,
hypesthesia, neuropathy, ataxia.
- Respiratory System: pleural
effusion, asthma,
hiccup, pneumothorax, laryngitis,
sinusitis, voice
alteration, epistaxis,
pneumonia.
- Skin and Appendages: skin
ulcer, herpes
simplex, contact dermatitis, fungal dermatitis,
furunculosis, skin nodule,
urticaria, acne.
- Special Senses: amblyopia,
blepheritis, parosmia,
taste loss.
- Urogenital System: urinary
tract infection,
leukorrhea, cystitis, nocturia,
dysuria, breast
pain, mastitis, oliguria,
vaginitis, kidney function
abnormal, vaginal
hemorrhage, hydronephrosis,
vaginal moniliasis.
AIDS-KS Patients
Information on adverse events is based on the experience
reported in 753 patients with AIDS-related KS enrolled in four studies.
The majority of patients were treated with 20 mg/m2 of
Doxil (doxorubicin HCl liposome
injection) every two to three weeks. The median
time on study was 127 days
and ranged from 1 to 811 days. The median
cumulative dose was
120 mg/m2 and ranged from 3.3 to 798.6 mg/m2
. Twenty-six patients (3.0%) received cumulative
doses of greater than 450 mg/m2 .
Of these 753 patients, 61.2% were considered p.o.
risk for KS tumor burden,
91.5% p.o. for immune
system, and 46.9% for systemic
illness; 36.2% were p.o.
risk for all three categories.
Patients’ median CD4
count was 21.0 cells/mm3
, with 50.8% of patients having less than 50 cells/mm3
. The mean absolute
neutrophil count
at study entry was approximately 3000 cells/mm3 .
Patients received a variety
of potentially myelotoxic
drugs in combination with Doxil. Of the 693 patients with concomitant
medication information,
58.7% were on one or more antiretroviral
medications; 34.9% patients were on zidovudine
(AZT), 20.8% on didanosine
(ddI), 16.5% on zalcitabine
(ddC), and 9.5% on stavudine
(D4T). A total of 85.1% patients were on PCP
prophylaxis, most (54.4%) on sulfamethoxazole/ trimethoprim. Eighty-five
percent of patients
were receiving antifungal
medications, primarily fluconazole (75.8%). Seventy-two percent
of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir,
and 16% foscarnet. In addition,
47.8% patients received colony stimulating factors (sargramostim/
filgrastim) sometime during their course of treatment.
Of the 753 patients enrolled in the Doxil clinical
trials, adverse event information was available for 705 patients.
In many instances it was
difficult to determine whether adverse events resulted from Doxil,
from concomitant therapy, or from the patients’ underlying disease(s).
Eighty-three percent
of the patients reported adverse events that were considered to
be possibly or probably related to the treatment
with Doxil.
Adverse reactions only infrequently (5%) led to discontinuation
of treatment. Those that did so included bone
marrow suppression,
cardiac adverse events,
infusion-related reactions, toxoplasmosis, palmar-plantar erythrodysesthesia,
pneumonia, cough/dyspnea, fatigue,
optic neuritis,
progression of a
non-KS tumor, allergy
to penicillin, and unspecified reasons.
Probably and Possibly Drug-Related Adverse Events Reported in
³ 5%
of AIDS-KS Patients
|
|
Refractory or
Intolerant
AIDS-KS Patients
|
Total AIDS-KS
Patients
|
|
Number of Patients
|
77
|
705
|
|
Number of Patients Reporting Adverse Events
|
57 (74.0%)
|
586 (83.1%)
|
|
Adverse Event
|
|
Neutropenia
(ANC <1000/mm)3
|
34 (44.2%)
|
352 (49.9%)
|
|
Anemia
|
5 (6.5%)
|
137 (19.4%)
|
|
Nausea
|
14 (18.2%)
|
119 (16.9%)
|
|
Asthenia
|
5 (6.5%)
|
70 (9.9%)
|
|
Hypochromic Anemia
|
4 (5.2%)
|
69 (9.8%)
|
|
Thrombocytopenia
|
5 (6.5%)
|
65 (9.2%)
|
|
Fever
|
6 (7.8%)
|
64 (9.1%)
|
|
Alopecia
|
7 (9.1%)
|
63 (8.9%)
|
|
Alkaline Phosphatase Increase
|
1 (1.3%)
|
55 (7.8%)
|
|
Vomiting
|
6 (7.8%)
|
55 (7.8%)
|
|
Diarrhea
|
4 (5.2%)
|
55 (7.8%)
|
|
Stomatitis
|
4 (5.2%)
|
48 (6.8%)
|
|
Oral Moniliasis
|
1 (1.3%)
|
39 (5.5%)
|
The following additional (not in table) adverse events were
observed in AIDS-KS patients; only events considered at least possibly
drug-related by investigators are included.
Incidence 1% to 5%
- Body as a Whole: headache,
back pain,
infection, allergic
reaction, chills.
- Cardiovascular: chest
pain, hypotension,
tachycardia.
- Cutaneous: Herpes simplex, rash,
itching.
- Digestive System: mouth
ulceration, glossitis, constipation, aphthous stomatitis,
anorexia, dysphagia,
abdominal pain.
- Hematologic: hemolysis, increased prothrombin
time.
- Metabolic/Nutritional: SGPT
increase, weight loss,
hypocalcemia, hyperbilirubinemia, hyperglycemia.
- Other: dyspnea, albuminuria,
pneumonia, retinitis,
emotional lability, dizziness,
somnolence.
Incidence Less Than 1%
- Body As A Whole:
face edema,
cellulitis, sepsis,
abscess, radiation injury,
flu syndrome,
moniliasis, hypothermia,
injection site hemorrhage,
injection site
pain, cryptococcosis,
ascites.
- Cardiovascular System: thrombophlebitis,
cardiomyopathy, pericardial effusion,
hemorrhage, palpitation,
syncope, bundle
branch block, congestive
heart failure, cardiomegaly,
heart arrest, migraine,
thrombosis, ventricular arrhythmia.
- Digestive System: dyspepsia, cholestatic jaundice,
gingivitis, gastritis, ulcerative
proctitis, colitis,
esophageal ulcer,
esophagitis, gastrointestinal hemorrhage,
hepatic failure, leukoplakia
of mouth, pancreatitis,
ulcerative stomatitis,
hepatitis, hepatosplenomegaly,
increased appetite, jaundice, sclerosing
cholangitis, tenesmus, fecal impaction.
- Endocrine System: diabetes
mellitus.
- Hemic and Lymphatic System: eosinophilia,
lymphadenopathy, lymphangitis, lymphedema, petechia, thromboplastin
decrease.
- Metabolic/Nutritional Disorders: lactic dehydrogenase
increase, hypernatremia, creatinine
increase, BUN increase,
dehydration, edema, hypercalcemia,
hyperkalemia,
hyperlipemia, hyperuricemia,
hypoglycemia, hypokalemia, hypolipemia, hypomagnesemia,
hyponatremia,
hypophosphatemia, hypoproteinemia, ketosis, weight
gain.
- Musculoskeletal System: myalgia,
arthralgia, bone
pain, myositis.
- Nervous System: paresthesia,
insomnia, peripheral
neuritis, depression, neuropathy,
anxiety, convulsion,
hypotonia, acute
brain syndrome, confusion,
hemiplegia, hypertonia,
hypokinesia, vertigo.
- Respiratory System: pleural effusion,
asthma, bronchitis,
cough increase, hyperventilation,
pharyngitis, pneumothorax,
rhinitis, sinusitis.
- Skin and Appendages: maculopapular
rash, skin
ulcer, skin discoloration, herpes
zoster, exfoliative dermatitis,
cutaneous moniliasis,
erythema multiforme, erythema
nodosum, furunculosis, psoriasis,
pustular rash, skin necrosis,
urticaria, vesciculbullous
rash.
- Special Senses: otitis media, taste
perversion, abnormal vision, blindness, conjunctivitis,
eye pain,
optic neuritis,
tinnitus, visual field
defect.
- Urogenital System: hematuria,
balanitis, cystitis,
dysuria, genital edema,
glycosuria, kidney
failure.
DRUG INTERACTIONS
No formal drug interaction
studies have been conducted with Doxil . Until specific
compatibility
data are available, it is not recommended that Doxil be mixed
with other drugs. Doxil may interact with the conventional formulation
of doxorubicin HCl.
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