Approved Drug Label (PDF)
4
Contraindications
4 CONTRAINDICATIONS
(Additions and/or revisions are
underlined)
HYCAMTIN is contraindicated in patients who have a history of
severe hypersensitivity reactions to topotecan. Reactions have included
anaphylactoid reactions.
5
Warnings and Precautions
5.1 Myelosuppression
(Additions and/or revisions are underlined)
HYCAMTIN can cause severe
myelosuppression. The following safety data are based on an integrated safety database from
four trials in patients with
lung cancer (N = 682) who
received HYCAMTIN capsules
at a dose of 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day
cycle.
The median day for neutrophil and platelet nadirs occurred
on Day 15.Grade 4 neutropenia occurred
in 32% of the 682 patients, with a median duration
of7 days. Grade 4 neutropenia most commonly occurred during cycle 1 (20%
of patients). Clinical sequelae
of neutropenia included infection (17%), febrile neutropenia (4%), sepsis
(2%), and septic death (1%). Grade
4 thrombocytopenia occurred
in 6%, with a median duration
of 3 days.
Grade 3 or 4 anemia occurred in 25%.
HYCAMTIN can cause fatal typhlitis
(neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia,
and abdominal pain.
Administer the first cycle
of HYCAMTIN capsules
only to patients with a baseline
neutrophil count greater than
or equal to 1,500/mm3 and
a platelet count greater than
or equal to 100,000/mm3. Monitor blood cell counts
frequently during treatment. Withhold and reduce
dose of HYCAMTIN capsules based on
neutrophil counts, platelet counts and hemoglobin levels.
5.2 Diarrhea
(Additions and/or revisions are
underlined)
Diarrhea, including severe
and life-threatening diarrhea requiring hospitalization,
can occur with HYCAMTIN capsules.
Diarrhea can occur at the
same time as drug-induced
neutropenia and its sequelae.
In the 682 patients who
received HYCAMTIN capsules in the four lung cancer
trials, the incidence of diarrhea
caused by HYCAMTIN
capsules was 22%, including Grade 3 (4%) and
Grade 4 (0.4%). The
incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia was 5%. The median
time to onset of Grade 2 to 4 diarrhea
was 9 days in the group receiving HYCAMTIN capsules.
Monitor patients for diarrhea and treat
with antidiarrheals at the first
sign of diarrhea. Withhold and dose
reduce as recommended
based on severity.
5.3 Interstitial Lung Disease
(Additions and/or revisions are
underlined)
Interstitial lung disease (ILD), including
fatalities, can occur with HYCAMTIN.
Underlying risk factors include
history of ILD,
pulmonary fibrosis, lung cancer, thoracic radiation,
and use of pneumotoxic drugs or
colony stimulating factors.
Monitor for pulmonary symptoms indicative
of ILD. Permanently discontinue
HYCAMTIN capsules if ILD is confirmed.
5.4 Embryo-Fetal Toxicity
(Additions and/or revisions are underlined)
Based on animal data, HYCAMTIN can cause
fetal harm when administered to a pregnant woman. Topotecan caused
embryolethality, fetotoxicity, and teratogenicity in
rats and rabbits when administered during organogenesis.
Advise women of the potential risk to fetus Advise
females of reproductive potential
to use effective contraception during
treatment and for at least 6 months after the
last dose of HYCAMTIN
capsules. Advise
males with a female partner of reproductive potential
to use effective contraception
during treatment with HYCAMTIN
capsules and for 3 months after the last dose.
6
Adverse Reactions
6 ADVERSE REACTIONS
(Additions and/or revisions are
underlined)
The
following serious adverse reactions are described elsewhere in the labeling:
6.1 Clinical Trials Experience
(Additions and/or revisions are underlined)
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed
in the clinical trials of a drug
cannot be directly compared with rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
The data in the Warnings and Precautions
and below reflects exposure to
HYCAMTIN capsules in 682 patients
with recurrent lung cancer in four randomized,
open label trials, including
275 patients with
small lung cell
lung cancer (SCLC) (Studies
478, 065 and 396), and 407 patients with non-small
cell lung cancer (NSCLC) (Study 387),
who
received at least
one dose of HYCAMTIN
capsules. Patients in these
trials had advanced lung
cancer and received prior chemotherapy in the
first-line setting. received
HYCAMTIN capsules 2.3 mg/m2 orally once daily
for 5 consecutive days, starting on Day 1 of a 21-day
cycle. The median number of cycles was
3 (range:
1 to 20).
The safety of HYCAMTIN capsules was evaluated in a randomized trial (Study 478) conducted
in 70 patients with
recurrent SCLC .
In the 682 patients who
received HYCAMTIN capsules
in the four lung cancer trials, 39 deaths (6%) occurred
within 30 days after
the last dose for a reason other than progressive disease:
13 due to hematologic toxicity, 5 due to non-hematologic toxicity (2
from diarrhea), and
21 due to other causes.
Table 1
describes the hematologic and non-hematologic
adverse reactions that occurred in greater
than 5% of patients
treated with HYCAMTIN capsules
in these trials.
Table 1. Adverse Reactions Occurring in Greater than or Equal
to 5% of Patients with
Lung Cancer
…
6.2 Postmarketing Experience
(Newly
added subsection)
The following reactions have been identified during post
approval use of HYCAMTIN.
Because these reactions are reported
voluntarily from a population of unknown size, it is not always possible
to reliably estimate
their frequency or establish
a causal relationship to drug exposure.
Gastrointestinal: Gastrointestinal perforation
General and Administration
Site Conditions: Mucosal inflammation
Hypersensitivity: Allergic manifestations, anaphylactoid reactions,
angioedema
7
Drug Interactions
7.1 Effect of Other Drugs on HYCAMTIN
(Subsection
has been revised)
P-glycoprotein or Breast Cancer Resistance Protein Inhibitor
Concomitant use of a P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitor increases topotecan AUC, which
may increase the risk of adverse reactions. Avoid concomitant use HYCAMTIN capsules with P-gp
inhibitors or BCRP inhibitors.
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions are
underlined)
Risk Summary
Based on
animal data and
its mechanism of action, HYCAMTIN can cause fetal
harm when administered to a pregnant
woman. There are no available
clinical data on the use of HYCAMTIN
in pregnancy. Topotecan
caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar
to the clinical dose. Advise pregnant women of the potential risk to a fetus.
In the U.S.
general population, the background risk
of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized
pregnancies.
Data
Animal Data
In rabbits,
an intravenous dose of 0.10 mg/kg/day [about equal
to the 1.5 mg/m2 clinical intravenous dose based on
body surface area (BSA)] given on days
6 through 20 of gestation
caused maternal toxicity, embryolethality, and
reduced fetal body weight. In
the rat,
an intravenous dose of 0.23
mg/kg/day (about equal to the 1.5 mg/m2 clinical
intravenous dose based
on BSA) given for 14
days before mating through gestation day 6 caused fetal resorption, microphthalmia, pre-implant
loss, and mild maternal toxicity. Administration of an intravenous dose of 0.10
mg/kg/day (about half the
1.5 mg/m2 clinical
intravenous dose based on BSA)
to rats on days 6 through
17 of gestation caused an increase in post-implantation mortality.
This dose also caused an increase in total fetal malformations. The most frequent malformations were of the
eye (microphthalmia, anophthalmia,
rosette formation of the retina, coloboma of the retina,
ectopic orbit), brain (dilated
lateral and third ventricles), skull, and vertebrae.
8.2 Lactation
(Additions
and/or revisions are underlined)
There are no data on the
presence of
topotecan or its metabolites
in human milk, or their effects
on the breastfed infant
or milk production. Lactating rats
excrete high concentrations of topotecan into milk. Because
of the potential for serious adverse reactions
in breastfed infants, advise women not to breastfeed during treatment with HYCAMTIN and
for 1 week after the
last dose.
Data
Following intravenous administration of topotecan
to lactating rats at a dose of 4.72 mg/m2 (about twice the 1.5 mg/m2 clinical intravenous dose based
on BSA),
topotecan was excreted into milk at concentrations up
to 48- fold higher than
those in plasma.
8.3 Females and Males of Reproductive Potential
(Subsection
title and subsection has been revised)
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating HYCAMTIN capsules.
Contraception
HYCAMTIN can cause fetal harm when administered
to a pregnant woman.
Females
Advise female patients of reproductive
potential to use effective contraception
during treatment with HYCAMTIN capsules and for 6 months after the last dose.
Males
HYCAMTIN capsules may damage spermatozoa, resulting in possible genetic and fetal abnormalities.
Advise males with a
female partner of reproductive potential
to use effective contraception
during treatment with HYCAMTIN capsules and for 3 months after the last dose.
Infertility
Females
HYCAMTIN can have both
acute and long-term effects on
fertility.
Males
Effects on spermatogenesis have occurred in animals administered topotecan.
8.5 Geriatric Use
(Additions and/or revisions are
underlined)
Of the 682 patients with
lung cancer who received HYCAMTIN
capsules in the four clinical
trials, 33% were aged 65 years and
older, while 4.8% were aged
75 years
and older. Treatment-related diarrhea
was more frequent in patients aged greater than or equal to 65 years (28%) compared with those younger than 65 years (19%)
No overall differences in effectiveness were observed
between patients 65 years and
older and younger
patients.
8.6 Renal Impairment
(Additions
and/or revisions are underlined)
No dosage adjustment
is recommended for patients
with creatinine clearance
(CLcr) greater than or equal to 50 mL/min.
Reduce the dose of HYCAMTIN
capsules in patients with
CLcr less than 49 mL/min.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Myelosuppression
Inform patients that HYCAMTIN
decreases blood cell counts, such
as white blood cells, platelets,
and red blood cells. Instruct
patients to notify their healthcare provider promptly
for fever or
other signs of infection.
…
Interstitial Lung Disease
Inform patients of the risks of
severe ILD. Advise patients to contact their healthcare
provider immediately to report new
or worsening respiratory symptoms.
Embryo-Fetal Toxicity
Advise
females of reproductive potential and males with female partners of reproductive
potential of the potential risk to a fetus. Advise
women to contact their
healthcare provider
if they become pregnant, or if pregnancy is suspected
during treatment with HYCAMTIN
capsules.
Advise
females of
reproductive potential to use effective contraception
during treatment HYCAMTIN
and for 6 months after the last
dose of HYCAMTIN capsules.
Advise males with a female partner of reproductive potential
to use effective contraception
during treatment and for 3
months after the last dose of HYCAMTIN capsules.
Lactation
Advice women to discontinue breastfeeding during treatment and for 1 week after
the· last dose of HYCAMTIN capsules
Infertility
Advise male and female patients of the potential risk for impaired fertility
PATIENT INFORMATION
(Format has changed, please refer
to the label)
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