WARNING: BONE MARROW
SUPPRESSION
Topotecan for injection can cause severe
myelosuppression. Administer only to patients with baseline neutrophil counts
of greater than or equal to 1,500 cells/mm3and platelet counts greater than or equal to 100,000 cells/mm3. Monitor blood cell
counts[see Warnings and
Precautions (5.1)].
Indications and Usage for TopotecanOvarian Cancer
Topotecan for injection, as a
single agent, is indicated for the treatment of patients with metastatic
carcinoma of the ovary after disease progression on or after initial or
subsequent chemotherapy.
Small Cell Lung Cancer
Topotecan for injection, as a
single agent, is indicated for the treatment of patients with small cell lung
cancer with platinum-sensitive disease who progressed at least 60 days after
initiation of first-line chemotherapy.
Cervical Cancer
Topotecan for injection in
combination with cisplatin is indicated for the treatment of patients with
Stage IV-B, recurrent, or persistent carcinoma of the cervix not amenable to
curative treatment.
Topotecan Dosage and Administration
Verify dose using body surface
area prior to dispensing. Recommended dosage should generally not exceed 4 mg
intravenously [see Overdosage
(10)].
Ovarian Cancer
Recommended Dose and Schedule:
The recommended dose of
Topotecan for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5
consecutive days, starting on Day 1 of a 21-day course.
Small Cell Lung Cancer
Recommended Dose and Schedule
The recommended dose of
Topotecan for injection is 1.5 mg/m2by intravenous infusion over 30 minutes daily for 5 consecutive
days, starting on Day 1 of a 21-day course.
Cervical Cancer
Recommended Dose and Schedule
The recommended dose of
Topotecan for injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on Days 1,
2, and 3 in combination with cisplatin 50 mg/m2 on Day 1, repeated every
21 days.
Dose Modifications
Hematologic Toxicities
For
single-agent use, dose reduce Topotecan for injection to 1.25 mg/m2for:
neutrophil counts of less than
500 cells/mm3, or administer granulocyte-colony stimulating factor (G-CSF)
starting no sooner than 24 hours following the last dose of Topotecan for
injection.
platelet counts less than
25,000 cells/mm3during previous cycle.
For
combination use with cisplatin, dose reduce Topotecan for injection to 0.60
mg/m2(and further to 0.45 mg/m2if
necessary) for:
febrile neutropenia (defined
as neutrophil counts less than 1,000 cells/mm3with temperature of greater
than or equal to 38.0°C (100.4°F), or administer G-CSF starting no sooner than
24 hours following the last dose of Topotecan for injection.
platelet counts less than
25,000 cells/mm3during previous cycle.
Renal
Impairment
For
single-agent use, dose reduce Topotecan for injection to 0.75 mg/m2in patients with moderate renal impairment (creatinine clearance
[Clcr] = 20 to 39 mL/min). Insufficient data are available in patients with
severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation
for Topotecan for injection [see Use in
Specific Populations (8.6), Clinical
Pharmacology (12.3)].
Preparation and Intravenous
Administration
Topotecan for injection is a
cytotoxic drug. Follow applicable special handling and disposable procedures.1
Preparation
and Administration
Reconstitute each 4-mg vial of
Topotecan for injection with 4 mL Sterile Water for Injection, USP. Dilute the
appropriate volume of the reconstituted solution in either 0.9% Sodium Chloride
Intravenous Infusion, USP or 5% Dextrose in Water Injection, USP prior to
administration.
Stability
Unopened vials of Topotecan
for injection are stable until the date indicated on the package when stored
between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the
original carton. Because the vials contain no preservative, contents should be
used immediately after reconstitution.
Reconstituted vials of
Topotecan for injection diluted for infusion are stable at approximately 20° to
25°C (68° to 77°F) and ambient lighting conditions for 24 hours.
Dosage Forms and Strengths
For injection: 4-mg (Topotecan
free base) lyophilized powder in single-use vial for reconstitution; light
yellow to greenish cake powder.
Contraindications
Topotecan for injection is
contraindicated in patients who have a history of severe hypersensitivity
reactions to Topotecan.
Warnings and PrecautionsBone Marrow Suppression
Bone marrow suppression
(primarily neutropenia) is the dose-limiting toxicity of Topotecan for
injection. Neutropenia is not cumulative over time. Severe myelotoxicity has
been reported when Topotecan for injection is used in combination with cisplatin [see Drug
Interactions (7)].
·
The following data on
myelosuppression are based on an integrated safety database from 8 trials (N =
879) using Topotecan for injection at 1.5 mg/m2by intravenous infusion over
30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course
in patients with ovarian cancer and small cell lung cancer and from one trial
in patients with cervical cancer (N = 147) using Topotecan for injection 0.75 mg/m2by intravenous infusion over
30 minutes daily on Days 1, 2, and 3 repeated every 21 days in combination with
cisplatin 50 mg/m2on Day 1.
Neutropenia
·
Monotherapy: Grade 4
neutropenia (less than 500 cells/mm3) occurred in 78% of patients, with a median duration of 7 days
and was most common during Course 1 of treatment (58% of patients). Grade 4
neutropenia associated with infection occurred in 13% of patients and febrile
neutropenia occurred in 5% of patients. Sepsis occurred in 4% of patients and
was fatal in 1% of patients. Pancytopenia has been reported.
·
Combination with cisplatin:
Grade 4 neutropenia occurred in 48% of patients.
Thrombocytopenia
·
Monotherapy: Grade 4
thrombocytopenia (less than 25,000/mm3) occurred in 27% of patients, with a median duration of 5 days.
·
Combination with cisplatin:
Grade 4 thrombocytopenia occurred in 7% of patients.
Anemia
·
Monotherapy: Grade 3 or 4
anemia (less than 8 g/dL) occurred in 37% of patients.
·
Combination with cisplatin:
Grade 3 or Grade 4 anemia occurred in 40% of patients.
Administer Topotecan for
injection only to patients with a baseline neutrophil count of greater than or
equal to 1,500 cells/mm3 and platelet count greater than or equal to 100,000/mm3. Monitor peripheral blood
counts frequently during treatment with Topotecan for injection. Refer to
Section 2.4 for dose modification guidelines for hematological toxicities in
subsequent courses. Do not treat patients with subsequent courses of Topotecan
for injection until neutrophils recover to greater than 1,000 cells/mm3, platelets recover to greater
than 100,000 cells/mm3, and hemoglobin levels recover to 9.0 g/dL (with transfusion if
necessary).
Neutropenic Enterocolitis
Topotecan can cause fatal
typhilitis (neutropenic enterocolitis). Consider the possibility of typhilitis
in patients presenting with fever, neutropenia, and abdominal pain.
Interstitial Lung Disease
Interstitial lung disease
(ILD), including fatalities, has occurred with Topotecan for injection. Underlying
risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic
radiation, and use of pneumotoxic drugs and/or colony stimulating factors.
Monitor patients for pulmonary symptoms indicative of ILD (e.g., cough, fever,
dyspnea, and/or hypoxia), and discontinue Topotecan for injection if a new
diagnosis of ILD is confirmed.
Embryofetal Toxicity
Based on animal data,
Topotecan for injection 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 females of
reproductive potential to use effective contraception during treatment and for
at least 1 month after the last dose of Topotecan for injection. Advise women
of the potential risk to a fetus [see Use in
Specific Populations (8.1, 8.3)].
Extravasation and Tissue Injury
Extravasation with Topotecan
for injection has been observed; severe cases have been reported. If signs or
symptoms of extravasation occur, immediately stop administration of Topotecan
for injection and institute recommended management procedures [see Adverse Reactions (6)].
Adverse Reactions
The following serious adverse
reactions are described below and elsewhere in the labeling:
·
Bone Marrow Suppression [see Warnings and
Precautions (5.1)]
·
Neutropenic
Enterocolitis [see Warnings
and Precautions (5.2)]
·
Interstitial Lung
Disease [see Warnings
and Precautions (5.3)]
·
Extravasation and Tissue
Injury[see Warnings and
Precautions (5.5)]
Clinical Trials Experience
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.
Ovarian
Cancer
Table 1 shows the Grade 3/4
hematologic and major non-hematologic adverse reactions in the
Topotecan/paclitaxel comparator trial in ovarian cancer.
Table 1. Adverse Reactions Experienced by
≥5% of Ovarian Cancer Patients Randomized to Receive Topotecan for Injection
or Paclitaxel
|
|
aDeath related to sepsis occurred in 2% of
patients receiving Topotecan for injection and 0% of patients receiving
paclitaxel.
|
|
b Pain includes body pain, skeletal
pain, and back pain.
|
|
Adverse Reaction
|
Topotecan for Injection
(n = 112)
|
Paclitaxel
(n = 114)
|
|
Hematologic Grade 3/4
|
%
|
%
|
|
Grade 4
neutropenia (<500 cells/mm3)
|
80
|
21
|
|
Grade 3/4 anemia
(Hgb <8 g/dL)
|
41
|
6
|
|
Grade 4
thrombocytopenia (<25,000 plts/mm3)
|
27
|
3
|
|
Febrile
neutropenia
|
23
|
4
|
|
Non-hematologic Grade 3/4
|
%
|
%
|
|
Infections and infestations
Sepsisa
|
5
|
2
|
|
Respiratory, thoracic, and mediastinal disorders
Dyspnea
|
6
|
5
|
|
Gastrointestinal disorders
Abdominal pain
Constipation
Diarrhea
Intestinal obstruction
Nausea
Vomiting
|
5
5
6
5
10
10
|
4
0
1
4
2
3
|
|
General disorders and administrative site conditions
Fatigue
Asthenia
Painb
|
7
5
5
|
6
3
7
|
Small
Cell Lung Cancer
Table 2 shows the Grade 3/4
hematologic and major non-hematologic adverse reactions in the Topotecan/CAV
(cyclophosphamide-doxorubicin-vincristine) comparator trial in small cell lung
cancer.
Table 2. Adverse Reactions Experienced by
≥ 5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan for
Injection or CAV
|
|
aDeath related to sepsis occurred in 3% of
patients receiving Topotecan for injection and 1% of patients receiving CAV.
|
|
bPain includes body pain, skeletal pain,
and back pain.
|
|
Adverse Reaction
|
Topotecan
for Injection
(n=107)
|
CAV
(n=104)
|
|
Hematologic Grade 3/4
|
%
|
%
|
|
Grade 4
neutropenia
(<500 cells/mm3)
|
70
|
72
|
|
Grade 3/4 anemia
(Hgb <8 g/dL)
|
42
|
20
|
|
Grade 4
thrombocytopenia
(<25,000 plts/mm3)
|
29
|
5
|
|
Febrile
neutropenia
|
28
|
26
|
|
Non-hematologic Grade 3/4
|
%
|
%
|
|
Infections and infestations
|
|
|
|
Sepsisa
|
5
|
5
|
|
Respiratory, thoracic, and mediastinal disorders
|
|
|
|
Dyspnea
|
9
|
14
|
|
Pneumonia
|
8
|
6
|
|
Gastrointestinal disorders
|
|
|
|
Abdominal pain
|
6
|
4
|
|
Nausea
|
8
|
6
|
|
General disorders and administrative site conditions
|
|
|
|
Fatigue
|
6
|
10
|
|
Asthenia
|
9
|
7
|
|
Painb
|
5
|
7
|
Hepatobiliary
Disorders in Ovarian and Small Cell Lung Cancer Patients Receiving Topotecan for injection: Based
on the combined experience of 453 patients with metastatic ovarian carcinoma,
and 426 patients with small cell lung cancer treated with Topotecan for
injection, Grade 1 transient elevations in hepatic enzymes occurred in 8% of
patients. Grade 3/4 elevations occurred in 4%. Grade 3/4 elevated bilirubin
occurred in less than 2% of patients.
Cervical
Cancer
In the comparative trial with
Topotecan for injection plus cisplatin versus cisplatin in patients with
cervical cancer, the most common dose-limiting adverse reaction was
myelosuppression. Table 3 shows the hematologic and non-hematologic adverse
reactions in patients with cervical cancer.
Table 3. Adverse Reactions Experienced by
≥5% of Patients with Cervical Cancer Randomized to Receive Topotecan for
Injection plus Cisplatin or Cisplatin Monotherapy (Between Arm Difference
≥2%)a
|
|
aIncludes patients who were eligible and
treated.
|
|
bData were collected using NCI Common
Toxicity Criteria, v. 2.0.
|
|
cGrades 1 through 4 only. There were 3
patients who experienced deaths with investigator-designated attribution. The
first patient experienced a Grade 5 hemorrhage in which the drug-related
thrombocytopenia aggravated the event. A second patient experienced bowel
obstruction, cardiac arrest, pleural effusion, and respiratory failure which
were not treatment-related but probably aggravated by treatment. A third
patient experienced a pulmonary embolism and adult respiratory distress
syndrome; the latter was indirectly treatment-related.
|
|
d Constitutional includes fatigue
(lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors,
chills, sweating, and weight gain or loss.
|
|
ePain includes abdominal pain or cramping,
arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic),
dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia,
neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal
or perirectal pain, and tumor pain.
|
|
fHigh-level terms were included if the
between-arm difference was ≥10%.
|
|
Adverse Reaction
|
Topotecan for Injection plus Cisplatin
(n = 140)
%
|
Cisplatin
(n = 144)
%
|
|
Hematologic
|
|
|
|
Neutropenia
Grade 3 (<1,000-500 cells/mm3)
Grade 4 (<500 cells/mm3)
|
26
48
|
1
1
|
|
Anemia
Grade 3 (Hgb <8-6.5 g/dL)
Grade 4 (Hgb <6.5 g/dL)
|
34
6
|
19
3
|
|
Thrombocytopenia
Grade 3 (<50,000-10,000 cells/mm3)
Grade 4 (<10,000 cells/mm3)
|
26
7
|
3
0
|
|
Non-hematologicb,c
|
|
|
|
General disorders and administrative site conditions
Constitutionald
Paine
|
69
59
|
62
50
|
|
Gastrointestinal disorders
Vomiting
Stomatitis-pharyngitis
Other
|
40
6
63
|
37
0
56
|
|
Dermatologyf
|
48
|
20
|
|
Infection-febrile neutropeniaf
|
28
|
18
|
|
Cardiovascularf
|
25
|
15
|
Postmarketing Experience
The following reactions have
been identified during postmarketing use of Topotecan for injection. Because
they are reported voluntarily from a population of unknown size, estimates of
frequency cannot be made. These reactions have been chosen for inclusion due to
a combination of their seriousness, frequency of reporting, or potential causal
connection to Topotecan for injection.
Blood
and Lymphatic System Disorders
Severe bleeding (in
association with thrombocytopenia) [see Warnings
and Precautions (5.1)].
Immune
System Disorders
Allergic manifestations,
anaphylactoid reactions.
Gastrointestinal
Disorders
Abdominal pain potentially
associated with neutropenic enterocolitis [see Warnings
and Precautions (5.2)].
Pulmonary
Disorders
Interstitial lung
disease [see Warnings
and Precautions (5.3)].
Skin
and Subcutaneous Tissue Disorders
Angioedema, severe dermatitis,
severe pruritus.
General
Disorders and Administration Site Conditions
Extravasation [see Warnings and
Precautions (5.5)].
Drug InteractionsG CSF
Concomitant administration
with G–CSF can prolong the duration of neutropenia. If G–CSF is used, it should
be started no sooner than 24 hours following the last dose of Topotecan for
injection.
USE IN SPECIFIC POPULATIONSPregnancy
Risk Summary
Based on animal data,
Topotecan for injection can cause fetal harm when administered to a pregnant
woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in
rats and rabbits when administered during organogenesis at doses similar to the
clinical dose [see Data]. There are
no available human data informing the drug-associated risk. Advise pregnant
women of the potential risk to a fetus. The background risk of major birth
defects and miscarriage for the indicated populations are unknown; however, the
background risk in the US general population of major birth defects is 2% to 4%
and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal
Data: In rabbits, a dose of 0.10 mg/kg/day
(about equal to the clinical dose on a mg/m2basis) given on Days 6 through
20 of gestation caused maternal toxicity, embryolethality, and reduced fetal
body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical
dose on a mg/m2basis) 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 clinical dose on a mg/m2basis) given 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.
Lactation
Risk Summary
It is not known whether this
drug is present in human milk; however, Topotecan is excreted in rat milk at
high concentrations [see Data]. Because
many drugs are present in human milk and because of the potential for serious adverse
reactions in nursing infants with Topotecan for injection, advise nursing
mothers to discontinue breastfeeding during treatment with Topotecan for
injection.
Data
Animal
Data: Following intravenous administration
of Topotecan to lactating rats at a dose of 4.72 mg/m2(about twice the clinical dose
on a mg/m2basis), Topotecan was excreted into milk at concentrations up to
48-fold higher than those in plasma.
Females and Males of
Reproductive Potential
Contraception
Females: Advise female patients of reproductive potential to use
effective contraception during treatment with Topotecan for injection and for
one month after the last dose. Advise females to contact their healthcare
provider if they become pregnant, or if pregnancy is suspected, while taking
Topotecan for injection [see Use in
Specific Populations (8.1)].
Males: Topotecan for injection may damage spermatozoa, resulting
in possible genetic and fetal abnormalities. Advise males with a female sexual
partner of reproductive potential to use effective contraception during and for
three months after treatment with Topotecan for injection [see Nonclinical Toxicology (13.1)].
Infertility
Females: Topotecan for injection may have both acute and long-term
effects on fertility [see Nonclinical Toxicology
(13.1)].
Males: Effects on spermatogenesis have been observed in animals
administered Topotecan for injection. Advise males of the potential risk for
impaired fertility and to seek counseling on fertility and family planning
options prior to starting treatment [see
Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness in
pediatric patients have not been established.
Geriatric Use
Of the 879 patients with
metastatic ovarian cancer or small cell lung cancer in clinical trials of
Topotecan for injection, 32% (n = 281) were aged 65 years and older, while 3.8%
(n = 33) were aged 75 years and older. Of the 140 patients with Stage IV-B,
relapsed, or refractory cervical cancer in clinical trials of Topotecan for
injection who received Topotecan for injection plus cisplatin in the randomized
clinical trial, 6% (n = 9) were 65 years of age and older, while 3% (n = 4)
were aged 75 years and older.
No overall differences in
effectiveness or safety were observed between these patients and younger adult
patients, and other reported clinical experience has not identified differences
in responses between the elderly and younger adult patients.
Renal Impairment
The systemic exposure to both
Topotecan lactone and total Topotecan increased in patients with moderate renal
impairment (Clcr = 20 to 39 mL/min) compared with patients with normal renal
function (Clcr greater than 60 mL/min). Reduce the dose of Topotecan for
injection in patients with moderate renal impairment (Clcr = 20 to 39 mL/min).
No dosage adjustment of Topotecan for injection is recommended for patients
with mild renal impairment (Clcr 40 to 60 mL/min) [see
Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Insufficient data are
available in patients with severe renal impairment (Clcr less than 20mL/min) to
provide a dosage recommendation for Topotecan for injection.
Overdosage
Overdoses (up to 10-fold of
the prescribed dose) occurred in patients treated with intravenous Topotecan.
The primary complication of overdosage is bone marrow suppression. The observed
signs and symptoms of overdose are consistent with the known adverse reactions
associated with Topotecan for injection for intravenous use [see Adverse Reactions (6.1, 6.2]. In addition, elevated
hepatic enzymes and mucositis have been reported following overdose. One patient
received a single dose of 40 mg/m2of intravenous Topotecan and developed gastrointestinal
toxicity, skin toxicity, and myelosuppresion leading to septic shock. Another
patient received a single dose of 35 mg/m2 and experienced severe,
reversible neutropenia.
There is no known antidote for
overdosage with Topotecan for injection. If an overdose is suspected, monitor
the patient for bone marrow suppression and institute supportive-care measures
(such as prophylactic use of G-CSF and antibiotic therapy) as appropriate.
Topotecan Description
Topotecan is a semi-synthetic
derivative of camptothecin and is an anti-tumor drug with topoisomerase
I-inhibitory activity. The chemical name for Topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione. 1.25 hydrochloride. It has the molecular
formula C23H23N3O5•1.25HCl and a molecular weight of 467.02. It is soluble in
water and melts with decomposition at 213° to 218°C.
Topotecan hydrochloride has
the following structural formula:
Topotecan for injection is
supplied as a sterile, lyophilized, buffered, light yellow to greenish cake
powder available in single-dose vials. Each vial contains Topotecan
hydrochloride equivalent to 4 mg of Topotecan as free base. The reconstituted
solution ranges in color from yellow to yellow-green and is intended for
administration by intravenous infusion.
Inactive ingredients are
mannitol, 48 mg, and tartaric acid, 20 mg. Hydrochloric acid and sodium
hydroxide may be used to adjust the pH. The solution pH ranges from 2.5 to 3.5.
Topotecan - Clinical PharmacologyMechanism of Action
Topoisomerase I relieves
torsional strain in DNA by inducing reversible single-strand breaks. Topotecan
binds to the topoisomerase I-DNA complex and prevents religation of these
single-strand breaks. The cytotoxicity of Topotecan is thought to be due to
double-strand DNA damage produced during DNA synthesis, when replication
enzymes interact with the ternary complex formed by Topotecan, topoisomerase I,
and DNA. Mammalian cells cannot efficiently repair these double strand breaks.
Pharmacokinetics
Following administration of
Topotecan for injection at doses of 0.5 to 1.5 mg/m2 administered as a
30-minute infusion to cancer patients, Topotecan exhibited multiexponential
pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure
(AUC) is approximately dose-proportional.
Distribution
Binding of Topotecan to plasma
proteins is approximately 35%.
Metabolism
Topotecan undergoes a
reversible pH-dependent hydrolysis of its lactone moiety; it is the lactone
form that is pharmacologically active. At pH ≤4, the lactone is exclusively
present, whereas the ring-opened hydroxy-acid form predominates at physiologic
pH. In vitro studies in human liver
microsomes indicate Topotecan is metabolized to an N-demethylated metabolite.
The mean metabolite:parent AUC ratio was about 3% for total Topotecan and
Topotecan lactone following IV administration.
Excretion
Renal clearance is the primary
route of Topotecan elimination.
In a mass balance/excretion
trial in 4 patients with solid tumors, the overall recovery of total Topotecan
and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4% ±
2.3% of the administered IV dose. Mean values of 50.8% ± 2.9% as total
Topotecan and 3.1% ± 1.0% as N-desmethyl Topotecan were excreted in the urine
following IV administration. Fecal elimination of total Topotecan accounted for
17.9% ± 3.6% while fecal elimination of N-desmethyl Topotecan was 1.7% ± 0.6%.
An O-glucuronidation metabolite of Topotecan and N-desmethyl Topotecan has been
identified in the urine.
Specific
Populations
Gender: Plasma clearance of Topotecan lactone in male patients was
approximately 24% higher than that in female patients, largely reflecting
difference in body size.
Age: Population pharmacokinetic analysis in female patients did
not identify age as a significant factor. Decreased renal clearance, which is
common in the elderly, is a more important determinant of Topotecan
clearance [see Dosage
and Administration (2.4), Use in
Specific Populations (8.5)].
Renal
Impairment: In patients with mild
renal impairment (Clcr = 40 to 60 mL/min), plasma clearance of Topotecan
lactone was decreased by 33% compared with patients with normal renal function
(Clcr greater than 60 mL/min). In patients with moderate renal impairment (Clcr
= 20 to 39 mL/min), plasma clearance of Topotecan lactone was reduced by 65%
compared with patients with normal renal function. Dosage adjustment is
recommended for patients with moderate renal impairment. No dosage adjustment
is required in patients with mild renal impairment [see Dosage
and Administration (2.4), Use in
Specific Populations (8.6)].
Hepatic
Impairment: Plasma clearance of
Topotecan with hepatic impairment (serum bilirubin levels between 1.7 and 15.0
mg/dL) was decreased by 33% compared with patients with normal hepatic function
(serum bilirubin levels less than 1.7 mg/dL).
Drug
Interactions
Effects
of Topotecan on Drug-Metabolizing Enzymes: In vitro inhibition studies using marker
substrates for human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E,
CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities
of these enzymes were not altered by Topotecan.
Cisplatin: Administration of cisplatin (60 or 75 mg/m2 on Day 1) before
Topotecan (0.75 mg/m2/day on Days 1 to 5) in 9 patients with ovarian cancer had no
significant effect on the Cmax and AUC of total Topotecan.
Topotecan (0.3 mg/m2IV daily on Days 2 to 6) had
no effect on the pharmacokinetics of free platinum in 15 patients with ovarian
cancer who were administered cisplatin 50 mg/m2 (n = 9) or 75 mg/m2 (n = 6) on Day 2 after
paclitaxel 110 mg/m2 on Day 1. Topotecan (0.75 mg/m2IV daily on Days 1 to 5) had
no effect on dose-normalized (60 mg/m2) Cmax values of free platinum in 13 patients with ovarian cancer
who were administered 60 mg/m2 (n = 10) or 75 mg/m2 (n = 3) cisplatin on Day
1.
Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment
of Fertility
Carcinogenicity testing of
Topotecan has not been performed. Topotecan is known to be genotoxic to
mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y
mouse lymphoma cells and clastogenic to cultured human lymphocytes with and
without metabolic activation. It was also clastogenic to mouse bone marrow.
Topotecan did not cause mutations in bacterial cells.
Topotecan given to female rats
prior to mating at a dose of 1.4 mg/m2 IV (about equal to the clinical dose on a mg/m2 basis) caused
superovulation possibly related to inhibition of follicular atresia. This dose
given to pregnant female rats also caused increased pre-implantation loss.
Studies in dogs given 0.4 mg/m2 IV (about 0.25 times the clinical dose on a mg/m2 basis) of Topotecan
daily for a month suggest that treatment may cause an increase in the incidence
of multinucleated spermatogonial giant cells in the testes. Topotecan may
impair fertility in women and men.
Clinical StudiesOvarian Cancer
Topotecan for injection was
studied in 2 clinical trials of 223 patients given Topotecan with metastatic
ovarian carcinoma. All patients had disease that had recurred on, or was
unresponsive to, a platinum-containing regimen. Patients in these 2 trials
received an initial dose of 1.5 mg/m2 given by intravenous infusion over 30 minutes for 5
consecutive days, starting on day 1 of a 21-day course.
One trial was a randomized
trial of 112 patients treated with Topotecan for injection (1.5 mg/m2/day × 5 days starting on Day
1 of a 21-day course) and 114 patients treated with paclitaxel (175 mg/m2 over 3 hours on Day 1 of
a 21-day course). All patients had recurrent ovarian cancer after a
platinum-containing regimen or had not responded to at least 1 prior
platinum-containing regimen. Patients who did not respond to the trial therapy,
or who progressed, could be given the alternative treatment. The efficacy
outcome measures were response rate, response duration, and time to
progression.
The results of the trial did
not show statistically significant improvements in response rates, response
duration, time to progression, and overall survival as shown in Table 4.
Table 4. Efficacy of Topotecan for
Injection versus Paclitaxel in Ovarian Cancer
|
|
HR = hazard-ratio; CI = confidence
interval.
|
|
aThe calculation for duration of response
was based on the interval between first response and time to progression.
|
|
Parameter
|
Topotecan for Injection
(n=112)
|
Paclitaxel
(n=114)
|
|
Overall response
rate (95% CI)
Complete response rate
|
21% (13% to 28%)
5%
|
14% (8% to 20%)
3%
|
|
Partial response
rate
|
16%
|
11%
|
|
Response
durationa(months)
|
|
|
|
Median (95%
CI)
|
6.0 (5.1 to 7.6)
|
5.0 (3.7 to 7.8)
|
|
Time to
progression (months)
|
|
|
|
Median (95% CI)
|
4.4 (2.8 to 5.4)
|
3.4 (2.7 to 4.2)
|
|
HR (Topotecan for
injection:paclitaxel) (95% CI)
|
0.76 (0.57 to 1.02)
|
|
Survival
(months)
|
|
|
|
Median (95% CI)
|
14.5 (10.7 to 16.5)
|
12.2 (9.7 to 15.8)
|
|
HR (Topotecan
for injection:paclitaxel) (95% CI)
|
0.97 (0.71 to 1.34)
|
The median time to response
was 7.6 weeks (range: 3.1 to 21.7) with Topotecan for injection compared with
6.0 weeks (range: 2.4 to 18.1) with paclitaxel. In the crossover phase, 8 of 61
(13%) patients who received Topotecan for injection after paclitaxel had a
partial response and 5 of 49 (10%) patients who received paclitaxel after
Topotecan for injection had a response (2 complete responses).
Topotecan for injection was
active in ovarian cancer patients who had developed resistance to
platinum-containing therapy, defined as tumor progression while on, or tumor
relapse within 6 months after completion of, a platinum-containing regimen. One
complete and 6 partial responses were seen in 60 patients, for a response rate
of 12%. In the same trial, there were no complete responders and 4 partial
responders on the paclitaxel arm, for a response rate of 7%.
Topotecan for injection was
also studied in an open-label, non-comparative trial in 111 patients with
recurrent ovarian cancer after treatment with a platinum-containing regimen, or
who had not responded to 1 prior platinum-containing regimen. The response rate
was 14% (95% CI: 7% to 20%). The median duration of response was 22 weeks
(range: 4.6 to 41.9 weeks). The time to progression was 11.3 weeks (range: 0.7
to 72.1 weeks). The median survival was 67.9 weeks (range: 1.4 to 112.9 weeks).
Small Cell Lung Cancer
Topotecan for injection was
studied in 426 patients with recurrent or progressive small cell lung cancer in
1 randomized, comparative trial and in 3 single-arm trials.
Randomized
Comparative Trial
In a randomized, comparative,
Phase 3 trial, 107 patients were treated with Topotecan for injection (1.5 mg/m2/day × 5 days starting on Day
1 of a 21-day course) and 104 patients were treated with CAV (1,000 mg/m2 cyclophosphamide, 45
mg/m2 doxorubicin,
2 mg vincristine administered sequentially on Day 1 of a 21-day course). All
patients were considered sensitive to first-line chemotherapy (responders who
then subsequently progressed greater than or equal to 60 days after completion
of first-line therapy). A total of 77% of patients treated with Topotecan for
injection and 79% of patients treated with CAV received platinum/etoposide with
or without other agents as first-line chemotherapy. The efficacy outcome
measures were response rate and duration of response.
The results of the trial did
not show statistically significant improvements in response rates, response
duration, time to progression, and overall survival as shown in Table 5.
Table 5. Efficacy of Topotecan For
Injection Versus CAV (cyclophosphamide-doxorubicin-vincristine) in Small Cell
Lung Cancer Patients Sensitive to First-Line Chemotherapy
|
|
HR = hazard-ratio; CI = confidence
interval.
|
|
aThe calculation for duration of response
was based on the interval between first response and time to progression.
|
|
Parameter
|
Topotecan for injection (n=107)
|
CAV
(n=104)
|
|
Overall response
rate (95% CI)
|
24% (16% to 32%)
|
18% (11% to 26%)
|
|
Complete
response rate
|
0%
|
1%
|
|
Partial response
rate
|
24%
|
17%
|
|
Response
durationa (months)
Median (95% CI)
|
3.3 (3.0 to 4.1)
|
3.5 (3.0 to 5.3)
|
|
Time to
progression (months)
|
|
|
|
Median (95% CI)
|
3.1 (2.6 to 4.1)
|
2.8 (2.5 to 3.2)
|
|
HR (Topotecan
for injection:CAV) (95% CI)
|
0.92 (0.69 to 1.22)
|
|
Survival
(months)
|
|
|
|
Median (95% CI)
|
5.8 (4.7 to 6.8)
|
5.8 (5.0 to 7.0)
|
|
HR (Topotecan
for injection:CAV) (95% CI)
|
1.04 (0.78 to 1.39)
|
The time to response was
similar in both arms: Topotecan for injection median of 6 weeks (range: 2.4 to
15.7) versus CAV median 6 weeks (range: 5.1 to 18.1).
Changes on a disease-related
symptom scale in patients who received Topotecan for injection or who received
CAV are presented in Table 6. It should be noted that not all patients had all
symptoms, nor did all patients respond to all questions. Each symptom was rated
on a 4-category scale with an improvement defined as a change in 1 category
from baseline sustained over 2 courses. Limitations in interpretation of the
rating scale and responses preclude formal statistical analysis.
Table 6: Percentage of Patients with
Symptom Improvementa: Topotecan for Injection versus CAV in Patients with Small Cell Lung
Cancer
|
|
aDefined as improvement sustained over at
least 2 courses compared with baseline.
|
|
bNumber of patients with baseline and at
least 1 post-baseline assessment.
|
|
Symptom
|
Topotecan for injection (n=107)
|
CAV
(n=104)
|
|
|
nb
|
(%)
|
nb
|
(%)
|
|
Shortness of
breath
Interference with daily activity
Fatigue
Hoarseness
Cough
Insomnia
Anorexia
Chest pain
Hemoptysis
|
68
67
70
40
69
57
56
44
15
|
(28)
(27)
(23)
(33)
(25)
(33)
(32)
(25)
(27)
|
61
63
65
38
61
53
57
41
12
|
(7)
(11)
(9)
(13)
(15)
(19)
(16)
(17)
(33)
|
Single-Arm
Trials:
Topotecan for injection was
also studied in 3 open-label, non-comparative trials in a total of 319 patients
with recurrent or progressive small cell lung cancer after treatment with
first-line chemotherapy. In all 3 trials, patients were stratified as either
sensitive (responders who then subsequently progressed greater than or equal to
90 days after completion of first-line therapy) or refractory (no response to
first-line chemotherapy or who responded to first-line therapy and then
progressed within 90 days of completing first-line therapy). Response rates
ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory
patients. Median time to progression and median survival were similar in all 3
trials and the comparative trial.
Cervical Cancer
In a comparative trial, 147
eligible women were randomized to Topotecan for injection (0.75 mg/m2/day IV over 30 minutes × 3
consecutive days starting on Day 1 of a 21-day course) plus cisplatin (50 mg/m2 on Day 1) and 146
eligible women were randomized to cisplatin (50 mg/m2 IV on Day 1 of a 21-day
course). All patients had histologically confirmed Stage IV-B, recurrent, or
persistent carcinoma of the cervix considered not amenable to curative
treatment with surgery and/or radiation. Fifty-six percent (56%) of patients
treated with Topotecan for injection plus cisplatin and 56% of patients treated
with cisplatin had received prior cisplatin with or without other agents as
first-line chemotherapy.
Median survival of eligible
patients receiving Topotecan for injection plus cisplatin was 9.4 months (95%
CI: 7.9 to 11.9) compared with 6.5 months (95% CI: 5.8 to 8.8) among patients
randomized to cisplatin alone with a log rank P-value
of 0.033 (significance level was 0.044 after adjusting for the interim
analysis). The unadjusted hazard ratio for overall survival was 0.76 (95% CI:
0.59 to 0.98).
Figure
1. Overall Survival Curves Comparing Topotecan for Injection plus Cisplatin
versus CisplatinMonotherapy in Cervical Cancer Patients
REFERENCES
1.
"OSHA Hazardous
Drugs." OSHA.
http://www.osha.gov/SLTC/hazardousdrugs/index.html.
How Supplied/Storage and HandlingHow Supplied
Topotecan for injection is
supplied as a sterile, lyophilized, buffered, light yellow to greenish cake
powder. Topotecan for injection is supplied in 4-mg (free base) single-dose
vials.
NDC 50742-404-01 (package of
1)
Storage and Handling
Store at 20° to 25°C (68° and
77°F) [see USP Controlled Room Temperature].
Protect vials from light in
the original cartons. Handle and dispose of Topotecan for injection consistent
with recommendations for the handling and disposal of hazardous drugs1.
Patient Counseling Information
· Bone
Marrow Suppression
Inform patients that Topotecan
for injection decreases blood cell counts such as white blood cells, platelets,
and red blood cells. Advise patients to notify their healthcare provider
promptly for fever, other signs of infection (e.g., chills, cough, or burning
pain on urination), or bleeding. Inform patients that frequent blood tests will
be performed while taking Topotecan for injection to monitor for the occurrence
of bone marrow suppression.
· Embryofetal
Toxicity
Advise patients to contact
their healthcare provider if they become pregnant, or if pregnancy is suspected
during treatment with Topotecan for injection. Advise females of reproductive
potential to use effective contraception during treatment and for 1 month after
the last dose of Topotecan for injection. Advise males with a female sexual
partner of reproductive potential to use effective contraception during
treatment and for 3 months after the last dose of Topotecan for injection [see Warnings and
Precautions (5.4), Use
in Specific Populations (8.1, 8.3].
· Lactation
Advise nursing mothers to discontinue
breastfeeding during treatment with Topotecan for injection [see Use in
Specific Populations (8.2)].
· Infertility
Advise male and female
patients of the potential risk for impaired fertility and possible family
planning options [see Use in
Specific Populations (8.3)].
· Asthenia
and Fatigue
Advise patients that Topotecan
for injection may cause asthenia or fatigue. These symptoms may impair the
ability to safely drive or operate machinery.
Manufactured
for:
Ingenus Pharmaceuticals, LLC
4190 Millenia Boulevard,
Orlando,
FL 32839-6408.
Customer toll free number:
1-877-748-1970
Manufactured
by:
Ingensu Pharamceuticals, GmbH
Via Cadepiano 24, Barbengo,
Ticino 6917, Switzerland
Revised: 12/2016
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
Vial label
Carton label
|
Topotecan Topotecan injection,
powder, lyophilized, for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN PRESCRIPTION
DRUG LABEL
|
Item Code
(Source)
|
NDC:50742-404
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Topotecan HYDROCHLORIDE (Topotecan)
|
Topotecan
|
4 mg
in 4 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MANNITOL
|
|
|
TARTARIC ACID
|
|
|
SODIUM HYDROXIDE
|
|
|
HYDROCHLORIC ACID
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:50742-404-01
|
4 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA206962
|
12/07/2016
|
|
|
|
Labeler - Ingenus Pharmaceuticals, LLC (833250017)
|
|
Registrant - Novast Laboratories, Ltd. (527695995)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Ingenus
Pharmaceuticals GmbH
|
|
482730327
|
analysis(50742-404),
label(50742-404), manufacture(50742-404), pack(50742-404),
sterilize(50742-404)
|
Revised:
09/2017
Ingenus
Pharmaceuticals, LLC
