Tell the doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Hycamtin. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
WARNING
MYELOSUPPRESSION HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm³ and platelet counts greater than or equal to 100,000/mm³. Monitor blood cell counts [see WARNINGS AND PRECAUTIONS].
DESCRIPTION
Topotecan is a topoisomerase inhibitor. 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 monohydrochloride. The molecular formula is C23H23N3O5•HCl and the molecular weight is 457.9 g/mol. It is soluble in water and melts with decomposition at 213°C to 218°C. Topotecan hydrochloride has the following structural formula:
HYCAMTIN (topotecan) for injection, for intravenous use is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each 4 mg vial contains 4 mg topotecan hydrochloride as free base. The reconstituted solution ranges in color from yellow to yellow-green.
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.
HYCAMTIN® for injection, as a single agent, is indicated
for the treatment of patients with metastatic ovarian cancer after disease
progression on or after initial or subsequent chemotherapy.
Small Cell Lung Cancer
HYCAMTIN for injection, as a
single agent, is indicated for the treatment of patients with small cell lung
cancer (SCLC) with platinum-sensitive disease who progressed at least 60 days
after initiation of first-line chemotherapy.
Cervical Cancer
HYCAMTIN for injection, in
combination with cisplatin, is indicated for the treatment of patients with
Stage IV-B, recurrent, or persistent cervical cancer not amenable to curative
treatment.
DOSAGE AND ADMINISTRATION
Important Safety Information
Verify dosage using body surface area. Do not exceed a
single dose of 4 mg intravenously.
Recommended Dosage For Ovarian Cancer
The recommended dosage of HYCAMTIN 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 cycle until disease progression or unacceptable
toxicity.
Recommended Dosage For Small Cell Lung Cancer (SCLC)
The recommended dosage of HYCAMTIN 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 cycle.
Recommended Dosage For Cervical Cancer
The recommended dosage of HYCAMTIN 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, of a 21-day cycle.
Dose Modifications For Adverse Reactions
Hematologic
Do not administer subsequent cycles of HYCAMTIN for
injection until neutrophils recover to greater than 1,000/mm³, platelets
recover to greater than 100,000/mm³, and hemoglobin levels recover to greater
than or equal to 9 g/dL (with transfusion if necessary).
For HYCAMTIN for injection as a single agent, reduce the
dose to 1.25 mg/m²/day for:
neutrophil counts of less than 500/mm³ or administer
granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours
following the last dose
platelet counts less than 25,000/mm³ during previous
cycle
For HYCAMTIN for injection in combination with cisplatin,
reduce the dose to 0.6 mg/m²/day (and further to 0.45 mg/m² if necessary) for:
febrile neutropenia (defined as neutrophil counts less
than 1,000/mm³ with 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
platelet counts less than 25,000/mm³ during previous
cycle
Dosage Modification For Renal Impairment
For HYCAMTIN for injection as a single agent, reduce the
dose to 0.75 mg/m²/day for patients with creatinine clearance (CLcr) of 20 to
39 mL/min (calculated with the Cockcroft-Gault method using ideal body weight) [see
CLINICAL PHARMACOLOGY].
Preparation and Intravenous Administration
Visually inspect for particulate matter and discoloration
prior to administration, whenever solution and container permit.
Preparation
Reconstitute each 4 mg vial of HYCAMTIN 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.
Stability
Because the vials contain no preservative, use contents
immediately after reconstitution. Discard any unused portion.
Store reconstituted product diluted for infusion at approximately
20°C to 25°C (68°F to 77°F) protected from light for no more than 24 hours.
Discard after 24 hours.
HOW SUPPLIED
Dosage Forms And Strengths
For injection: 4 mg (free base) of topotecan as a light
yellow to greenish lyophilized powder in single-dose vial for reconstitution.
Storage And Handling
HYCAMTIN for injection is
supplied as a sterile, lyophilized, buffered, light yellow to greenish powder
for reconstitution in 4-mg (free base) single-dose vials.
NDC 0078-0674-61 (package of 1)
Store between 20°C and 25°C
(68°F and 77°F) [see USP Controlled Room Temperature] in original
carton. Protect from light.
HYCAMTIN for injection is a
cytotoxic drug. Follow applicable handling and disposal procedures.
Distributed by: Novartis Pharmaceuticals Corporation East
Hanover, New Jersey 07936. Revised: Sep 2018
Interstitial Lung Disease [see WARNINGS AND
PRECAUTIONS]
Extravasation and Tissue Injury [see WARNINGS AND
PRECAUTIONS]
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.
The data in Warnings and Precautions reflect exposure to
HYCAMTIN for injection from eight trials in which 879 patients with ovarian
cancer or small cell lung cancer (SCLC) received HYCAMTIN for injection 1.5
mg/m² by intravenous infusion daily for 5 consecutive days, starting on Day 1
of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients
with cervical cancer received HYCAMTIN for injection 0.75 mg/m² by intravenous
infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m² by intravenous
infusion on Day 1, of a 21-day cycle.
Ovarian Cancer
The safety of HYCAMTIN for injection was evaluated in a
randomized trial conducted in 226 patients with metastatic ovarian cancer
(Study 039) [see Clinical Studies]. Table 1 shows the incidence of Grade
3 and 4 hematologic and non-hematologic adverse reactions that occurred in
patients receiving HYCAMTIN for injection.
Table 1: Adverse Reactions Occurring in Greater than
or Equal to 5% of Patients with Ovarian Cancer in Study 039
Adverse Reaction
HYCAMTIN for injection
(n = 112)
Paclitaxel
(n = 114)
Grade 3-4 (%)
Grade 3-4 (%)
Hematologic
Grade 4 neutropenia (< 500/mm³)
80
21
Grade 3 or 4 anemia (Hgb < 8 g/dL)
41
6
Grade 4 thrombocytopenia (< 25,000/mm³)
27
3
Febrile neutropenia
23
4
Non-Hematologic
Infections
Sepsisa
5
2
Respiratory, thoracic, and mediastinal
Dyspnea
6
5
Gastrointestinal
Vomiting
10
3
Nausea
10
2
Diarrhea
6
1
Abdominal pain
5
4
Intestinal obstruction
5
4
Constipation
5
0
General and administrative site conditions
Fatigue
7
6
Painb
5
7
Asthenia
5
3
a Death related to sepsis occurred in 2% of
patients receiving HYCAMTIN and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain.
Small Cell Lung Cancer (SCLC)
The safety of HYCAMTIN for injection was evaluated in
randomized, comparative trial in patients with recurrent or progressive SCLC
(Study 090) [seeClinical Studies]. Table 2 shows the Grade 3 or 4
hematologic and non-hematologic adverse reactions in patients with SCLC.
Table 2: Adverse Reactions Occurring in Greater than
or Equal to 5% of Patients with Small Cell Lung Cancer in Study 090
Adverse Reactions
HYCAMTIN for injection
(n = 107)
CAVc
(n = 104)
Grade 3-4 (%)
Grade 3-4 (%)
Hematologic
Grade 4 neutropenia (< 500/mm³)
70
72
Grade 3 or 4 anemia (Hgb < 8 g/dL)
42
20
Grade 4 thrombocytopenia (< 25,000/mm³)
29
5
Febrile neutropenia
28
26
Non-Hematologic
Infections
Sepsisa
5
5
Respiratory, thoracic, and mediastinal
Dyspnea
9
14
Pneumonia
8
6
Gastrointestinal
Nausea
8
6
Abdominal pain
6
4
General and administrative site conditions
Asthenia
9
7
Fatigue
6
10
Painb
5
7
a Death related to sepsis occurred in 3% of
patients receiving HYCAMTIN and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. c CAV = cyclophosphamide, doxorubicin and vincristine.
Hepatobiliary Disorders In Ovarian And Small Cell Lung
Cancer
Based on the combined experience of 453 patients with
metastatic ovarian cancer and 426 patients with SCLC treated with HYCAMTIN for
injection, Grade 3 or 4 increases aspartate transaminase (AST) or alanine
transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred
in less than 2%.
Cervical Cancer
The safety of HYCAMTIN for injection was evaluated in a
comparative trial of HYCAMTIN with cisplatin versus cisplatin as a single agent
in patients with cervical cancer (Study GOG 0179). Table 3 shows the
hematologic and non-hematologic adverse reactions in patients with cervical
cancer.
Table 3: Adverse Reactions Occurring in Greater than
or Equal to 5% of Patients with Cervical Cancer (Between-Arm Difference ≥
2%)a in Study GOG 0179
Adverse Reaction
HYCAMTIN for injection with Cisplatin
(n = 140) %
Cisplatin
(n = 144) %
Hematologic
Neutropenia
Grade 3 (< 1,000-500/mm³)
26
1
Grade 4 (< 500/mm³)
48
1
Anemia
Grade 3 (Hgb < 8-6.5 g/dL)
34
19
Grade 4 (Hgb < 6.5 g/dL)
6
3
Thrombocytopenia
Grade 3 (< 50,000-10,000/mm³)
26
3
Grade 4 (< 10,000/mm³)
7
0
Non-Hematologicb,c
General and administrative site conditions
Constitutionald
69
62
Paine
59
50
Gastrointestinal
Vomiting
40
37
Stomatitis-pharyngitis
6
0
Other
63
56
Dermatologyf
48
20
Infection
Febrile neutropeniaf
28
18
Cardiovascularf
25
15
a Includes patients who were eligible and
treated. b Severity based on using National Cancer Institute (NCI) Common
Toxicity Criteria (CTC), Version 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. e Pain 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. f High-level terms were included if the between-arm difference was
≥ 10%.
Postmarketing Experience
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.
Blood and Lymphatic System: severe bleeding (in
association with thrombocytopenia)
Grade 4 neutropenia occurred in 78% of 879 patients, with
a median duration of 7 days and was most common during Cycle 1 (58% of
patients). Grade 4 neutropenia associated with infection occurred in 13% and
febrile neutropenia occurred in 5%. Sepsis occurred in 4% of patients and was
fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration
of 5 days. Grade 3 or 4 anemia occurred in 37% of patients.
Combination With Cisplatin
Grade 4 neutropenia occurred in 48% and Grade 4
thrombocytopenia occurred in 7% of 147 patients. Grade 3 or 4 anemia occurred
in 40% of patients.
Topotecan 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 for injection only
to patients with a baseline neutrophil count of greater than or equal to
1,500/mm³ and a platelet count greater than or equal to 100,000/mm³. Monitor
blood counts frequently during treatment. Withhold and reduce dose of HYCAMTIN
for injection based on neutrophil counts, platelet counts and hemoglobin levels
[see DOSAGE AND ADMINISTRATION].
Interstitial Lung Disease
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 for injection if ILD is confirmed.
Extravasation And Tissue Injury
Extravasation, including severe cases, can occur with
HYCAMTIN for injection. If signs or symptoms of extravasation occur,
immediately stop administration of HYCAMTIN for injection and institute
recommended management procedures [seeADVERSE REACTIONS].
Embryo-Fetal Toxicity
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 a fetus. Advise females of
reproductive potential to use effective contraception during treatment and for
6 months after the last dose of HYCAMTIN for injection. Advise males with a
female partner of reproductive potential to use effective contraception during
treatment with HYCAMTIN for injection and for 3 months after the last dose [see
Use In Specific Populations, Nonclinical Toxicology].
Nonclinical Toxicology
Carcinogenesis, 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 an
intravenous dose of 1.4 mg/m² [about equal to the clinical dose based on body
surface area (BSA)] 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 at an intravenous dose
of 0.4 mg/m² (about 0.25 times the clinical dose based on BSA) of topotecan
daily for a month suggest that treatment may cause an increase in the incidence
of multinucleated spermatogonial giant cells in the testes.
Use In Specific Populations
Pregnancy
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 (see Data). 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 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 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 dose based on BSA)
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
There are no data on the
presence of topotecan or its metabolites in human milk or their effects on the
breastfed infant or on milk production. Lactating rats excrete high
concentrations of topotecan in milk (see Data).
Because of the potential for
serious adverse reactions in breastfed infants, advise women not to breastfeed
during treatment with HYCAMTIN for injection 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 dose
based on BSA) to lactating rats, topotecan was excreted into milk at
concentrations up to 48-fold higher than those in plasma.
Females And Males Of Reproductive Potential
Pregnancy Testing
Verify pregnancy status of females of reproductive
potential prior to initiating HYCAMTIN for injection [see Use In Specific
Populations].
Contraception
HYCAMTIN can cause fetal harm when administered to a
pregnant woman [see Use In Specific Populations].
Females
Advise females of reproductive potential to use effective
contraception during treatment with HYCAMTIN for injection and for 6 months
after the last dose.
Males
HYCAMTIN 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 for injection and for 3 months after the last dose [see Nonclinical
Toxicology].
Infertility
Females
HYCAMTIN can have both acute and long-term effects on
fertility [see Nonclinical Toxicology].
Males
Effects on spermatogenesis occurred in animals
administered topotecan [see Nonclinical Toxicology].
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 HYCAMTIN for injection, 32% were
aged 65 years and older, while 3.8% were aged 75 years and older. Of the 140
patients with Stage IV-B, relapsed, or refractory cervical cancer in clinical
trials of HYCAMTIN for injection who received HYCAMTIN with cisplatin in the
randomized clinical trial, 6% were aged 65 years and older, while 3% were aged
75 years and older. No overall differences in effectiveness or safety were
observed between these patients and younger patients and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients.
Renal Impairment
Reduce the dose of HYCAMTIN for injection in patients
with a CLcr of 20 to 39 mL/min [see DOSAGE AND ADMINISTRATION, CLINICAL
PHARMACOLOGY]. No dosage adjustment is recommended for patients with CLcr
greater than or equal to 40 mL/min. Insufficient data are available in patients
with CLcr less than 20 mL/min to provide a dosage recommendation for HYCAMTIN
for injection.
Overdosage & Contraindications
OVERDOSE
Overdoses (up to 10-fold of the recommended dose) have
occurred in patients receiving intravenous topotecan. The primary complication
of overdosage is myelosuppression. Elevated hepatic enzymes, mucositis,
gastrointestinal toxicity, and skin toxicity have occurred with overdosages. If
an overdose is suspected, monitor the patient closely for myelosuppression and
institute supportive-care measures as appropriate.
CONTRAINDICATIONS
HYCAMTIN is contraindicated in patients who have a
history of severe hypersensitivity reactions to topotecan. Reactions have
included anaphylactoid reactions [see ADVERSE REACTIONS].
Clinical Pharmacology
Mechanism 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 re-ligation 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 HYCAMTIN for injection at
doses of 0.5 to 1.5 mg/m² (0.1 to 0.3 times the recommended single agent dose)
administered as a 30-minute infusion, area under the curve (AUC) increases
proportionally with dose.
Distribution
Protein binding of topotecan is
approximately 35%.
Elimination
The terminal half-life of topotecan is 2 to 3
hours following intravenous administration.
Metabolism
Topotecan undergoes a
reversible pH-dependent hydrolysis of its pharmacologically active lactone
moiety. At pH less than or equal to 4, the lactone is exclusively present,
whereas the ring-opened hydroxy-acid form predominates at physiologic pH.
Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean
metabolite: parent AUC ratio was about 3% for total topotecan and topotecan
lactone following intravenous administration.
Excretion
The overall recovery of total
topotecan and its N-desmethyl metabolite in urine and feces over 9 days
averaged 73% ± 2% following an intravenous dose. Mean values of 51% ± 3% as
total topotecan and 3% ± 1% as Ndesmethyl topotecan were excreted in the urine.
Fecal elimination of total topotecan accounted for 18% ± 4% 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
No clinically significant
differences in the pharmacokinetics of topotecan were observed based on age,
sex, or hepatic impairment following intravenous administration.
Patients With Renal Impairment
Compared to patients with CLcr (calculated by the
Cockcroft-Gault method using ideal body weight) greater than 60 mL/min, plasma
clearance of topotecan lactone decreased by 33% in patients with CLcr 40-60
mL/min and decreased 65% in patients with CLcr 20-39 mL/min. The effect on
topotecan pharmacokinetics in patients with CLcr less than 20 mL/min is unknown
[seeDOSAGE AND ADMINISTRATION].
Drug Interaction Studies
Clinical Studies
No clinically significant changes in topotecan
pharmacokinetics were observed when coadministered cisplatin.
No clinically significant changes in the pharmacokinetics
of free platinum were observed in patients coadministered cisplatin with
topotecan.
In Vitro Studies
Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9,
CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase.
Clinical Studies
Ovarian Cancer
The efficacy of HYCAMTIN for injection was evaluated in
two clinical trials of 223 patients with metastatic ovarian cancer. All
patients had disease that had recurred on, or was unresponsive to, a
platinum-containing regimen. Patients in these trials received an initial dose
of 1.5 mg/m² as an intravenous infusion for 5 consecutive days, starting on Day
1 of a 21-day cycle.
One trial (Study 039) was a randomized trial of 112
patients who received HYCAMTIN for injection and of 114 patients who received
paclitaxel (175 mg/m² intravenously over 3 hours on Day 1 of a 21-day cycle).
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 overall response
rate, response duration, time to progression, and overall survival (OS).
The results of the trial did not show statistically
significant improvements in response rates, response duration, time to
progression, and OS as shown in Table 4.
Table 4: Efficacy Results in Ovarian Cancer in Study 039
Parameter
HYCAMTIN for injection
(n = 112)
Paclitaxel
(n = 114)
Overall response rate (95% CI)
21% (13%, 28%)
14% (8%, 20%)
Complete response rate
5%
3%
Partial response rate
16%
11%
Response durationa (months)
Median (95% CI)
6 (5.1, 7.6)
5 (3.7, 7.8)
Time to progression (months)
Median (95% CI)
4.4 (2.8, 5.4)
3.4 (2.7, 4.2)
Hazard ratio (95% CI)
0.76 (0.57, 1.02)
Overall survival (months)
Median (95% CI)
14.5 (10.7, 16.5)
12.2 (9.7, 15.8)
Hazard ratio (95% CI)
0.97 (0.71, 1.34)
Abbreviation: CI, confidence interval. a The calculation for response duration was based on the interval
between first response and time to progression.
The median time to response was
7.6 weeks (3.1 weeks to 5 months) with HYCAMTIN for injection compared with 6
weeks (2.4 weeks to 4.1 months) with paclitaxel. In the cross-over phase, 13%
of 61 patients who received HYCAMTIN after paclitaxel had a partial response
and 10% of 49 patients who received paclitaxel after HYCAMTIN had a response (2
complete responses).
HYCAMTIN 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%.
HYCAMTIN 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%, 20%). The median duration of response was 5 months (4.6 weeks to
9.6 months). The time to progression was 2.6 months (5 days to 1.4 years). The
median survival was 1.3 years (1.4 weeks, to 2.2 years).
Small Cell Lung Cancer
The efficacy of HYCAMTIN for injection
was evaluated in 426 patients with recurrent or progressive small cell lung
cancer (SCLC) in a randomized, comparative trial and in 3 single-arm trials.
Randomized Comparative Trial
In a randomized, comparative
trial, 211 patients were randomized 1:1 to receive HYCAMTIN for injection (1.5
mg/m² once daily intravenously for 5 days starting on Day 1 of a 21-day cycle)
or CAV (cyclophosphamide 1,000 mg/m², doxorubicin 45 mg/m², vincristine 2 mg
administered sequentially on Day 1 of a 21-day cycle). 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 HYCAMTIN 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 overall response rate, response duration, time to progression or
OS.
The results of the trial did
not show statistically significant improvements in response rate, response
duration, time to progression, or OS as shown in Table 5.
Table 5: Efficacy Results in
Patients with Small Cell Lung Cancer Sensitive to First-Line Chemotherapy in
Study 090
Parameter
HYCAMTIN for injection
(n = 107)
CAVb
(n = 104)
Overall response rate (95% CI)
24% (16%, 32%)
18% (11%, 26%)
Complete response rate
0%
1%
Partial response rate
24%
17%
Response durationa (months)
Median (95% CI)
3.3 (3, 4.1)
3.5 (3, 5.3)
Time to progression (months)
Median (95% CI)
3.1 (2.6, 4.1)
2.8 (2.5, 3.2)
Hazard ratio (95% CI)
0.92 (0.69, 1.22)
Overall survival (months)
Median (95% CI)
5.8 (4.7, 6.8)
5.7 (5, 7)
Hazard ratio (95% CI)
1.04 (0.78, 1.39)
Abbreviations: CI, confidence interval. a The calculation for duration of response was based on the interval
between first response and time to progression. b CAV = cyclophosphamide, doxorubicin and vincristine.
The median time to response was similar in both arms:
HYCAMTIN, 6 weeks (2.4 weeks to 3.6 months) versus CAV, 6 weeks (5.1 weeks to
4.2 months).
Changes on a disease-related
symptom scale 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: Symptom Improvementa in Patients with Small
Cell Lung Cancer in Study 090
Symptom
HYCAMTIN for injection
(n = 107)
CAV
(n = 104)
nb
(%)
nb
(%)
Shortness of breath
68
28
61
7
Interference with daily activity
67
27
63
11
Fatigue
70
23
65
9
Hoarseness
40
33
38
13
Cough
69
25
61
15
Insomnia
57
33
53
19
Anorexia
56
32
57
16
Chest pain
44
25
41
17
Hemoptysis
15
27
12
33
a Defined as improvement sustained over at
least 2 courses compared with baseline. b Number of patients with baseline and at least 1 post-baseline
assessment.
Single-Arm Trials
HYCAMTIN for injection was also
studied in three open-label, non-comparative trials (Studies 014, 092 and 053)
in a total of 319 patients with recurrent or progressive SCLC after treatment
with first-line chemotherapy. In all three 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
three trials and the comparative trial.
Cervical Cancer
The efficacy of HYCAMTIN for injection was evaluated in a
multi-center, randomized (1:1), open-label study (Study GOG 0179) conducted in
147 patients with histologically confirmed Stage IV-B, recurrent, or persistent
cervical cancer considered not amenable to curative treatment with surgery
and/or radiation. Patients were randomized to HYCAMTIN for injection (0.75 mg/m²
once daily intravenously for 3 consecutive days starting on Day 1 of a 21-day
cycle) with cisplatin (50 mg/m² intravenously on Day 1) or cisplatin as a
single agent. Fifty-six percent of patients treated with HYCAMTIN with
cisplatin and 56% of patients treated with cisplatin had received prior
cisplatin with or without other agents as first-line chemotherapy. The efficacy
outcome measure was OS.
Median OS of eligible patients receiving HYCAMTIN with
cisplatin was 9.4 months (95% CI: 7.9, 11.9) compared with 6.5 months (95% CI:
5.8, 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 OS was 0.76 (95% CI: 0.59, 0.98).
Figure 1: Kaplan-Meier Curves for Overall Survival in
Cervical Cancer in Study GOG 0179
Inform patients that HYCAMTIN
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, or bleeding [see WARNINGS AND PRECAUTIONS].
Interstitial Lung Disease (ILD)
Inform patients of the risks of
severe ILD. Advise patients to contact their healthcare provider immediately to
report new or worsening respiratory symptoms [see WARNINGS AND
PRECAUTIONS].
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 for injection [see WARNINGS AND PRECAUTIONS, Use In Specific
Populations].
Advise females of reproductive potential to use effective
contraception during treatment and for 6 months after the last dose of HYCAMTIN
for injection [see Use In Specific Populations].
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 for injection [see Use In Specific Populations, Nonclinical
Toxicology].
Lactation
Advise women to discontinue breastfeeding during treatment
and for 1 week after the last dose of HYCAMTIN for injection [see Use In Specific
Populations].
