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`HY:LXX
`PRESCRIBING INFORMATION
`
`HYCAMTIN®
`(topotecan hydrochloride)
`For Injection
`FOR INTRAVENOUS USE
`
`WARNING
` HYCAMTIN (topotecan hydrochloride) for Injection should be administered under the
`supervision of a physician experienced in the use of cancer chemotherapeutic agents.
`Appropriate management of complications is possible only when adequate diagnostic and
`treatment facilities are readily available.
` Therapy with HYCAMTIN should not be given to patients with baseline neutrophil counts of
`less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression,
`primarily neutropenia, which may be severe and result in infection and death, frequent peripheral
`blood cell counts should be performed on all patients receiving HYCAMTIN.
`
`DESCRIPTION
` HYCAMTIN (topotecan hydrochloride) is a semi-synthetic derivative of camptothecin and is
`an anti-tumor drug with topoisomerase I-inhibitory activity.
` HYCAMTIN for Injection is supplied as a sterile lyophilized, buffered, light yellow to
`greenish 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.
` 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. It has the molecular formula C23H23N3O5•HCl and a molecular weight of
`457.9.
`Topotecan hydrochloride has the following structural formula:
`
`It is soluble in water and melts with decomposition at 213° to 218°C.
`
`1
`
`AVENTIS EXHIBIT 2206
`Mylan v. Aventis IPR2016-00712
`
`

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`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 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: The pharmacokinetics of topotecan have been evaluated in cancer patients
`following doses of 0.5 to 1.5 mg/m2 administered as a 30-minute infusion. Topotecan exhibits
`multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure
`(AUC) is approximately dose-proportional. Binding of topotecan to plasma proteins is about
`35%.
` Metabolism and Elimination: 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.
` Renal clearance is an important determinant of topotecan elimination (see Special
`Populations: Renal Impairment).
`
`In a mass balance/excretion study 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. These metabolites, topotecan-O-glucuronide and N-desmethyl topotecan-
`O-glucuronide, were less than 2% of the administered dose.
`Special Populations: Gender: The overall mean topotecan plasma clearance in male patients
`was approximately 24% higher than that in female patients, largely reflecting difference in body
`size.
` Geriatrics: Topotecan pharmacokinetics have not been specifically studied in an elderly
`population, but 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 PRECAUTIONS and DOSAGE AND
`ADMINISTRATION).
` Race: The effect of race on topotecan pharmacokinetics has not been studied.
` Renal Impairment: In patients with mild renal impairment (creatinine clearance of 40 to
`60 mL/min.), topotecan plasma clearance was decreased to about 67% of the value in patients
`with normal renal function. In patients with moderate renal impairment (Clcr of 20 to
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`39 mL/min.), topotecan plasma clearance was reduced to about 34% of the value in control
`patients, with an increase in half-life. Mean half-life, estimated in 3 renally impaired patients,
`was about 5.0 hours. Dosage adjustment is recommended for these patients (see DOSAGE AND
`ADMINISTRATION).
` Hepatic Impairment: Plasma clearance in patients with hepatic impairment (serum
`bilirubin levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients
`without hepatic impairment. Topotecan half-life increased slightly, from 2.0 hours to 2.5 hours,
`but these hepatically impaired patients tolerated the usual recommended topotecan dosage
`regimen (see DOSAGE AND ADMINISTRATION).
`Drug Interactions: Pharmacokinetic studies of the interaction of topotecan with concomitantly
`administered medications have not been formally investigated. In vitro inhibition studies using
`marker substrates known to be metabolized by 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. Enzyme inhibition by
`topotecan has not been evaluated in vivo.
` Administration of cisplatin (60 or 75 mg/m2 on Day 1) before topotecan (0.75 mg/m2/day on
`Days 1-5 in 9 patients with ovarian cancer had no significant effect on the Cmax and AUC of
`total topotecan.
` Topotecan 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 before topotecan 0.3 mg/m2 IV daily on days 2-6. Topotecan had
`no effect on dose-normalized (60 mg/m2) Cmax values of free platimun in 13 patients with ovarian
`cancer who were administered 60 mg/m2 (n = 10) or 75 mg/m2 (n = 3) cisplatin on day 1 before
`topotecan 0.75 mg/m2 IV daily on days 1-5.
` No pharmacokinetic data are available following topotecan (0.75 mg/m2/day for 3 consecutive
`days) and cisplatin (50 mg/m2/day on day 1) in patients with cervical cancer.
`Pharmacodynamics: The dose-limiting toxicity of topotecan is leukopenia. White blood cell
`count decreases with increasing topotecan dose or topotecan AUC. When topotecan is
`administered at a dose of 1.5 mg/m2/day for 5 days, an 80% to 90% decrease in white blood cell
`count at nadir is typically observed after the first cycle of therapy.
`
`CLINICAL STUDIES
`Ovarian Cancer: HYCAMTIN 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 studies 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 study was a randomized trial of 112 patients treated with HYCAMTIN (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
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`platinum-containing regimen or had not responded to at least 1 prior platinum-containing
`regimen. Patients who did not respond to the study therapy, or who progressed, could be given
`the alternative treatment.
` Response rates, response duration, and time to progression are shown in Table 1.
`
`Table 1. Efficacy of HYCAMTIN Versus Paclitaxel in Ovarian Cancer
`
`HYCAMTIN
`Parameter
`(n = 112)
`Complete response rate
`5%
`Partial response rate
`16%
`Overall response rate
`21%
`95% Confidence interval
`13 to 28%
`(p-value)
`Response duration* (weeks)
`Median
`95% Confidence interval
`hazard-ratio
`
`(HYCAMTIN:paclitaxel)
`(p-value)
`Time to progression (weeks)
`Median
`95% Confidence interval
`hazard-ratio
`
`(HYCAMTIN:paclitaxel)
`(p-value)
`
`n = 23
`25.9
`22.1 to 32.9
`
`(0.20)
`
`
`0.78
`(0.48)
`
`
`0.76
`(0.07)
`
`Paclitaxel
`(n = 114)
`3%
`11%
`14%
`8 to 20%
`
`n = 16
`21.6
`16.0 to 34.0
`
`
`18.9
`12.1 to 23.6
`
`
`14.7
`11.9 to 18.3
`
`Survival (weeks)
`Median
`95% Confidence interval
`
`hazard-ratio
`0.97
`
`(HYCAMTIN:paclitaxel)
`(0.87)
`(p-value)
`* The calculation for duration of response was based on the interval between first response and
`time to progression.
`
`
`63.0
`46.6 to 71.9
`
`
`53.0
`42.3 to 68.7
`
`
` The median time to response was 7.6 weeks (range 3.1 to 21.7) with HYCAMTIN compared
`to 6.0 weeks (range 2.4 to 18.1) with paclitaxel. Consequently, the efficacy of HYCAMTIN may
`not be achieved if patients are withdrawn from treatment prematurely.
`
`In the crossover phase, 8 of 61 (13%) patients who received HYCAMTIN after paclitaxel had
`a partial response and 5 of 49 (10%) patients who received paclitaxel after HYCAMTIN had a
`response (2 complete responses).
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` HYCAMTIN 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 study, there were no
`complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.
` HYCAMTIN 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: HYCAMTIN was studied in 426 patients with recurrent or
`progressive small cell lung cancer in 1 randomized, comparative study and in 3 single-arm
`studies.
` Randomized Comparative Study: In a randomized, comparative, Phase 3 trial,
`107 patients were treated with HYCAMTIN (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 ≥60 days after completion of first-line therapy). A total of 77% of
`patients treated with HYCAMTIN and 79% of patients treated with CAV received
`platinum/etoposide with or without other agents as first-line chemotherapy.
` Response rates, response duration, time to progression, and survival are shown in Table 2.
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`CAV
`(n = 104)
`1%
`17%
`18%
`
`6%
`(–6 to 18%)
`
`n = 26
`14.4
`13.1 to 18.0
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`n = 19
`15.3
`13.1 to 23.1
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`1.42 (0.73 to 2.76)
`(0.30)
`
`Table 2. Efficacy of HYCAMTIN Versus CAV (cyclophosphamide-doxorubicin-vincristine)
`in Small Cell Lung Cancer Patients Sensitive to First-Line Chemotherapy
`
`HYCAMTIN
`Parameter
`(n = 107)
`Complete response rate
`0%
`Partial response rate
`24%
`Overall response rate
`24%
`Difference in overall response rates
`95% Confidence interval of the difference
`Response duration* (weeks)
`Median
`95% Confidence interval
`hazard-ratio
`
`(HYCAMTIN:CAV) (95% CI)
`(p-value)
`Time to progression (weeks)
`Median
`95% Confidence interval
`hazard-ratio
`
`(HYCAMTIN:CAV) (95% CI)
`(p-value)
`
`
`13.3
`11.4 to 16.4
`
`
`12.3
`11.0 to 14.1
`
`
`0.92 (0.69 to 1.22)
`(0.55)
`
`Survival (weeks)
`Median
`95% Confidence interval
`
`hazard-ratio
`1.04 (0.78 to 1.39)
`
`(HYCAMTIN:CAV) (95% CI)
`(0.80)
`(p-value)
`* The calculation for duration of response was based on the interval between first response and
`time to progression.
`
`
`25.0
`20.6 to 29.6
`
`
`24.7
`21.7 to 30.3
`
`
` The time to response was similar in both arms: HYCAMTIN 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 HYCAMTIN or who
`received CAV are presented in Table 3. 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.
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`CAV
`(n = 104)
`
`Table 3. Percentage of Patients With Symptom Improvement*: HYCAMTIN Versus CAV
`in Patients With Small Cell Lung Cancer
`HYCAMTIN
`(n = 107)
`
`(%)
`(7)
`(11)
`(9)
`(13)
`(15)
`(19)
`(16)
`(17)
`(33)
`
`n†
`n†
`(%)
`Symptom
`61
`(28)
`68
`Shortness of breath
`63
`(27)
`67
`Interference with daily activity
`65
`(23)
`70
`Fatigue
`38
`(33)
`40
`Hoarseness
`61
`(25)
`69
`Cough
`53
`(33)
`57
`Insomnia
`57
`(32)
`56
`Anorexia
`41
`(25)
`44
`Chest pain
`12
`(27)
`15
`Hemoptysis
`* Defined as improvement sustained over at least 2 courses compared to baseline.
`† Number of patients with baseline and at least 1 post-baseline assessment.
`
` Single-Arm Studies: HYCAMTIN 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 studies, patients were stratified as either sensitive (responders
`who then subsequently progressed ≥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 studies and the comparative study.
`Cervical Cancer: In a comparative trial, 147 eligible women were randomized to HYCAMTIN
`(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 HYCAMTIN 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 in the HYCAMTIN plus cisplatin treatment arm was 9.4
`months (95% CI: 7.9 to 11.9) compared to 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).
`
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`Figure 1. Overall Survival Curves Comparing HYCAMTIN plus Cisplatin versus Cisplatin
`Monotherapy in Cervical Cancer Patients
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`INDICATIONS AND USAGE
` HYCAMTIN is indicated for the treatment of:
`• metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy.
`• small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical
`studies submitted to support approval, sensitive disease was defined as disease responding to
`chemotherapy but subsequently progressing at least 60 days (in the Phase 3 study) or at least
`90 days (in the Phase 2 studies) after chemotherapy (see CLINICAL STUDIES).
` HYCAMTIN in combination with cisplatin is indicated for the treatment of:
`• stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative
`treatment with surgery and/or radiation therapy.
`
`CONTRAINDICATIONS
` HYCAMTIN is contraindicated in patients who have a history of hypersensitivity reactions to
`topotecan or to any of its ingredients. HYCAMTIN should not be used in patients who are
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`pregnant or breast-feeding, or those with severe bone marrow depression.
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`•
`
`WARNINGS
` Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of
`HYCAMTIN. Neutropenia is not cumulative over time. The following data on
`myelosuppression is based on:
`•
`the combined experience of 879 patients with metastatic ovarian cancer or small cell lung
`cancer treated with HYCAMTIN monotherapy at a dose of 1.5 mg/m2/day x 5 days.
`the experience of 140 patients with cervical cancer randomized to receive HYCAMTIN
`0.75 mg/m2/day on days 1, 2, and 3 plus cisplatin 50 mg/m2 on day 1.
`Neutropenia:
`• Ovarian and small cell lung cancer experience: Grade 4 neutropenia (<500 cells/mm3)
`was most common during course 1 of treatment (60% of patients) and occurred in 39% of
`all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a
`median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of
`patients, and sepsis was fatal in 1%.
`• Cervical cancer experience: Grade 3 and grade 4 neutropenia affected 26% and 48% of
`patients, respectively.
`Thrombocytopenia:
`• Ovarian and small cell lung cancer experience: Grade 4 thrombocytopenia
`(<25,000/mm3) occurred in 27% of patients and in 9% of courses, with a median duration
`of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to
`15% of patients in 4% of courses.
`• Cervical cancer experience: Grade 3 and grade 4 thrombocytopenia affected 26% and 7%
`of patients, respectively.
`Anemia:
`• Ovarian and small cell lung cancer experience: Grade 3/4 anemia (<8 g/dL) occurred in
`37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were
`needed in 52% of patients in 22% of courses.
`• Cervical cancer experience: Grade 3 and grade 4 anemia affected 34% and 6% of
`patients, respectively.
`In ovarian cancer, the overall treatment-related death rate was 1%. In the comparative study in
`
`small cell lung cancer, however, the treatment-related death rates were 5% for HYCAMTIN and
`4% for CAV.
`Monitoring of Bone Marrow Function: HYCAMTIN should be administered only in
`patients with adequate bone marrow reserves, including baseline neutrophil count of at least
`1,500 cells/mm3 and platelet count at least 100,000/mm3. Frequent monitoring of peripheral
`blood cell counts should be instituted during treatment with HYCAMTIN. Patients should not be
`treated with subsequent courses of HYCAMTIN until neutrophils recover to >1,000 cells/mm3,
`platelets recover to >100,000 cells/mm3, and hemoglobin levels recover to 9.0 g/dL (with
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`transfusion if necessary). Severe myelotoxicity has been reported when HYCAMTIN is used in
`combination with cisplatin (see Drug Interactions).
`Pregnancy: HYCAMTIN may cause fetal harm when administered to a pregnant woman. The
`effects of topotecan on pregnant women have not been studied. If topotecan is used during a
`patient’s pregnancy, or if a patient becomes pregnant while taking topotecan, she should be
`warned of the potential hazard to the fetus. Fecund women should be warned to avoid becoming
`pregnant. In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m2 basis)
`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/m2 basis) given for 14 days before mating through gestation day 6 caused fetal resorption,
`microphthalmia, pre-implant loss, and mild maternal toxicity. A dose of 0.10 mg/kg/day (about
`half the clinical dose on a mg/m2 basis) 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.
`
`PRECAUTIONS
`General: Inadvertent extravasation with HYCAMTIN has been associated only with mild local
`reactions such as erythema and bruising.
`Information for Patients: As with other chemotherapeutic agents, HYCAMTIN may cause
`asthenia or fatigue; if these symptoms occur, caution should be observed when driving or
`operating machinery.
`Hematology: Monitoring of bone marrow function is essential (see WARNINGS and
`DOSAGE AND ADMINISTRATION).
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity testing of
`topotecan has not been performed. Topotecan, however, 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.
`Drug Interactions: Concomitant administration of G-CSF can prolong the duration of
`neutropenia, so if G-CSF is to be used, it should not be initiated until day 6 of the course of
`therapy, 24 hours after completion of treatment with HYCAMTIN.
` Myelosuppression was more severe when HYCAMTIN, at a dose of 1.25 mg/m2/day ×
`5 days, was given in combination with cisplatin at a dose of 50 mg/m2 in Phase 1 studies. In one
`study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with
`neutropenic sepsis.
` Greater myelosuppression is also likely to be seen when HYCAMTIN is used in combination
`with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining
`HYCAMTIN with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent
`
`10
`
`

`
`285
`286
`287
`288
`289
`290
`291
`292
`293
`294
`295
`296
`297
`298
`299
`300
`301
`302
`303
`304
`305
`306
`307
`308
`309
`310
`311
`312
`
`313
`314
`315
`316
`317
`318
`
`interaction on myelosuppression has been reported. Coadministration of a platinum agent on
`day 1 of HYCAMTIN dosing required lower doses of each agent compared to coadministration
`on day 5 of the HYCAMTIN dosing schedule.
` For information on the pharmacokinetics, efficacy, safety, and dosing of HYCAMTIN at a
`dose of 0.75 mg/m2/day days 1, 2, and 3 in combination with cisplatin 50 mg/m2 on day 1 for
`cervical cancer, see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE
`REACTIONS, and DOSAGE AND ADMINISTRATION.
`Pregnancy: Pregnancy Category D. (See WARNINGS.)
`Nursing Mothers: It is not known whether the drug is excreted in human milk. Breast-feeding
`should be discontinued when women are receiving HYCAMTIN (see
`CONTRAINDICATIONS).
`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 studies of HYCAMTIN, 32% (n = 281) were 65 years of age and older, while 3.8%
`(n = 33) were 75 years of age and older. Of the 140 patients with stage IVB, relapsed, or
`refractory cervical cancer in clinical studies of HYCAMTIN who received HYCAMTIN plus
`cisplatin in the randomized clinical trial, 6% (n = 9) were 65 years of age and older, while 3%
`(n = 4) were 75 years of age 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, but greater sensitivity of some older individuals cannot be ruled out.
` There were no apparent differences in the pharmacokinetics of topotecan in elderly patients,
`once the age-related decrease in renal function was considered (see CLINICAL
`PHARMACOLOGY).
` This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions
`to this drug may be greater in patients with impaired renal function. Because elderly patients are
`more likely to have decreased renal function, care should be taken in dose selection, and it may
`be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).
`
`ADVERSE REACTIONS
`Ovarian Cancer and Small Cell Lung Cancer: Data in the following section are based on
`the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients
`with small cell lung cancer treated with HYCAMTIN. Table 5 lists the principal hematologic
`toxicities, and Table 6 lists non-hematologic toxicities occurring in at least 15% of patients.
`
`
`11
`
`

`
`Table 5. Summary of Hematologic Adverse Events in Patients Receiving HYCAMTIN
`Patients
`Courses
`n = 879
`n = 4124
`% Incidence
`% Incidence
`
`
`97
`81
`78
`39
`
`
`97
`80
`32
`11
`
`
`69
`42
`27
`9
`
`
`89
`71
`37
`14
`15
`4
`52
`22
`
`Hematologic Adverse Event
`Neutropenia
` <1,500 cells/mm3
` <500 cells/mm3
`Leukopenia
` <3,000 cells/mm3
` <1,000 cells/mm3
`Thrombocytopenia
` <75,000/mm3
` <25,000/mm3
`Anemia
` <10 g/dL
` <8 g/dL
`Platelet transfusions
`RBC transfusions
`
`
`
`319
`
`320
`
`
`
`12
`
`

`
`Table 6. Summary of Non-hematologic Adverse Events in Patients Receiving HYCAMTIN
`All Grades
`Grade 3
`Grade 4
`% Incidence
`% Incidence
`% Incidence
`n = 879
`n = 4124 n = 879
`n = 4124 n = 879
`n = 4124
`Patients Courses
`Patients Courses
`Patients Courses
`
`
`
`
`
`
`43
`15
`NR
`NR
`23
`7
`
`
`
`
`1
`
`<1
`
`
`2
`<1
`
`2
`1
`1
`1
`1
`<1
`
`
`NA
`<1
`
`
`2
`<1
`1
`1
`
`
`<1
`
`<1
`
`
`3
`0
`
`1
`1
`1
`1
`2
`<1
`
`
`NA
`0
`
`
`0
`<1
`1
`2
`
`
`<1
`
`0
`
`
`1
`0
`
`<1
`<1
`<1
`<1
`<1
`<1
`
`
`NA
`0
`
`
`0
`<1
`<1
`<1
`
`13
`
`
`19
`
`18
`
`
`22
`15
`
`64
`45
`32
`29
`22
`18
`
`
`49
`16
`
`
`29
`28
`23
`25
`
`
`9
`
`7
`
`
`11
` 7
`
`42
`22
`14
`15
`10
`8
`
`
`54
` 6
`
`
`22
`11
`11
`13
`
`
`2
`
`1
`
`
`5
`1
`
`7
`4
`3
`2
`2
`1
`
`
`NA
`1
`
`
`5
`1
`2
`4
`
`Non-hematologic
`Adverse Event
`Infections and infestations
`
`Sepsis or pyrexia/infection with
`neutropenia*
`Metabolism and nutrition disorders
` Anorexia
`Nervous system disorders
` Headache
`Respiratory, thoracic, and mediastinal
`disorders
` Dyspnea
` Coughing
`Gastrointestinal disorders
` Nausea
` Vomiting
` Diarrhea
` Constipation
` Abdominal pain
` Stomatitis
`Skin and subcutaneous tissue
`disorders
` Alopecia
` Rash†
`General disorders and administrative
`site conditions
` Fatigue
` Pyrexia
` Pain‡
` Asthenia
`NA = Not applicable
`NR = Not reported separately
`* Does not include Grade 1 sepsis or pyrexia.
`† Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
`‡ Pain includes body pain, back pain, and skeletal pain.
`
` Premedications were not routinely used in these clinical studies.
`Hematologic: (See WARNINGS.)
`Nervous System Disorders: Headache (18% of patients) was the most frequently reported
`neurologic toxicity. Paresthesia occurred in 7% of patients but was generally grade 1.
`Respiratory, Thoracic, and Mediastinal Disorders: The incidence of grade 3/4 dyspnea
`was 4% in ovarian cancer patients and 12% in small cell lung cancer patients.
`Gastrointestinal Disorders: The incidence of nausea was 64% (8% grade 3/4), and vomiting
`occurred in 45% (6% grade 3/4) of patients (see Table 5). The prophylactic use of antiemetics
`was not routine in patients treated with HYCAMTIN. Thirty-two percent of patients had diarrhea
`(4% grade 3/4), 29% constipation (2% grade 3/4), and 22% had abdominal pain (4% grade 3/4).
`
`321
`
`322
`323
`324
`325
`326
`327
`328
`329
`330
`331
`332
`333
`334
`335
`336
`337
`
`

`
`338
`339
`340
`341
`342
`343
`344
`345
`346
`347
`
`Grade 3/4 abdominal pain was 6% in ovarian cancer patients and 2% in small cell lung cancer
`patients.
`Skin and Subcutaneous Tissue Disorders: Total alopecia (grade 2) occurred in 31% of
`patients.
`Hepatobiliary Disorders: Grade 1 transient elevations in hepatic enzymes occurred in 8% of
`patients. Greater elevations, grade 3/4, occurred in 4%. Grade 3/4 elevated bilirubin occurred in
`<2% of patients.
` Table 7 shows the grade 3/4 hematologic and major non-hematologic adverse events in the
`topotecan/paclitaxel comparator trial in ovarian cancer.
`
`
`14
`
`

`
`348
`349
`
`Table 7. Comparative Toxicity Profiles for Ovarian Cancer Patients Randomized to
`Receive HYCAMTIN or Paclitaxel
`
`HYCAMTIN
`Patients
`Courses
`n = 112
`n = 597
`%
`%
`
`
`80
`36
`
`
`41
`16
`
`
`27
`10
`23
`6
`%
`%
`
`
`5
`1
`2
`NA
`
`
`4
`1
`
`
`1
`<1
`
`
`6
`2
`
`
`5
`1
`5
`1
`6
`2
`5
`1
`10
`3
`1
`<1
`10
`2
`
`
`1
`<1
`
`
`0
`0
`
`
`
`Paclitaxel
`Patients
`Courses
`n = 114
`n = 589
`%
`%
`
`
`21
`9
`
`
`6
`2
`
`
`3
`<1
`4
`1
`%
`%
`
`
`2
`<1
`0
`NA
`
`
`0
`0
`
`
`2
`1
`
`
`5
`1
`
`
`4
`1
`0
`0
`1
`<1
`4
`1
`2
`<1
`1
`<1
`3
`<1
`
`
`1
`<1
`
`
`1
`<1
`
`
`
`<1
`
`
`2
`<1
`
`3
`
`
`6
`2
`
`<1
`
`
`2
`<1
`
`1
`
`
`7
`2
`
`15
`
`
`
`Adverse Event
`Hematologic Grade 3/4
`Grade 4 neutropenia
` (<500 cells/mm3)
`Grade 3/4 anemia
` (Hgb <8 g/dL)
`Grade 4 thrombocytopenia
` (<25,000 plts/mm3)
`Pyrexia/Grade 4 neutropenia
`Non-hematologic Grade 3/4
`Infections and infestations
` Documented sepsis
` Death related to sepsis
`Metabolism and nutrition disorders
` Anorexia
`Nervous system disorders
` Headache
`Respiratory, thoracic, and mediastinal disorders
` Dyspnea
`Gastrointestinal disorders
` Abdominal pain
` Constipation
` Diarrhea
`
`Intestinal obstruction
` Nausea
`
`Stomatitis
` Vomiting
`Hepatobiliary Disorders
` Hepatic enzymes increased*
`Skin and subcutaneous tissue disorders
` Rash†
`Musculoskeletal, connective tissue, and bone
`disorders
` Arthralgia
`General disorders and administrative site
`conditions
`
`Fatigue
` Malaise
`
`

`
`*
`
`1
`3
`2
`5
` Asthenia
`<1
`1
`<1
`2
` Chest pain
`2
`3
`0
`0
` Myalgia
`Pain‡
`2
`7
`1
`5
`
`Increased hepatic enzymes includes increased SGOT/AST, increased SGPT/ALT, and increased hepatic
`enzymes.
`† Rash also includes pruritus, rash erythematous, urticaria, dermatitis, bullous eruption, and maculopapular rash.
`‡ Pain includes body pain, skeletal pain, and back pain.
`
` Premedications were not routinely used in patients randomized to HYCAMTIN, whereas
`patients receiving paclitaxel received routine pretreatment with corticost