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HYCAMTIN (Injection, Solution)

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dailymed-drugs:905rdfs:labelHYCAMTIN (Injection, Solution)lld:dailymed
dailymed-drugs:905dailymed-instance:dosageOvarian Cancer and Small Cell Lung Cancer: Prior to administration of the first course of HYCAMTIN, patients must have a baseline neutrophil count of>1,500 cells/mmand a platelet count of>100,000 cells/mm. The recommended dose of HYCAMTIN is 1.5 mg/mby intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 3 ovarian clinical trials was 9 to 12 weeks, and median time to response in 4 small cell lung cancer trials was 5 to 7 weeks. In the event of severe neutropenia during any course, the dose should be reduced by 0.25 mg/m(to 1.25 mg/m) for subsequent courses. Doses should be similarly reduced if the platelet count falls below 25,000 cells/mm. Alternatively, in the event of severe neutropenia, G-CSF may be administered following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).<br/>Cervical Cancer: Prior to administration of the first course of HYCAMTIN, patients must have a baseline absolute neutrophil count of>1,500 cells/mmand a platelet count of>100,000 cells/mm. The recommended dose of HYCAMTIN is 0.75 mg/mby intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/mby intravenous infusion on day 1 repeated every 21 days (a 21-day course). Dosage adjustments for subsequent courses of HYCAMTIN in combination with cisplatin are specific for each drug.<br/>Adjustment of Dose in Special Populations:<br/>Hepatic Impairment: No dosage adjustment appears to be required for treating patients with impaired hepatic function (plasma bilirubin>1.5 to<10 mg/dL).<br/>Renal Functional Impairment: No dosage adjustment of HYCAMTIN appears to be required for treating patients with mild renal impairment (Cl40 to 60 mL/min.). Dosage adjustment of HYCAMTIN to 0.75 mg/mis recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for HYCAMTIN. HYCAMTIN in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine���1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine>1.5 mg/dL.Insufficient data are available regarding continuing monotherapy with HYCAMTIN after cisplatin discontinuation in patients with cervical cancer.<br/>Elderly Patients: No dosage adjustment appears to be needed in the elderly other than adjustments related to renal function (see CLINICAL PHARMACOLOGY and PRECAUTIONS).lld:dailymed
dailymed-drugs:905dailymed-instance:descripti...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 greenishpowder 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 CHNO���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.lld:dailymed
dailymed-drugs:905dailymed-instance:clinicalP...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.<br/>Pharmacokinetics: The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/madministered 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%.<br/>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.<br/>Special Populations:<br/>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.<br/>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).<br/>Race: The effect of race on topotecan pharmacokinetics has not been studied.<br/>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 (Clof 20 to 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).<br/>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).<br/>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/mon day 1) before topotecan (0.75 mg/m/day on days 1-5) in 9 patients with ovarian cancer had no significant effect on the Cand 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/m(n = 9) or 75 mg/m(n = 6) on day 2 after paclitaxel 110 mg/mon day 1 before topotecan 0.3 mg/mIV daily on days 2-6. Topotecan had no effect on dose-normalized (60 mg/m) Cvalues of free platinum in 13 patients with ovarian cancer who were administered 60 mg/m(n = 10) or 75 mg/m(n = 3) cisplatin on day 1 before topotecan 0.75 mg/mIV daily on days 1-5. No pharmacokinetic data are available following topotecan (0.75 mg/m/day for 3 consecutive days) and cisplatin (50 mg/m/day on day 1) in patients with cervical cancer.<br/>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/m/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.lld:dailymed
dailymed-drugs:905dailymed-instance:activeIng...dailymed-ingredient:topotec...lld:dailymed
dailymed-drugs:905dailymed-instance:contraind...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 pregnant or breast-feeding, or those with severe bone marrow depression.lld:dailymed
dailymed-drugs:905dailymed-instance:supplyHYCAMTIN for Injection is supplied in 4-mg (free base) single-dose vials. NDC 0007-4201-01 (package of 1) NDC 0007-4201-05 (package of 5)<br/>Storage: Store the vials protected from light in the original cartons at controlled room temperature between 20��and 25��C (68��and 77��F) [see USP].<br/>Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.lld:dailymed
dailymed-drugs:905dailymed-instance:boxedWarn...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/mm. 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.lld:dailymed
dailymed-drugs:905dailymed-instance:activeMoi...dailymed-ingredient:topotec...lld:dailymed
dailymed-drugs:905dailymed-instance:precautio...General: Inadvertent extravasation with HYCAMTIN has been associated only with mild local reactions such as erythema and bruising.<br/>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.<br/>Hematology: Monitoring of bone marrow function is essential (see WARNINGS and DOSAGE AND ADMINISTRATION).<br/>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.<br/>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. Myelosuppressionwas more severe when HYCAMTIN, at a dose of 1.25 mg/m/day��5 days, was given in combination with cisplatin at a dose of 50 mg/min 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 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/m/day on days 1, 2, and 3 in combination with cisplatin 50 mg/mon day 1 for cervical cancer, see CLINICAL PHARMACOLOGY, CLINICAL STUDIES, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.<br/>Pregnancy: Pregnancy Category D. (See WARNINGS.)<br/>Nursing Mothers: HYCAMTIN is contraindicated during breastfeeding (see CONTRAINDICATIONS).<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been established.<br/>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 IV-B, 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).lld:dailymed
dailymed-drugs:905dailymed-instance:overdosag...There is no known antidote for overdosage with HYCAMTIN. The primary anticipated complication of overdosage would consist of bone marrow suppression. One patient on a single-dose regimen of 17.5 mg/mgiven on day 1 of a 21-day cycle had received a single dose of 35 mg/m. This patient experienced severe neutropenia (nadir of 320/mm) 14 days later but recovered without incident. The LDin mice receiving single intravenous infusions of HYCAMTIN was 75 mg/m(CI 95%: 47 to 97).lld:dailymed
dailymed-drugs:905dailymed-instance:genericMe...topotecan hydrochloridelld:dailymed
dailymed-drugs:905dailymed-instance:fullNameHYCAMTIN (Injection, Solution)lld:dailymed
dailymed-drugs:905dailymed-instance:adverseRe...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 4 lists the principal hematologic toxicities, and Table 5 lists non-hematologic toxicities occurring in at least 15% of patients. 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.<br/>Hematologic: (See WARNINGS.)<br/>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.<br/>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.<br/>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 4). 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).Grade 3/4 abdominal pain was 6% in ovarian cancer patients and 2% in small cell lung cancer patients.<br/>Skin and Subcutaneous Tissue Disorders: Total alopecia (grade 2) occurred in 31% of patients.<br/>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 6 shows the grade 3/4 hematologic and major non-hematologic adverse events in the topotecan/paclitaxel comparator trial in ovarian cancer. 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 corticosteroids, diphenhydramine, and histamine receptor type 2 blockers. Table 7 shows the grade 3/4 hematologic and major non-hematologic adverse events in the topotecan/CAV comparator trial in small cell lung cancer. 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 CAV received routine pretreatment with corticosteroids, diphenhydramine, and histamine receptor type 2 blockers.<br/>Cervical Cancer: In the HYCAMTIN plus cisplatin versus cisplatin comparative trial in cervical cancer patients, the most common dose-limiting toxicity was myelosuppression. Table 8 shows the hematologic adverse events and Table 9 shows the non-hematologic adverse events in cervical cancer patients. Includes patients who were eligible and treated. Data were collected using NCI Common Toxicity Criteria, v. 2.0. Includes patients who were eligible and treated. Grades 1 through 4 only. There were 3 patients who experienced grade 5 deaths with investigator-designated attribution. One was 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. Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. 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.<br/>Postmarketing Reports of Adverse Events: Reports of adverse events in patients taking HYCAMTIN received after market introduction, which are not listed above, include the following:<br/>Blood and Lymphatic System Disorders: Rare: Severe bleeding (in association with thrombocytopenia).<br/>Immune System Disorders: Infrequent: Allergic manifestations; rare: Anaphylactoid reactions.<br/>Gastrointestinal Disorders: Abdominal pain potentially associated with neutropenic colitis (see WARNINGS).<br/>Skin and Subcutaneous Tissue Disorders: Rare: Angioedema, severe dermatitis, severe pruritus.lld:dailymed
dailymed-drugs:905dailymed-instance:warningBone 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:<br/>Neutropenia:<br/>Thrombocytopenia:<br/>Anemia: 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.<br/>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/mmand platelet count at least 100,000/mm. 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/mm, platelets recover to>100,000 cells/mm, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary). Severe myelotoxicity has been reported when HYCAMTIN is used in combination with cisplatin (see Drug Interactions).<br/>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. Women should be warned to avoid becoming pregnant. (See CONTRAINDICATIONS.) In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/mbasis) 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/mbasis) 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/mbasis) 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.lld:dailymed
dailymed-drugs:905dailymed-instance:indicatio...HYCAMTIN is indicated for the treatment of: HYCAMTIN in combination with cisplatin is indicated for the treatment of:lld:dailymed
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