Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/905
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
HYCAMTIN (Injection, Solution)
|
| dailymed-instance:dosage |
Ovarian 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).
|
| dailymed-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.
|
| dailymed-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.
|
| dailymed-instance:activeIng... | |
| dailymed-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.
|
| dailymed-instance:supply |
HYCAMTIN 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.
|
| dailymed-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.
|
| dailymed-instance:activeMoi... | |
| dailymed-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).
|
| dailymed-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).
|
| dailymed-instance:genericMe... |
topotecan hydrochloride
|
| dailymed-instance:fullName |
HYCAMTIN (Injection, Solution)
|
| dailymed-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.
|
| dailymed-instance:warning |
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:<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.
|
| dailymed-instance:indicatio... |
HYCAMTIN is indicated
for the treatment of: HYCAMTIN in combination
with cisplatin is indicated for the treatment of:
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
HYCAMTIN
|