Topotecan

421.45

421.45

231-595-7

7M7YKX2N15

641007

DTXSID3042685

C1413

L01CE01|L01XX17|L - Antineoplastic and immunomodulating agents

2942000000

103

0.5

yellow liquid

1.5±0.1 g/cm3

−114 °C(lit.)

>100 °C(lit.)

12 °C

1.734

H2O: soluble

2-8°C

613 psi ( 21.1 °C)

1.3 (vs air)

Henry's Law constant = 1.59X10-24 atm-cu m/mol at 25 °C (est)

pKa1 = 1.74 (imine); pKa2 = 8.00 (benzyl alcohol); pKa3 = 9.83 (amine) (est)

Light yellow to greenish powder, mp 213-218 °C (decomposes). Soluble in water up to 1 mg/mL. Hygroscopic. Heant and light sensitive /Topotecan hydrochloride/|Hydroxyl radical reaction rate constant = 2.63X10-10 cu cm/molec-sec at 25 °C (est)|Ozone radical reaction rate constant = 1.16X10-15 cu cm/molec-sec at 25 °C (est)

II

8

UN 3286 3/PG 2

2

36/37/38-67-35-20-11-34-48-46-36

26-45-36/37/39-37/39-36-22-24/25-16-7

MW4025000

T,C,F,Xi

Stable under recommended storage conditions.

P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Waste treatment methods. Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including topotecan hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Topotecan hydrochloride/

|Danger|H301 (19.15%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 47 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Warning|H341: Suspected of causing genetic defects [Warning Germ cell mutagenicity]|P201, P202, P281, P308+P313, P405, and P501

Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

The primary anticipated complication of overdosage would consist of bone marrow suppression.|IDENTIFICATION AND USE: Topotecan is antineoplastic medication acting as topoisomerase I inhibitor. HUMAN EXPOSURE AND TOXICITY: The dose-limiting toxicity of topotecan is leukopenia. Topotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan. Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease. Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia. Case report describes a patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. Topotecan was clastogenic to cultured human lymphocytes with and without metabolic activation. ANIMAL STUDIES: Single dose toxicity was investigated in rodents and dogs following intravenous administration of topotecan. Doses of 56, 148 or 74 mg/ sq m were lethal in mice, rats or dogs respectively. Target organs of toxicity were bone marrow, lymphoid tissues, gastrointestinal tract and ovaries. In repeat dose experiments at or below the maximum tolerated dose, the toxicity profile was characterized by myelotoxicity (neutropenia, thrombocytopenia, lymphopenia and anemia), lymphoid depletion and gastrointestinal effects. Furthermore, other tissues with a rapid cell turnover, such as hair follicles and testis were affected. The main dose-limiting toxicity was the effect on bone marrow. In surviving animals, effects were reversible after termination of treatment. In mice, a single treatment with a cytotoxic agent causes cognitive impairment. Studies in dogs given about 1/4th the clinical dose of the drug daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes. Topotecan given to female rats prior to mating at a dose equal to the clinical dose caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Topotecan was mutagenic to L5178Y mouse lymphoma cells with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells. Topotecan is also a germ cell mutagen and its effect is more pronounced during the post-meiotic stages through a mechanism that may involve increases in DNA oxidative stress.

Chemotherapy with irinotecan and topotecan in combination with other agents is associated with serum enzyme elevations in up 15% of patients depending upon the dose, other agents used, the frequency of monitoring and degree of elevation that is reported. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. Marked elevations occur in 1% to 4% of patients, but rarely require dose modification. Genetic variants in hepatic transporters and metabolic enzymes have been associated with predisposition to irinotecan toxicity, including OATP 1B1 (SLC01B1), UGT1A1 and CYP 3A4. However, the major toxicities of irinotecan are hematologic and diarrhea, and liver test elevations are rare causes of drug interruption or dose modification.

Topotecan is a substrate of the efflux transporters P-glycoprotein (Pgp, ABCB1) and ABCG2 (breast cancer resistance protein (BRCP)). Concomitant use of elacridar (not commercially available in the US), an inhibitor of both P-glycoprotein and ABCG2 transporters, with oral topotecan resulted in a 2.5-fold increase in the area under the plasma concentration-time curve (AUC) for both topotecan lactone, the pharmcologically active form of the drug, and total topotecan. Concomitant use of oral topotecan with inhibitors of P-glycoprotein (e.g., cyclosporine, ketoconazole, ritonavir, saquinavir) also resulted in substantial increases in topotecan exposure. In one study, concomitant use of cyclosporine administered within 4 hours of an oral dose of topotecan resulted in a 2- to 3-fold increase in the AUCs of both topotecan lactone and total topotecan. The manufacturer states that concomitant use of oral topotecan with Pgp inhibitors should be avoided. If topotecan is used concomitantly with a Pgp (ABCB1) and/or an ABCG2 inhibitor, careful monitoring for signs of toxicity should be performed.|Topotecan (TpT) is a major inhibitory compound of topoisomerase (topo) I that plays important roles in gene transcription and cell division. We have previously reported that heparin and heparan sulfate (HS) might be transported to the cell nucleus and they can interact with topoisomerase I. We hypothesized that heparin and HS might interfere with the action of TpT. To test this hypothesis we isolated topoisomerase I containing cell nuclear protein fractions from normal liver, liver cancer tissues, and hepatoma cell lines. The enzymatic activity of these extracts was measured in the presence of heparin, liver HS, and liver cancer HS. In addition, topo I activity, cell viability, and apoptosis of HepG2 and Hep3B cells were investigated after heparin and TpT treatments. Liver cancer HS inhibited topo I activity in vitro. Heparin treatment abrogated topo I enzyme activity in Hep3B cells, but not in HepG2 cells, where the basal activity was higher. Heparin protected the two hepatoma cell lines from TpT actions and decreased the rate of TpT induced S phase block and cell death. These results suggest that heparin and HS might interfere with the function of TpT in liver and liver cancer.|The severity of drug-induced myelosuppression may be increased when IV topotecan is used in combination with other cytotoxic agents, and dosage reduction may be necessary. Severe myelotoxicity, in some cases resulting in fatalities from sepsis, has occurred during combined therapy with IV topotecan and other antineoplastic agents (e.g., cisplatin, paclitaxel). A sequence-dependent interaction has been reported when IV topotecan is administered concomitantly with cisplatin; lower doses of each drug were required with administration of cisplatin on day 1 of the topotecan dosing schedule compared with administration of cisplatin on day 5 of the topotecan dosing schedule.|Concurrent administration of granulocyte colony-stimulating factor (G-CSF) can prolong the duration of neutropenia associated with IV topotecan therapy. If G-CSF (filgrastim) is to be used concomitantly, therapy should be initiated 24 hours after the final dose of IV topotecan (i.e., beginning on day 6 of the 21-day treatment course for monotherapy or beginning on day 4 of the 21-day treatment course for combination therapy with IV topotecan and cisplatin).

LD50 Mouse iv 74.85 mg/sq m (CI 95%: 47.22 to 97.41)

Because elimination of oral and IV topotecan may be prolonged in patients with renal impairment and geriatric patients may have decreased renal function, the risk of adverse effects may be greater in such patients. Careful dosage selection and monitoring of renal function are advised in geriatric patients receiving topotecan.|... In patients with pre-existing interstitial pulmonary fibrosis even less is known. This report describes an unfortunate patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. To our knowledge this is the first pathology confirmation of diffuse alveolar damage in a patient developing dyspnea following topotecan therapy. The frequency with which camptothecin-related dyspnea is associated with diffuse alveolar damage might be underestimated and is of special concern in patients with limited pulmonary reserve.|Topotecan can cause fetal toxicity when administered to pregnant women. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. The manufacturer states that use of oral topotecan is contraindicated in pregnant and nursing women.|Hycamtin is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Hycamtin should not be used in patients with severe bone marrow depression.|Myelosuppression, principally neutropenia, is the dose-limiting toxicity of topotecan, and use of the drug is contraindicated in patients with severe myelosuppression. Oral and IV topotecan therapy should not be initiated in patients with baseline neutrophil counts less than 1500/cu mm or platelet counts less than 100,000/cu mm.

35%

Topotecan is manufactured from Camptothecin, a natural plant substance found in Camptothecin acuminata (Family: Nyssaceae) and Nothapodytes nimmoniana (Synonym: Mappia foetida, Family: Icacinaceae)(1,2).

EXPERIMENTAL: In lactating rats receiving IV topotecan at a dosage of 4.72 mg/sq m, high concentrations of the drug (i.e., up to 48 times higher than plasma concentrations) were distributed into milk. It is not known whether topotecan is distributed into human milk.

For the treatment of advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation therapy.|FDA Label|Hycamtin capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.Topotecan is indicated for the treatment of patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy.Hycamtin capsules are indicated as monotherapy for the treatment of adult patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.|Topotecan monotherapy is indicated for the treatment of patients with relapsed small-cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with the combination.|Topotecan monotherapy is indicated for the treatment of patients with relapsed small cell lung cancer [SCLC] for whom re-treatment with the first-line regimen is not considered appropriate., , Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination.,|Topotecan monotherapy is indicated for the treatment of:patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapypatients with relapsed small cell lung cancer (SCLC) for whom re-treatment with thefirst-line regimen is not considered appropriate.Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination.|Topotecan monotherapy is indicated for the treatment of:, , , patients with metastatic carcinoma of the ovary after failure of first line or subsequent therapy;, patients with relapsed small cell lung cancer [SCLC] for whom re-treatment with the first-line regimen is not considered appropriate., , , Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination.,|Topotecan monotherapy is indicated for the treatment of patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line regimen is not considered appropriate.Topotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment free interval to justify treatment with the combination.|Topotecan is indicated for the treatment of patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy.|Drug: Topotecanhydrochloride

Irinotecan and topotecan are semisynthetic derivatives of the plant alkaloid camptothecin and are used as antineoplastic agents in the therapy of colorectal, ovarian and non-small cell lung cancer. Both irinotecan and topotecan are associated with an appreciable rate of serum enzyme elevations during therapy, and irinotecan has been implicated in causing steatohepatitis when given as cyclic anticancer therapy.

Antineoplastic Agents

Topoisomerase I Inhibitors|Hycamtin is indicated for the treatment of: metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy and 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. /Included in US product label/|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. /Included in US product label/|Hycamtin is indicated for the treatment of 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. /Incuded in US product label/

/BOXED WARNING/ WARNING: BONE MARROW SUPPRESSION. Do not give Hycamtin to patients with baseline neutrophil counts less than 1,500 cells/cu mm. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving Hycamtin.|Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan. Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease. Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia. If a new diagnosis of interstitial lung disease is confirmed, the manufacturer states that topotecan therapy should be discontinued. Dyspnea was reported in 22% and coughing in 15% of patients receiving IV topotecan for ovarian cancer or small cell lung cancer. Grade 3 or 4 dyspnea occurred in 6% of patients receiving IV topotecan for ovarian cancer and in 9% of patients receiving the drug for small cell lung cancer. Grade 3 or 4 pneumonia was reported in 8% of patients receiving IV topotecan for recurrent or progressive small cell lung cancer in a clinical trial. Among patients receiving IV topotecan and cisplatin for cervical cancer, adverse respiratory effects occurred in 17% of patients.|Myelosuppression, principally neutropenia, is the dose-limiting toxicity of topotecan, and use of the drug is contraindicated in patients with severe myelosuppression. Oral and IV topotecan therapy should not be initiated in patients with baseline neutrophil counts less than 1500/mm3 or platelet counts less than 100,000/cu mm. Frequent monitoring of peripheral blood cell counts is required during topotecan therapy. Patients should be informed that topotecan may decrease blood cell counts and that frequent blood tests will be performed to monitor for the development of bone marrow suppression. Patients also should be advised to contact their clinician if fever, other signs of infection (e.g., chills, cough, burning pain on urination), or bleeding develops during therapy.|Topotecan can cause fetal toxicity when administered to pregnant women. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. The manufacturer states that use of oral topotecan is contraindicated in pregnant and nursing women.|For more Drug Warnings (Complete) data for Topotecan (25 total), please visit the HSDB record page.

Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug.

Compounds that inhibit the activity of DNA TOPOISOMERASE I. (See all compounds classified as Topoisomerase I Inhibitors.)

Renal clearance is an important determinant of topotecan elimination. 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. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 0.6%.|The pharmacokinetics of topotecan have been extensively studied in patients with normal renal function and there is one study of patients with mild to moderate renal insufficiency. However, the effect of hemodialysis on topotecan disposition has not been reported. The objective of this study was to characterize the disposition of topotecan in a patient with severe renal insufficiency receiving hemodialysis. Topotecan lactone disposition was characterized in a patient on and off hemodialysis. The topotecan lactone clearance determined after administration of topotecan alone and with hemodialysis was 5.3 L/hr per sq m vs 20.1 L/hr per sq m respectively. At 30 min after the completion of hemodialysis, the topotecan plasma concentration obtained was greater than that measured at the end of hemodialysis (i.e. 8.0 ng/mL vs 4.9 ng/mL), suggesting a rebound effect. The topotecan terminal half-life off dialysis was 13.6 hr, compared with an apparent half-life determined during hemodialysis of 3.0 hr. These results demonstrate that topotecan plasma clearance while on hemodialysis increased approximately fourfold. Hemodialysis may be an effective systemic clearance process for topotecan and should be considered in selected clinical situations (e.g. inadvertent overdose, severe renal dysfunction).|In lactating rats receiving IV topotecan at a dosage of 4.72 mg/sq m, high concentrations of the drug (i.e., up to 48 times higher than plasma concentrations) were distributed into milk. It is not known whether topotecan is distributed into human milk.|Following oral administration, about 57% of topotecan (administered daily for 5 days) is excreted in urine as unchanged drug (20%) and as the N-desmethyl metabolite (2%).47 Approximately 33% of the oral dose of topotecan was eliminated in feces as total topotecan and approximately 2% as N-desmethyl topotecan. Following IV administration, about 74% of a topotecan dose is excreted, mostly unchanged in urine (51%) and feces (18%) within 9 days; excretion of N-desmethyl topotecan in urine is approximately 3% and in feces is approximately 2%. O-Glucuronide metabolites of topotecan and N-desmethyl topotecan also have been detected in urine following oral and IV (less than 2% of the administered IV dose) administration of the drug.|No substantial gender-related differences in pharmacokinetics were reported in patients receiving oral topotecan. The average plasma clearance of IV topotecan was 24% higher in males than in females, mainly because of difference in body size.|For more Absorption, Distribution and Excretion (Complete) data for Topotecan (6 total), please visit the HSDB record page.

Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active.|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.

2-3 hours|The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/sq m administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours.|Topotecan has a terminal half-life of 3-6 hours following oral administration and 2-3 hours following IV administration of the drug.|... The objective of this study was to characterize the disposition of topotecan in a patient with severe renal insufficiency receiving hemodialysis. ... The topotecan terminal half-life off dialysis was 13.6 hr, compared with an apparent half-life determined during hemodialysis of 3.0 hr. ...

Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. 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. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor.|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.

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, and arrhythmias if they occur. 3. Treat nausea and vomiting with ondansetron or metoclopramide. Consider adding a benzodiazepine. Treat fluid losses caused by gastroenteritis with IV crystalloid fluids. 4. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Transfusions of packed red blood cells and platelets may be needed for episodes of bleeding. Recombinant erythropoietin may be useful for severe anemia, and hematopoietic colony-stimulating factors may be useful for neutropenia. ... /Antineoplastics/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastics/|Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective ... . /Antineoplastic/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for Topotecan (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Topotecan-induced neutropenia can cause neutropenic colitis (cecitis or typhlitis). Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.|/SIGNS AND SYMPTOMS/ Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with Hycamtin for intravenous use. In addition, elevated hepatic enzymes and mucositis have been reported following overdose.|/SIGNS AND SYMPTOMS/ Interstitial lung disease (sometimes fatal) has been reported during postmarketing experience with IV topotecan. Risk factors for developing interstitial lung disease include pulmonary fibrosis, lung cancer, exposure to thoracic radiation, use of drugs known to cause pulmonary toxicity, use of colony-stimulating factors (i.e., hematopoietic growth factors), and a history of interstitial lung disease. Patients should be monitored for symptoms suggestive of interstitial lung disease, including cough, fever, dyspnea, and/or hypoxia. If a new diagnosis of interstitial lung disease is confirmed, the manufacturer states that topotecan therapy should be discontinued.|/CASE REPORTS/ Drug-induced pulmonary toxicities of anticancer agents have been well described, but the pathophysiology of agents typically used in advanced disease has not been well studied. Symptoms of pulmonary drug toxicity in advanced lung cancer patients may frequently be attributed to disease progression, pulmonary embolism, or infection. In patients with pre-existing interstitial pulmonary fibrosis even less is known. This report describes an unfortunate patient with pre-existing pulmonary fibrosis and progressive extensive stage small cell lung cancer. After receiving a single intravenous dose of topotecan, the patient developed sub-acute respiratory failure, and died 15 days later with pathology findings of organizing, reparative phase, diffuse alveolar damage. To our knowledge this is the first pathology confirmation of diffuse alveolar damage in a patient developing dyspnea following topotecan therapy. The frequency with which camptothecin-related dyspnea is associated with diffuse alveolar damage might be underestimated and is of special concern in patients with limited pulmonary reserve.|For more Human Toxicity Excerpts (Complete) data for Topotecan (6 total), please visit the HSDB record page.

9 Dimethylaminomethyl 10 hydroxycamptothecin

Table: Topotacan Hydrochloride Preparations [Table#8209]

HPLC determination in plasma.

Human drugs -> Hycamtin -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Topotecan Hospira -> EMA Drug Category|Other antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Topotecan Actavis -> EMA Drug Category|Human drugs -> Potactasol -> EMA Drug Category|Human drugs -> Topotecan Teva -> EMA Drug Category|Human drugs -> Topotecan Eagle -> EMA Drug Category|Antineoplastic and immunomodulating agents -> Human pharmacotherapeutic group|Human drugs -> Evotopin -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients