Summary Of Exposure |
A) WITH THERAPEUTIC USE
1) The primary adverse effects reported with topoisomerase I inhibitors during therapeutic use have been myelosuppression (neutropenia/leukopenia and anemia), diarrhea with and without nausea and/or vomiting, and fever.
2) Other symptoms that have been reported frequently included: headache, dyspnea, increased coughing, abdominal pain, asthenia, paresthesia, alopecia and insomnia.
B) WITH POISONING/EXPOSURE
1) OVERDOSE: At the time of this review, limited overdose data is available for topoisomerase I inhibitors. a) IRINOTECAN: Single doses of 345 milligrams/square meter of irinotecan were given in US trials and single doses up to 750 milligrams/square meter have been given in non-US trials with effects similar to those reported at therapeutic doses.
b) TOPOTECAN: The primary anticipated effect in overdose would be myelosuppression.
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Vital Signs |
3.3.1) SUMMARY
A) Fever has been reported frequently with therapeutic use.
3.3.3) TEMPERATURE
A) Fever has been reported in patients following topoisomerase I inhibitor administration during therapy(Prod Info Camptosar(R) IV injection, 2008; Rowinsky et al, 1996b) and was one of the dose-limiting toxicities of topotecan therapy (Prod Info Hycamtin(R), topotecan hydrochloride, 2000). 1) Febrile episodes have been noted during periods of neutropenia, but have also occurred as fevers of unknown origin (Kantarjian et al, 1993).
B) IRINOTECAN - Neutropenic fever (defined as the National Cancer Institute grade 4 neutropenia and grade 2 or greater fever) occurred in 3% of patients (n=304); all recovered with supportive care (Prod Info Camptosar(R), irinotecan hydrochloride, 2000). C) TOPOTECAN - Neutropenic fever has been observed in up to 26% of patients (Prod Info Hycamtin(R), topotecan hydrochloride, 2000); hospitalization has been required in some patients (Law et al, 1994; Lynch et al, 1994). 1) Fever (range 39.9 to 41.8 degrees Celsius) unrelated to infection has developed within minutes to hours after receiving the first dose of topotecan (Rowinsky et al, 1996b).
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Cardiovascular |
3.5.1) SUMMARY
A) Vasodilation has been reported with therapeutic irinotecan use.
3.5.2) CLINICAL EFFECTS
A) VASODILATATION 1) WITH THERAPEUTIC USE a) IRINOTECAN: Vasodilation (11%) (flushing) has been observed following therapeutic use; NO intervention has been required (Prod Info Camptosar(R) IV injection, 2008).
B) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) TOPOTECAN: Asymptomatic hypotension occurred in up to 16% of patients treated with a 30 minute infusion of topotecan for 5 consecutive days every 3 weeks (van Warmerdam et al, 1995a).
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Respiratory |
3.6.1) SUMMARY
A) Dyspnea has been reported frequently with topoisomerase I inhibitor use; pneumonitis has occurred infrequently.
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) Dyspnea has been reported frequently following therapeutic use (Prod Info Hycamtin(R), topotecan hydrochloride, 2000; Prod Info Camptosar(R) IV injection, 2008). 1) INCIDENCE: 20% to 22% of patients have reported dyspnea during clinical trials with topoisomerase I inhibitors (Prod Info Hycamtin(R), topotecan hydrochloride, 2000; Prod Info Camptosar(R) IV injection, 2008); moderate to severe dyspnea occurred in 4% of patients given topotecan or irinotecan (Prod Info Hycamtin(R), topotecan hydrochloride, 2000).
2) COMORBIDITY - Of half the patients reporting dyspnea during clinical trials with IRINOTECAN, lung metastases and malignant pulmonary involvement were present. It is unknown how these underlying diseases contributed to dyspneic episodes (Prod Info Camptosar(R), irinotecan hydrochloride, 2000).
B) PNEUMONITIS 1) WITH THERAPEUTIC USE a) IRINOTECAN 1) Reports of nonfatal pneumonitis have occurred infrequently following irinotecan therapy and occurred during the neutropenic period (Slichenmyer & Von Hoff, 1990; Negoro et al, 1991; Masuda et al, 1992; Burris & Fields, 1994).
2) ONSET: Generally, the median time of toxicity was at 750 mg/m2 (range 400 to 1000 mg/m2) and occurred between the fifth to eighth dose (Negoro et al, 1991; Burris & Fields, 1994).
3) SIGNS/SYMPTOMS: Dyspnea on exertion, fever, eosinophilia, and a diffuse reticulonodular pattern on chest x-ray have been observed with this condition (Masuda et al, 1992; Burris & Fields, 1994). Corticosteroids have been used with equivocal results (Burris & Fields, 1994).
4) CASE REPORTS: Two patients developed pneumonitis along with dyspnea on exertion and high fever (>38 degrees Celsius). One patient responded to steroid therapy, while the second died from progressive respiratory insufficiency despite treatment (Masuda et al, 1992).
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Neurologic |
3.7.1) SUMMARY
A) Headache, asthenia, and paresthesia have occurred following topoisomerase I inhibitors administration.
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) SUMMARY - Headache is a frequent adverse effect of topoisomerase I inhibitors, but is usually not severe (Prod Info Hycamtin(R), topotecan hydrochloride, 2000; Prod Info Camptosar(R) IV injection, 2008).
b) INCIDENCE - Headache (21%) was the most frequently reported CNS effect following therapeutic use with topotecan (Prod Info Hycamtin(R), topotecan hydrochloride, 2000); 17% of patients reported headache with irinotecan use in clinical studies (Prod Info Camptosar(R) IV injection, 2008).
B) PARESTHESIA 1) WITH THERAPEUTIC USE a) INCIDENCE: Paresthesia (9%) has been reported with topotecan administration, however symptoms were considered mild (Prod Info Hycamtin(R), topotecan hydrochloride, 2000).
C) CENTRAL NERVOUS SYSTEM FINDING 1) WITH THERAPEUTIC USE a) INSOMNIA (19%) and DIZZINESS (15%) were reported following irinotecan use during clinical trials, however these symptoms could NOT be directly related to irinotecan administration (Prod Info Camptosar(R) IV injection, 2008).
D) FATIGUE 1) WITH THERAPEUTIC USE a) Asthenia occurred in 76% of patients receiving irinotecan during clinical use , most cases were mild to moderate (Prod Info Camptosar(R) IV injection, 2008) and has been reported in 19% of patients (all grades) following topotecan therapy (Prod Info HYCAMTIN(R) oral capsules, 2008).
E) DISTURBANCE IN SPEECH 1) WITH THERAPEUTIC USE a) CASE REPORT - A 49-year-old woman developed dysarthria after receiving irinotecan 350 milligrams per meter squared. Dysarthria was present during all 3 cycles of chemotherapy, and resolved approximately 2 hours after each infusion (Garcia et al, 1999).
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Gastrointestinal |
3.8.1) SUMMARY
A) Gastrointestinal effects (diarrhea, nausea, abdominal pain, constipation and vomiting) are frequently reported and can be severe.
3.8.2) CLINICAL EFFECTS
A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE 1) WITH THERAPEUTIC USE a) Gastrointestinal adverse events have been commonly reported following topoisomerase I inhibitors. Effects can include: abdominal pain, constipation, diarrhea, nausea, vomiting, stomatitis, mucositis, and anorexia (Prod Info Camptosar(R) IV injection, 2008).
B) DIARRHEA 1) WITH THERAPEUTIC USE a) IRINOTECAN 1) Diarrhea is a common major side effect of irinotecan which can occur shortly after therapy has been started (less than 24 hours) or a late symptom (the median onset of late diarrhea was 11 days). The effects appear to be mediated by different mechanisms (Prod Info Camptosar(R) IV injection, 2008). a) Early symptoms reflect a cholinergic response (Prod Info Camptosar(R) IV injection, 2008). Later symptoms (over 24 hours) can be severe and lead to dehydration and electrolyte imbalance. The mechanism of action of late-diarrhea has not been determined (Rothenberg, 1996). Therapy should be stopped if late diarrhea occurs (Prod Info Camptosar(R) IV injection, 2008). Symptoms have been fatal on several occasions (Rivory, 1996).
2) RISK FACTORS: The following are possible risk factors associated with chronic chemotherapy-induced diarrhea (CID) secondary to irinotecan therapy that can occur one or more days after the completion of the infusion (Anthony, 2007): 1) Short bowel syndrome
2) Performance status
3) Prior history of CID
4) Loperamide noncompliance
5) Uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) polymorphism (genetic susceptibility)
6) Gilbert's/unconjugated hyperbilirubinemia
7) Elevated bilirubin/aspartate transaminase (AST)/alanine transminase (ALT)
8) Cytochrome P450 (CYP) 2B6 and 3A4 inhibitors
9) Combination therapy (5-fluorouracil, bevacizumab)
10) BMI (neoadjuvant setting)
a) Genetic
3) Diarrhea appears to be a dose-limiting effect during therapy (Prod Info Camptosar(R) IV injection, 2008; Ogawa, 1999; Slichenmyer et al, 1993; Masuda et al, 1993; Burris & Fields, 1994). 4) INCIDENCE - Numerous studies have reported an incidence of 60% to 90%. Grade 3 (7 to 9 stools/day) and 4 (>10 stools/day) diarrhea have occurred in up to 20% to 41% of patients (Ohe et al, 1992; Burris & Fields, 1994; Negoro et al, 1991; Masuda et al, 1993). 5) PATIENT POPULATION - In one study, grade 3 or 4 late diarrhea was seen more frequently in patients >65 years than in younger patients (39.8% versus 23.4%, respectively) (Prod Info Camptosar(R), irinotecan hydrochloride, 2000). 6) CASE STUDIES - In a Phase I trial, diarrhea became ubiquitous at 90 mg/m2 (Masuda et al, 1993). In two studies, diarrhea became refractory to antidiarrheal therapy which included albumin tannate, atropine, scopolamine, and codeine phosphate (Masuda et al, 1993; Negoro et al, 1991). However, cumulative toxicity was NOT observed (Masuda et al, 1993). b) TOPOTECAN 1) CASE STUDIES - Diarrhea has been reported to be mild and transient; cumulative therapy was not indicative of further severe diarrhea (Law et al, 1994; Rowinsky et al, 1992; O'Reilly et al, 1996; van Warmerdam et al, 1995a; Kantarjian et al, 1993). Diarrhea responded to supportive therapy and was not a severe complication of treatment (O'Reilly et al, 1996; Rowinsky et al, 1994).
2) INCIDENCE - In one study of 682 patients, 22% reported diarrhea; 4.4% of cases were considered moderate to severe (Prod Info HYCAMTIN(R) oral capsules, 2008).
C) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) IRINOTECAN 1) INCIDENCE - In a clinical study (n=304), grade 1 to 4 nausea were reported in 86% of patients while vomiting occurred in 67% (Prod Info Camptosar(R) IV injection, 2008).
2) CASE STUDY - Severe symptoms were observed at dose levels greater than or equal to 125 mg/m2. Treatment with domperidone or metoclopramide was found to be ineffective in some cases (Negoro et al, 1991).
b) TOPOTECAN 1) INCIDENCE - In one clinical trial (n=682), nausea occurred in 33% (3% grade 3 or 4) of patients; vomiting developed in 21% (3.4% grade 3 or 4) (Prod Info HYCAMTIN(R) oral capsules, 2008).
2) ONSET - Rowinsky et al (1992) and Gore et al (1998) have reported that symptoms always occurred during drug administration and appeared to be NOT dose related. Despite frequent nausea and vomiting with topotecan therapy, standard antiemetics usually controlled nausea (Gore et al, 1998; Rowinsky et al, 1992; van Warmerdam et al, 1995a).
D) POISONING BY PARASYMPATHOMIMETIC DRUG 1) WITH THERAPEUTIC USE a) A cholinergic-like acute syndrome has been reported shortly after irinotecan (100 mg/m2 to 500 mg/m2 given over 30 minutes) infusions. The characteristic symptoms are abdominal cramping, diaphoresis, diarrhea, increased salivation, lacrimation, visual accommodation disturbances, rhinitis, and bradycardia (Rothenberg, 1996; Rivory, 1996) Potmesil, 1994; (Gandia et al, 1993).
b) Symptoms resolved spontaneously 1 to 2 hours after drug therapy was complete. Despite variable results, atropine (0.25 mg to 0.5 mg subcutaneously) resolved most symptoms including emesis in some cases (Potmesil, 1994; (Gandia et al, 1993).
c) ETIOLOGY - Its suggested that symptoms are due to a noncompetitive inhibition of acetylcholinesterase (Dodds & Rivory, 1999; Rivory, 1996).
E) ACUTE MUCOSITIS 1) WITH THERAPEUTIC USE a) TOPOTECAN - Mild to severe mucositis has been reported and may be a dose-limiting effect of topotecan therapy (Kantarjian et al, 1993; Rowinsky et al, 1996a; Rowinsky et al, 1996b; van Warmerdam et al, 1995). b) CASE STUDY 1) ONSET: Mucositis developed soon after therapy was completed (5 to 8 days) with symptoms peaking on day 8 with resolution by day 22 (Rowinsky et al, 1996b)
2) SYMPTOMS: Mucositis was reported in patients receiving 3.5 mg/m2/day to 4.5 mg/m2/day and was characterized by erythema and ulceration of the oral cavity and pharynx, dysphagia, and complaints of perianal pain in one patient (Rowinsky et al, 1996b).
3) Severity of symptoms did not appear dependent on the extent of prior therapy (Rowinsky et al, 1996b). Mucositis was severe at dose levels of 11.8 mg/m2 per course in leukemia patients (Kantarjian et al, 1993).
F) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) INCIDENCE: Abdominal pain has occurred in patients given topoisomerase I inhibitors (Prod Info Camptosar(R) IV injection, 2008; Prod Info HYCAMTIN(R) oral capsules, 2008). Severe abdominal (grade 3 and 4) pain was reported in up to 6% of patients receiving topotecan (Prod Info Camptosar(R) IV injection, 2008).
G) CONSTIPATION 1) WITH THERAPEUTIC USE a) Constipation has been reported in patients during clinical trials with irinotecan (Prod Info Camptosar(R) IV injection, 2008) .
H) LOSS OF APPETITE 1) WITH THERAPEUTIC USE a) Anorexia has been reported with topoisomerase I inhibitor therapy has commonly been reported but is usually not severe (Prod Info Camptosar(R) IV injection, 2008; Prod Info HYCAMTIN(R) oral capsules, 2008).
b) INCIDENCE - 16% of patients given topotecan and 43.9% receiving irinotecan complained of anorexia during clinical trials with these agents (Prod Info Camptosar(R) IV injection, 2008; Prod Info HYCAMTIN(R) oral capsules, 2008).
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Hepatic |
3.9.1) SUMMARY
A) Elevated hepatic enzymes have been observed with topoisomerase I inhibitors.
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) TOPOTECAN - Mild, transient elevations in SGOT/AST and SGPT/ALT were observed in up to 5% of patients receiving topotecan; moderately to severely elevated enzyme levels were reported in less than 1% of patients (Creemers et al, 1994; O'Dwyer et al, 1994; Prod Info Hycamtin(R), topotecan hydrochloride, 2000). 1) Infrequent reports of moderately elevated bilirubin levels have been observed in less than 3% of patients (Prod Info Hycamtin(R), topotecan hydrochloride, 2000).
2) Rowinsky et al (1996b) reported 3 patients who had moderate to severe elevated total bilirubin concentrations during 3 of 4 courses of topotecan administration at 5.75 mg/m2/day.
b) IRINOTECAN - Moderately to severely elevated liver enzymes have occurred infrequently following irinotecan therapy (Prod Info Camptosar(R) IV injection, 2008). 1) INCIDENCE - In several studies, elevation of serum transaminase levels and bilirubin have been reported in up to 20% of patients (Ohe et al, 1992; Ohno et al, 1990).
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Genitourinary |
3.10.1) SUMMARY
A) Renal insufficiency and hematuria have occurred infrequently with therapeutic administration of the topoisomerase I inhibitors.
3.10.2) CLINICAL EFFECTS
A) ACUTE RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) IRINOTECAN - Acute renal failure has been observed infrequently. Renal failure usually results from severe diarrhea-induced renal hypoperfusion secondary to volume depletion (Prod Info Camptosar(R) IV injection, 2008).
B) BLOOD IN URINE 1) WITH THERAPEUTIC USE a) TOPOTECAN - Minor microscopic hematuria (grade 1) was reported in 6 patients (24%) receiving 24-hour topotecan infusions for solid tumors. Although drug related toxicity cannot be ruled out, the cause remained unknown (van Warmerdam et al, 1995a).
C) RENAL FUNCTION TESTS ABNORMAL 1) WITH THERAPEUTIC USE a) TOPOTECAN - Infrequent reports of mild proteinuria and elevations of creatinine levels above 2 mg% have been observed following topotecan therapy (Kantarjian et al, 1993; van Warmerdam et al, 1995).
D) HEMORRHAGIC CYSTITIS 1) WITH THERAPEUTIC USE a) LACK OF EFFECT - Hemorrhagic cystitis has been reported as one of the dose-limiting toxicities of the parent compound camptothecin; this has NOT occurred with topotecan (Slichenmyer et al, 1993; Creemers et al, 1994; van Warmerdam et al, 1995a).
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Hematologic |
3.13.1) SUMMARY
A) Leukopenia, neutropenia, anemia, and thrombocytopenia have been reported with topoisomerase I inhibitor use. Fatal sepsis has occurred following severe myelosuppression with both agents.
3.13.2) CLINICAL EFFECTS
A) MYELOSUPPRESSION 1) WITH THERAPEUTIC USE a) Bone marrow suppression (primarily neutropenia and thrombocytopenia) is the dose-limiting hematologic toxicity of topoisomerase I inhibitors (Prod Info Hycamtin(R), topotecan hydrochloride, 2000; Rowinsky et al, 1996a; Masuda et al, 1992; Negoro et al, 1991).
B) NEUTROPENIA 1) WITH THERAPEUTIC USE a) SUMMARY - Neutropenia is frequent and a dose-limiting toxicity of topoisomerase I inhibitors (Prod Info HYCAMTIN(R) oral capsules, 2008; Prod Info Camptosar(R) IV injection, 2008). b) TOPOTECAN - Neutropenia is the primary dose-limiting toxicity of topotecan which is independent of drug scheduling in solid tumor patients and not cumulative over time (Prod Info HYCAMTIN(R) oral capsules, 2008; Rowinsky et al, 1992; Creemers et al, 1994; Law et al, 1994). 1) Severe (<500 cells/mm(cubed)) neutropenia has been commonly reported during the first course of treatment; effects last approximately seven days (Prod Info HYCAMTIN(R) oral capsules, 2008). 2) CASE STUDIES - In several studies, neutropenia was the principal dose-limiting toxicity of topotecan, at doses of 1.5 and 2.0 mg/m2/day. Neutropenic fever occurred (requiring hospitalization) in some cases (Rowinsky et al, 1992; O'Reilly et al, 1996; Law et al, 1994). a) However, Rowinsky et al (1992) reported that most cases did not result in fever. Patients who developed severe symptoms were those that were more likely to have received extensive prior treatment (Rowinsky et al, 1992).
c) IRINOTECAN - 26% of patients developed severe neutropenia (grade 3 to 4); 54% of patients had some degree of neutropenia after receiving a combination therapy that included irinotecan (Prod Info Camptosar(R) IV injection, 2008). 1) PATIENT POPULATION - Severe (grade 3 or 4) neutropenia was more frequently observed in patients who had received irradiation; age or gender did NOT influence the frequency of neutropenia (Prod Info Camptosar(R), irinotecan hydrochloride, 2000).
d) FEBRILE NEUTROPENIA - Neutropenic fever has occurred in 5.8% (combination therapy that included irinotecan) and 33% (topotecan) of patients receiving topoisomerase I inhibitors (Prod Info Camptosar(R) IV injection, 2008; Prod Info Hycamtin(R), topotecan hydrochloride, 2000; Law et al, 1994). e) NEUTROPENIC SEPSIS 1) IRINOTECAN: Deaths due to sepsis following severe neutropenia have been reported in some patients treated with irinotecan (Prod Info Camptosar(R) IV injection, 2008).
2) TOPOTECAN: Sepsis was fatal in 1% of patients receiving topotecan (Prod Info HYCAMTIN(R) oral capsules, 2008).
C) ANEMIA 1) WITH THERAPEUTIC USE a) Anemia has been reported following therapy with topoisomerase I inhibitors. 1) TOPOTECAN a) INCIDENCE: Severe anemia of grade 3 to 4 occurred in 25% of patients (Prod Info HYCAMTIN(R) oral capsules, 2008).
2) IRINOTECAN a) Mild to moderate anemia has been reported at various dose levels during therapy with irinotecan and did not appear to be a dose-related event (Negoro et al, 1991).
b) INCIDENCE: Severe anemia (grade 3 to 4) has been reported in 7% of patients; however up to 60.% of patients have reported some degree of anemia with therapy(Prod Info Camptosar(R) IV injection, 2008; Ohno et al, 1990).
D) LEUKOPENIA 1) WITH THERAPEUTIC USE a) Leukopenia has commonly been reported at therapeutic dose and appears to be a dose-limiting effect of topoisomerase I inhibitors (Negoro et al, 1991; Ohe et al, 1992; Masuda et al, 1993; van Warmerdam et al, 1995) (Slichemyer & Von Hoff, 1990). b) IRINOTECAN 1) INCIDENCE - Leukopenia has been reported in several small studies. Results are variable with a range of 25% up to 91% of patients developing leukopenia (Ohe et al, 1992; Ohno et al, 1990).
c) TOPOTECAN 1) INCIDENCE - 90% of patients have reported leukopenia with moderate effects (grade 3) occurring in 25% of patients and severe effects in 16% (Prod Info HYCAMTIN(R) oral capsules, 2008; van Warmerdam et al, 1995a).
E) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) TOPOTECAN 1) Thrombocytopenia has been reported frequently in conjunction with neutropenia (van Warmerdam et al, 1995a; Slichenmyer et al, 1993). In some studies it has been shown to be a dose-limiting effect of therapy (Creemers et al, 1994; van Warmerdam et al, 1995a). a) Platelet transfusions have been required for some patients (van Warmerdam et al, 1995a).
b) IRINOTECAN 1) Although thrombocytopenia has occurred with therapy (Slichenmyer & Von Hoff, 1990), serious symptoms are uncommon (Prod Info Camptosar(R) IV injection, 2008). However, Negoro et al (1991) reported that two patients died from the toxic effects of thrombocytopenia (Negoro et al, 1991).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) MACULOPAPULAR ERUPTION 1) WITH THERAPEUTIC USE a) TOPOTECAN: Macular papular rashes involving the trunk and extremities have been observed in patients in several studies, following as little as two courses of topotecan (Rowinsky et al, 1994; Rowinsky et al, 1996c). 1) ONSET: Generally, the rash was observed 4 to 8 days after therapy began and resolved by day 15 (Rowinsky et al, 1996c).
B) ERUPTION 1) WITH THERAPEUTIC USE a) IRINOTECAN: In clinical trials, 13% of patients with metastatic cancer of the colon developed a rash (Prod Info Camptosar(R) IV injection, 2008).
C) URTICARIA 1) WITH THERAPEUTIC USE a) IRINOTECAN: One patient developed giant urticaria at the site of a prick test after being previously treated with irinotecan (Negoro et al, 1991).
b) TOPOTECAN: Rash with urticaria developed in one patient treated at 2.5 mg/m2 of topotecan (Rowinsky et al, 1992).
D) EXCESSIVE SWEATING 1) WITH THERAPEUTIC USE a) IRINOTECAN: Diaphoresis has been reported frequently (range 16% to 63%) during therapy (Prod Info Camptosar(R) IV injection, 2008) at doses between 100 mg/m2 to 500 mg/m2 administered as a 30 minute intravenous infusion every 3 weeks (Gandia et al, 1993).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPERGLYCEMIA 1) WITH THERAPEUTIC USE a) IRINOTECAN: Hyperglycemia has been reported in some patients after receiving irinotecan; this has only been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance (Prod Info Camptosar(R) IV injection, 2008).
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Reproductive |
3.20.1) SUMMARY
A) Topotecan and irinotecan are classified as FDA pregnancy category D. In animal studies, topotecan use during organogenesis has resulted in embryolethality, fetotoxicity, and fetal malformations. It is not known if irinotecan or topotecan are excreted in human breast milk; however, studies have shown that both irinotecan and topotecan are excreted in the milk of lactating rats.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) IRINOTECAN LIPOSOME a) At the time of this review, there are no adequate or well-controlled studies to assess the teratogenic potential of irinotecan liposome in humans (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
2) TOPOTECAN a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info HYCAMTIN(R) intravenous injection, 2015; Prod Info HYCAMTIN(R) oral capsules , 2014).
B) ANIMAL STUDIES 1) IRINOTECAN a) In animal studies, teratogenicity (external, visceral, and skeletal abnormalities) was demonstrated with the administration of irinotecan IV at doses about one-fortieth of the corresponding AUC in patients administered 125 mg/m(2) (Prod Info Camptosar(R) IV injection, 2008)
2) IRINOTECAN LIPOSOME a) In animal studies, irinotecan hydrochloride IV administration in doses lower than the human dose resulted in teratogenicity. Effects included various external, visceral, and skeletal abnormalities (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
3) TOPOTECAN a) In animal studies, doses of topotecan approximately equal to the human clinical dose resulted in maternal toxicity, embryolethality, and reduced fetal body weight. Fetal resorption, microphthalmia, and preimplant loss were also reported. Doses of topotecan approximately one-half of the human clinical dose resulted in increases in post implantation mortality and total fetal malformations (Prod Info HYCAMTIN(R) intravenous injection, 2015; Prod Info HYCAMTIN(R) oral capsules , 2014).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) IRINOTECAN LIPOSOME a) At the time of this review, no data were available to assess the potential effects of exposure to irinotecan liposome during pregnancy in humans (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
2) TOPOTECAN a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info HYCAMTIN(R) intravenous injection, 2015; Prod Info HYCAMTIN(R) oral capsules , 2014).
B) IRINOTECAN 1) PREGNANCY CATEGORY a) Irinotecan has been classified as FDA Pregnancy Category D (Prod Info Camptosar(R) IV injection, 2008).
2) FETAL/NEONATAL ADVERSE REACTIONS a) Following use of irinotecan/fluorouracil/leucovorin (FOLFIRI regimen) in a 33-year-old pregnant woman with adenocarcinoma of the transverse colon, fetal growth and morphology were normal with no major defects or abnormalities detected. Chemotherapy was well tolerated with cycles repeated every 2 weeks. The patient was restaged at gestational week 29 after 3 cycles of chemotherapy. An abdominal MRI revealed progression of the hepatic and peripancreatic lesions. Chemotherapy was discontinued at gestational week 30 and the patient was admitted to surgery due to a perforated bowel. The patient underwent a cesarean section and transverse colon resection. The male infant weighed 1070 g at birth and had a reported Apgar score of 4 and 7 for the first and fifth minute, respectively. The infant was admitted to neonatal pathology due to prematurity and intrauterine growth restriction. After 48 hours the infant was extubated. After an additional 48 hours in continuous positive airway pressure, the infant resumed spontaneous breathing. After 28 days, the infant was transferred for stabilization where he was hospitalized for the first 70 days of life. Upon followup at 13-months of age, the infant was observed to be within normal limits and satisfactory in weight and physical and neurological development (Cirillo et al, 2012).
C) IRINOTECAN LIPOSOME 1) RISK SUMMARY a) There are no adequate or well-controlled studies of irinotecan liposome in pregnant women. Based on animal data and its mechanism of action, irinotecan liposome can cause fetal harm when administered to a pregnant woman (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
2) CONTRACEPTION a) Women of reproductive potential should use effective contraception during and for 1 month after the last dose. Male patients should use condoms during and for 4 months after the final dose (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
D) TOPOTECAN 1) RISK SUMMARY a) Do not administer topotecan to a pregnant woman. Inform women of the potential hazard to the fetus with prenatal topotecan exposure(Prod Info HYCAMTIN(R) intravenous injection, 2015).
2) CONTRACEPTION a) Women of reproductive potential should use effective contraception during and for at least 1 month after treatment. Male patients should use adequate contraception during and for at least 3 months after treatment (Prod Info HYCAMTIN(R) intravenous injection, 2015).
E) ANIMAL STUDIES 1) IRINOTECAN a) In animal studies, embryotoxicity, characterized by increased postimplantation loss and decreased numbers of live fetuses, was demonstrated with the administration of irinotecan approximately 0.2 times to one-half of the recommended human dose during organogenesis (Prod Info Camptosar(R) IV injection, 2008). Rat dams receiving irinotecan HCl following the period of organogenesis through weaning at doses of 6 mg/kg/day caused a decrease in learning ability and a decrease in female body weights in the offspring (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
2) TOPOTECAN a) During animal studies, doses of topotecan approximately equal to the human clinical dose resulted in maternal toxicity, embryolethality, and reduced fetal body weight. Fetal resorption, microphthalmia, and preimplant loss were also reported. Doses of topotecan approximately one-half of the human clinical dose resulted in increases in post implantation mortality and total fetal malformations (Prod Info HYCAMTIN(R) intravenous injection, 2015; Prod Info HYCAMTIN(R) oral capsules , 2014).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) IRINOTECAN LIPOSOME a) At the time of this review, no data were available to assess the potential effects of exposure to irinotecan liposome during lactation in humans (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
2) TOPOTECAN a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info HYCAMTIN(R) oral capsules , 2014; Prod Info HYCAMTIN(R) intravenous injection, 2014).
B) IRINOTECAN LIPOSOME 1) RISK SUMMARY a) Due to the potential risk to the infant, women should be advised not to breastfeed during therapy and for one month after the final dose (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
C) TOPOTECAN 1) RISK SUMMARY a) Discontinue breastfeeding (Prod Info HYCAMTIN(R) intravenous injection, 2015; Prod Info HYCAMTIN(R) oral capsules , 2014) or discontinue topotecan, taking into account the importance of the drug to the mother (Prod Info HYCAMTIN(R) oral capsules , 2014)
D) ANIMAL STUDIES 1) BREAST MILK a) IRINOTECAN: Irinotecan is present in rat milk (Prod Info ONIVYDE(TM) intravenous injection solution, 2015). Intravenous doses of radiolabeled irinotecan administered to lactating rats led to the appearance of radioactivity in milk after 5 minutes and concentrations up to 65-fold higher than those in plasma after 4 hours (Prod Info Camptosar(R) IV injection, 2008).
b) TOPOTECAN: Lactating female animals given IV topotecan doses approximately twice the human clinical dose led to topotecan milk concentrations that were up to 48-fold higher than those in plasma (Prod Info HYCAMTIN(R) intravenous injection, 2015; Prod Info HYCAMTIN(R) oral capsules , 2014).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) IRINOTECAN a) Intravenous administration of irinotecan at doses up to 6 mg/kg/day in rats and rabbits resulted in no significant adverse effects on fertility or general reproductive performance. However, multiple daily doses of irinotecan both in rodents and dogs at 20 mg/kg and 0.4 mg/kg, respectively, (corresponds to values in patients administered 125 mg/m(2)) caused atrophy of male reproductive organs (Prod Info Camptosar(R) IV injection, 2008).
2) IRINOTECAN LIPOSOME a) There are no human fertility studies of irinotecan liposome. In animal studies, irinotecan liposome injections approximately 3 times the human dose resulted in atrophy of male and female reproductive organs (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
3) TOPOTECAN a) Topotecan may result in impaired fertility in men and women. During animal studies, administration of topotecan at doses approximately one-half of the recommended dose resulted in superovulation, preimplantation loss, and an increased incidence of multinucleated spermatogonial giant cells in the testes (Prod Info HYCAMTIN(R) intravenous injection, 2015).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) IRINOTECAN LIPOSOME 1) At the time of this review, no studies have been performed by the manufacturer to evaluate any carcinogenic potential of irinotecan liposome in humans.
3.21.3) HUMAN STUDIES
A) LACK OF INFORMATION 1) IRINOTECAN LIPOSOME a) At the time of this review, no studies have been performed by the manufacturer to evaluate any carcinogenic potential of irinotecan liposome in humans.
B) TOPOTECAN 1) Topotecan is a probable carcinogen (Prod Info Hycamtin(R), topotecan hydrochloride, 2000).
3.21.4) ANIMAL STUDIES
A) IRINOTECAN 1) Animal studies (rats) with irinotecan showed a significant linear trend with dosage and the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas; long-term studies have not been conducted (Prod Info ONIVYDE(TM) intravenous injection solution, 2015; Prod Info Camptosar(R), irinotecan hydrochloride, 2000).
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Genotoxicity |
A) Irinotecan HCl was clastogenic in both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus tests in mice) studies (Prod Info ONIVYDE(TM) intravenous injection solution, 2015).
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