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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.


The dose-limiting toxicity of topotecan is leukopenia. White blood cell count decreases with increasing topotecan dose or topotecan AUC. When topotecan is administered at a dose of 1.5 mg/m²/day for 5 days, an 80% to 90% decrease in white blood cell count at nadir is typically observed after the first cycle of therapy.


The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m² administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional.


Binding of topotecan to plasma proteins is about 35%.


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.

In a mass balance/excretion trial 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 Ndesmethyl topotecan was 1.7% ± 0.6%. An O-glucuronidation metabolite of topotecan and Ndesmethyl topotecan has been identified in the urine. These metabolites, topotecan-Oglucuronide and N-desmethyl topotecan-O-glucuronide, were less than 2% of the administered dose.

Effect of 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.

Effect of Age

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 DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Effect of Race

The effect of race on topotecan pharmacokinetics has not been studied.

Effect of Renal Impairment

In patients with mild renal impairment (creatinine clearance of 40 to 60 mL/min), topotecan plasma clearance was decreased to about 67% of the value in patients with normal renal function. In patients with moderate renal impairment (Clcr of 20 to 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 patients with renal impairment, was about 5.0 hours. Dosage adjustment is recommended for these patients [see DOSAGE AND ADMINISTRATION].

Effect of 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 patients with hepatic impairment tolerated the usual recommended topotecan dosage regimen.

Drug Interactions

Pharmacokinetic trials 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.

Cisplatin: Administration of cisplatin (60 or 75 mg/m² on day 1) before topotecan (0.75 mg/m²/day on days 1 to 5) in 9 patients with ovarian cancer had no significant effect on the Cmax and AUC of total topotecan.

Topotecan had no effect on the pharmacokinetics of free platinum in 15 patients with ovarian cancer who were administered cisplatin 50 mg/m² (n = 9) or 75 mg/m² (n = 6) on day 2 after paclitaxel 110 mg/m² on day 1 before topotecan 0.3 mg/m² IV daily on days 2 to 6. Topotecan had no effect on dose-normalized (60 mg/m²) Cmax values of free platinum in 13 patients with ovarian cancer who were administered 60 mg/m² (n = 10) or 75 mg/m² (n = 3) cisplatin on day 1 before topotecan 0.75 mg/m² IV daily on days 1 to 5.

No pharmacokinetic data are available following topotecan (0.75 mg/m²/day for 3 consecutive days) and cisplatin (50 mg/m /day on day 1) in patients with cervical cancer.

Myelosuppression was more severe when HYCAMTIN was given in combination with cisplatin [see DRUG INTERACTIONS].

Clinical Studies

Ovarian Cancer

HYCAMTIN was studied in 2 clinical trials of 223 patients given topotecan with metastatic ovarian carcinoma. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these 2 trials received an initial dose of 1.5 mg/m² given by intravenous infusion over 30 minutes for 5 consecutive days, starting on day 1 of a 21-day course.

One trial was a randomized trial of 112 patients treated with HYCAMTIN (1.5 mg/m²/day x 5 days starting on day 1 of a 21-day course) and 114 patients treated with paclitaxel (175 mg/m² over 3 hours on day 1 of a 21-day course). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least 1 prior platinum-containing regimen. Patients who did not respond to the trial therapy, or who progressed, could be given the alternative treatment.

Response rates, response duration, and time to progression are shown in Table 7.

Table 7: Efficacy of HYCAMTIN Versus Paclitaxel in Ovarian Cancer

Parameter HYCAMTIN
(n = 112)
(n = 114)
Complete response rate 5% 3%
Partial response rate 16% 11%
Overall response rate 21% 14%
95% Confidence interval 13 to 28% 8 to 20%
(P-value) (0.20)
Response durationa (weeks) n = 23 n = 16
Median 25.9 21.6
95% Confidence interval 22.1 to 32.9 16.0 to 34.0
(HY C AMTIN: paclitaxel) 0.78
(P-value) (0.48)
Time to progression (weeks)
Median 18.9 14.7
95% Confidence interval 12.1 to 23.6 11.9 to 18.3
(HY C AMTIN: paclitaxel) 0.76
(P-value) (0.07)
Survival (weeks)
Median 63.0 53.0
95% Confidence interval 46.6 to 71.9 42.3 to 68.7
(HY C AMTIN: paclitaxel) 0.97
(P-value) (0.87)
a The calculation for duration of response was based on the interval between first response and time to progression.

The median time to response was 7.6 weeks (range: 3.1 to 21.7) with HYCAMTIN compared with 6.0 weeks (range: 2.4 to 18.1) with paclitaxel. Consequently, the efficacy of HYCAMTIN may not be achieved if patients are withdrawn from treatment prematurely.

In the crossover phase, 8 of 61 (13%) patients who received HYCAMTIN after paclitaxel had a partial response and 5 of 49 (10%) patients who received paclitaxel after HYCAMTIN had a response (2 complete responses).

HYCAMTIN was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. In the same trial, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.

HYCAMTIN was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. The response rate was 14% (95% CI: 7% to 20%). The median duration of response was 22 weeks (range: 4.6 to 41.9 weeks). The time to progression was 11.3 weeks (range: 0.7 to 72.1 weeks). The median survival was 67.9 weeks (range: 1.4 to 112.9 weeks).

Small Cell Lung Cancer

HYCAMTIN was studied in 426 patients with recurrent or progressive small cell lung cancer in 1 randomized, comparative trial and in 3 single-arm trials.

Randomized Comparative Trial

In a randomized, comparative, Phase 3 trial, 107 patients were treated with HYCAMTIN (1.5 mg/m²/day x 5 days starting on day 1 of a 21-day course) and 104 patients were treated with CAV (1,000 mg/m cyclophosphamide, 45 mg/m² doxorubicin, 2 mg vincristine administered sequentially on day 1 of a 21-day course). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed > 60 days after completion of first-line therapy). A total of 77% of patients treated with HYCAMTIN and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy.

Response rates, response duration, time to progression, and survival are shown in Table 8.

Table 8: Efficacy of HYCAMTIN Versus CAV (cyclophosphamide-doxorubicin-vincristine) in Small Cell Lung Cancer Patients Sensitive to First-Line Chemotherapy

Parameter HYCAMTIN
(n = 107)
(n = 104)
Complete response rate 0% 1%
Partial response rate 24% 17%
Overall response rate 24% 18%
Difference in overall response rates 6%
95% Confidence interval of the difference (-6 to 18%)
Response durationa (weeks) 6 2 II n n = 19
Median 14.4 15.3
95% Confidence interval 13.1 to 18.0 13.1 to 23.1
  (HYCAMTIN:CAV) (95% CI) 1.42 (0.73 to 2.76)
  (P-value) (0.30)
Time to progression (weeks)
Median 13.3 12.3
95% Confidence interval 11.4 to 16.4 11.0 to 14.1
  (HYCAMTIN:CAV) (95% CI) 0.92 (0.69 to 1.22)
  (P-value) (0.55)
Survival (weeks)
Median 25.0 24.7
95% Confidence interval 20.6 to 29.6 21.7 to 30.3
  (HYCAMTIN:CAV) (95% CI) 1.04 (0.78 to 1.39)
  (P-value) (0.80)
a The calculation for duration of response was based on the interval between first response and time to progression.

The time to response was similar in both arms: HYCAMTIN median of 6 weeks (range: 2.4 to 15.7) versus CAV median 6 weeks (range: 5.1 to 18.1).

Changes on a disease-related symptom scale in patients who received HYCAMTIN or who received CAV are presented in Table 9. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

Table 9: Percentage of Patients With Symptom Improvementa: HYCAMTIN Versus CAV in Patients With Small Cell Lung Cancer

(n = 107)
(n = 104)
nb (%) nb (%)
Shortness of breath 68 (28) 61 (7)
Interference with daily activity 67 (27) 63 (11)
Fatigue 70 (23) 65 (9)
Hoarseness 40 (33) 38 (13)
Cough 69 (25) 61 (15)
Insomnia 57 (33) 53 (19)
Anorexia 56 (32) 57 (16)
Chest pain 44 (25) 41 (17)
Hemoptysis 15 (27) 12 (33)
a Defined as improvement sustained over at least 2 courses compared with baseline.
b Number of patients with baseline and at least 1 post-baseline assessment.

Single-Arm Trials

HYCAMTIN was also studied in 3 open-label, non-comparative trials in a total of 319 patients with recurrent or progressive small cell lung cancer after treatment with first-line chemotherapy. In all 3 trials, patients were stratified as either sensitive (responders who then subsequently progressed > 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all 3 trials and the comparative trial.

Cervical Cancer

In a comparative trial, 147 eligible women were randomized to HYCAMTIN (0.75 mg/m²/day IV over 30 minutes x 3 consecutive days starting on day 1 of a 21-day course) plus cisplatin (50 mg/m² on day 1) and 146 eligible women were randomized to cisplatin (50 mg/m² IV on day 1 of a 21-day course). All patients had histologically confirmed Stage IVB, recurrent, or persistent carcinoma of the cervix considered not amenable to curative treatment with surgery and/or radiation. Fifty-six percent (56%) of patients treated with HYCAMTIN plus cisplatin and 56% of patients treated with cisplatin had received prior cisplatin with or without other agents as first-line chemotherapy.

Median survival of eligible patients receiving HYCAMTIN plus cisplatin was 9.4 months (95% CI: 7.9 to 11.9) compared with 6.5 months (95% CI: 5.8 to 8.8) among patients randomized to cisplatin alone with a log rank P-value of 0.033 (significance level was 0.044 after adjusting for the interim analysis). The unadjusted hazard ratio for overall survival was 0.76 (95% CI: 0.59 to 0.98).

Figure 1: Overall Survival Curves Comparing HYCAMTIN plus Cisplatin versus Cisplatin Monotherapy in Cervical Cancer Patients

Overall Survival Curves Comparing HYCAMTIN plus Cisplatin versus Cisplatin Monotherapy in Cervical Cancer Patients - Illustration

Last reviewed on RxList: 3/18/2014
This monograph has been modified to include the generic and brand name in many instances.


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