The following Structured Product Label (SPL) was submitted to the FDA by Sandoz Inc for the product Hycamtin (NDC 66758-102). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding warning: myelosuppression, 1 indications and usage, 2.1 recommended dosage, 2.2 dosage modifications for adverse reactions, 2.3 dosage modifications for renal impairment, 3 dosage forms and strengths, 4 contraindications, 5.1 myelosuppression, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm3 and platelet counts greater than or equal to 100,000/mm3. Monitor blood cell counts [see Warnings and Precautions (5.1)].
HYCAMTIN® capsules are indicated for the treatment of relapsed small cell lung cancer (SCLC) in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.
The recommended dosage of HYCAMTIN capsules is 2.3 mg/m2/day orally once daily, with or without food, for 5 consecutive days, starting on Day 1 of a 21-day cycle. Round the dose to the nearest 0.25 mg and prescribe the minimum number of 1 mg and 0.25 mg capsules. Prescribe the same number of capsules for each of the 5 dosing days.
Swallow capsules whole. Do not chew, crush, or divide the capsules.
Diarrhea
Do not administer HYCAMTIN capsules to patients with Grade 3 or 4 diarrhea. After recovery to Grade 1 or less, reduce the dose by 0.4 mg/m2/day for subsequent courses [see Warnings and Precautions (5.2)].
Hematologic
Reduce dose by 0.4 mg/m2/day for:
Capsules
HYCAMTIN is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions (6.2)].
HYCAMTIN can cause severe myelosuppression. The following safety data are based on an integrated safety database from four trials in patients with lung cancer (N = 682) who received HYCAMTIN capsules at a dose of 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle.
The median day for neutrophil and platelet nadirs occurred on Day 15. Grade 4 neutropenia occurred in 32% of the 682 patients, with a median duration of 7 days. Grade 4 neutropenia most commonly occurred during cycle 1 (20% of patients). Clinical sequelae of neutropenia included infection (17%), febrile neutropenia (4%), sepsis (2%), and septic death (1%). Grade 4 thrombocytopenia occurred in 6%, with a median duration of 3 days. Grade 3 or 4 anemia occurred in 25%.
HYCAMTIN can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain.
Administer the first cycle of HYCAMTIN capsules only to patients with a baseline neutrophil count greater than or equal to 1,500/mm3 and a platelet count greater than or equal to 100,000/mm3. Monitor blood cell counts frequently during treatment. Withhold and reduce dose of HYCAMTIN capsules based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration (2.2)].
Diarrhea, including severe and life-threatening diarrhea requiring hospitalization, can occur with HYCAMTIN capsules. Diarrhea can occur at the same time as drug-induced neutropenia and its sequelae. In the 682 patients who received HYCAMTIN capsules in the four lung cancer trials, the incidence of diarrhea caused by HYCAMTIN capsules was 22%, including Grade 3 (4%) and Grade 4 (0.4%). The incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia was 5%. The median time to onset of Grade 2 to 4 diarrhea was 9 days in the group receiving HYCAMTIN capsules.
Monitor patients for diarrhea and treat with antidiarrheals at the first sign of diarrhea. Withhold and dose reduce as recommended based on severity [see Dosage and Administration (2.2)].
Interstitial lung disease (ILD), including fatalities, can occur with HYCAMTIN. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors.
Monitor for pulmonary symptoms indicative of ILD. Permanently discontinue HYCAMTIN capsules if ILD is confirmed.
The following serious adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in the Warnings and Precautions and below reflects exposure to HYCAMTIN capsules in 682 patients with recurrent lung cancer enrolled in four randomized, open label trials, including 275 patients with small lung cell lung cancer (SCLC) (Studies 478, 065 and 396), and 407 patients with non-small cell lung cancer (NSCLC) (Study 387), who received at least one dose of HYCAMTIN capsules. Patients in these trials had advanced lung cancer and received prior chemotherapy in the first-line setting. Patients received HYCAMTIN capsules 2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. The median number of cycles was 3 (range: 1 to 20).
The safety of HYCAMTIN capsules was evaluated in a randomized trial (Study 478) conducted in 70 patients with recurrent SCLC [see Clinical Studies (14)].
In the 682 patients who received HYCAMTIN capsules in the four lung cancer trials, 39 deaths (6%) occurred within 30 days after the last dose for a reason other than progressive disease: 13 due to hematologic toxicity, 5 due to non-hematologic toxicity (2 from diarrhea), and 21 due to other causes.
Table 1 describes the hematologic and non-hematologic adverse reactions that occurred in greater than 5% of patients treated with HYCAMTIN capsules in these trials.
Adverse Reactions Adverse reactions were graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0. |
|
| ||||
N = 70 | N = 682 | |||||
All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
Hematologic | ||||||
Anemia | 94 | 15 | 10 | 98 | 18 | 7 |
Neutropenia | 91 | 28 | 33 | 83 | 24 | 32 |
Thrombocytopenia | 81 | 30 | 7 | 81 | 29 | 6 |
Non-hematologic | ||||||
Nausea | 27 | 1 | 0 | 33 | 3 | 0 |
Vomiting | 19 | 1 | 0 | 21 | 3 | 0.4 |
Diarrhea | 14 | 4 | 1 | 22 | 4 | 0.4 |
Fatigue | 11 | 0 | 0 | 19 | 4 | 0.1 |
Alopecia | 10 | 0 | 0 | 20 | 0.1 | 0 |
Pyrexia | 7 | 1 | 0 | 5 | 1 | 1 |
Anorexia | 7 | 0 | 0 | 14 | 2 | 0 |
Asthenia | 3 | 0 | 0 | 7 | 2 | 0 |
The following reactions have been identified during post approval use of HYCAMTIN. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
P-glycoprotein or Breast Cancer Resistance Protein Inhibitor
Concomitant use of a P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitor increases topotecan AUC [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions. Avoid concomitant use HYCAMTIN capsules with P-gp inhibitors or BCRP inhibitors.
Risk Summary
Based on animal data and its mechanism of action, HYCAMTIN can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of HYCAMTIN in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal Data
Risk Summary
There are no data on the presence of topotecan or its metabolites in human milk, or their effects on the breastfed infant or milk production. Lactating rats excrete high concentrations of topotecan into milk (see Data). Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with HYCAMTIN and for 1 week after the last dose.
Data
Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the 1.5 mg/m2 clinical intravenous dose based on BSA), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating HYCAMTIN capsules [see Use in Specific Populations (8.1)].
Contraception
HYCAMTIN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Females
Advise female patients of reproductive potential to use effective contraception during treatment with HYCAMTIN capsules and for 6 months after the last dose.
Males
HYCAMTIN capsules may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with HYCAMTIN capsules and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Females
HYCAMTIN can have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].
Males
Effects on spermatogenesis have occurred in animals administered topotecan [see Nonclinical Toxicology (13.1)].
Safety and effectiveness in pediatric patients have not been established.
Of the 682 patients with lung cancer who received HYCAMTIN capsules in the four clinical trials, 33% were aged 65 years and older, while 4.8% were aged 75 years and older. Treatment-related diarrhea was more frequent in patients aged greater than or equal to 65 years (28%) compared with those younger than 65 years (19%) [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. No overall differences in effectiveness were observed between patients 65 years and older and younger patients.
No dosage adjustment is recommended for patients with creatinine clearance (CLcr) greater than or equal to 50 mL/min. Reduce the dose of HYCAMTIN capsules in patients with CLcr less than 49 mL/min [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
Overdoses (up to 5-fold of the prescribed dose) have occurred in patients receiving HYCAMTIN capsules. The primary complication of overdosage is myelosuppression. Mucositis have occurred with overdosages. If an overdose is suspected, monitor the patient closely for myelosuppression and institute supportive-care measures as appropriate.
Topotecan is a topoisomerase inhibitor. 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. The molecular formula is C23H23N3O5•HCl and the molecular weight is 457.9 g/mol. It is soluble in water and melts with decomposition at 213°C to 218°C.
Topotecan hydrochloride has the following structural formula:
Topotecan Hydrochloride Chemical Structure (Hycamtin Spl Graphic 01)
HYCAMTIN capsules, contain topotecan hydrochloride, the content of which is expressed as topotecan free base. Each 0.25 mg and 1 mg capsule contain topotecan hydrochloride equivalent to 0.25 mg and 1 mg topotecan free-base, respectively. The excipients are gelatin, glyceryl monostearate, hydrogenated vegetable oil, and titanium dioxide. The capsules are imprinted with edible black ink. The 1 mg capsules also contain red iron oxide.
Topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation 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.
Following administration of HYCAMTIN capsules at doses of 1.2 to 3.1 mg/m2 (0.52 to 1.35 times the recommended dose) administered daily for 5 days, the area under the curve (AUC) increased proportionally with dose.
Absorption
The time to the peak plasma concentrations is between 1 to 2 hours following oral administration. The oral bioavailability of topotecan is approximately 40%.
Food Effect
Following a high-fat meal, the AUC was similar in the fed and fasted states, while Tmax was delayed from 1.5 to 3 hours for topotecan lactone and from 3 to 4 hours for total topotecan.
Distribution
Protein binding of topotecan is approximately 35%.
Elimination
The mean terminal half-life (t½) of topotecan is 3 to 6 hours following oral administration.
Metabolism
Topotecan undergoes a reversible pH-dependent hydrolysis of a pharmacologically active lactone moiety. At pH less than or equal to 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. The mean metabolite: parent AUC ratio was less than 10% for total topotecan and topotecan lactone.
Excretion
The overall recovery of drug-related material following 5 daily doses of topotecan was 57% of the administered oral dose. In the urine, 20% of the orally administered dose was excreted as total topotecan and 2% was excreted as N-desmethyl topotecan. Fecal elimination of total topotecan accounted for 33%, while fecal elimination of the active metabolite N-desmethyl topotecan accounted for 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 6% (range: 4% to 8%) of the total drug-related material accounted for in the urine and feces.
Specific Populations
No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following oral administration.
Racial and Ethnic Groups
In patients with creatinine clearance (CLcr) greater than 80 mL/min, the dose-normalized AUCinf to topotecan lactone and total topotecan each were approximately 30% higher in Asians compared to Whites
Patients with Renal Impairment
The mean dose-normalized for total topotecan and topotecan lactone AUCinf increased in advanced cancer patients with renal impairment compared to patients with CLcr greater than 80 mL/min as presented in Table 2 [see Dosage and Administration (2.3)]. Prior platinum-based chemotherapy had no effect on the systemic exposure to both total topotecan and topotecan lactone in patients with CLcr greater than 80 mL/min.
Renal Impairment | Geometric Mean Dose-Normalized AUCinf | |
Total Topotecan | Topotecan Lactone | |
Whites | ||
| 70% | 34% |
Asians | ||
| 26% | 34% |
Drug Interaction Studies
Clinical Studies
Effect of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Inhibitors
Following coadministration of escalating doses of a dual inhibitor of BCRP and P-gp, the AUCinf of topotecan lactone and total topotecan increased approximately 2.5-fold compared to topotecan alone [see Drug Interactions (7.1)].
Coadministration of single oral dose of cyclosporine A (15 mg/kg), an inhibitor of P-gp, multidrug-resistance-associated protein (MRP-1) and CYP3A4, within 4 hours of oral topotecan increased the dose-normalized AUC0-24h of topotecan lactone and total topotecan 2- to 3-fold compared to topotecan alone [see Drug Interactions (7.1)].
Effect of Gastric Acid Reducing Agents
No clinically significant changes in the pharmacokinetics of oral topotecan were observed when coadministered with ranitidine, a histamine-2 receptor antagonist.
In Vitro Studies
Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A, or dihydropyrimidine dehydrogenase.
Carcinogenicity testing of topotecan has not been done. Nevertheless, topotecan 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.
Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m2 [(about 0.6 times the 2.3 mg/m2 oral clinical dose based on body surface area (BSA)] caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given an intravenous dose of 0.4 mg/m2 (about 0.2 times the 2.3 mg/m2 oral clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.
The efficacy of HYCAMTIN capsules was studied in 141 patients with relapsed SCLC in a randomized, controlled, open-label trial (Study 478). The patients were prior responders (complete or partial) to first-line chemotherapy, were not considered candidates for standard intravenous chemotherapy and had relapsed at least 45 days from the end of first-line chemotherapy. Patients were randomized 1:1 to HYCAMTIN capsules (2.3 mg/m2 orally once daily for 5 consecutive days, starting on Day 1 of a 21-day cycle) with best supportive care (BSC) or BSC alone. The major efficacy outcome measure was overall survival (OS).
Patients randomized to HYCAMTIN capsules with BSC received a median of 4 courses (range: 1 to 10) and maintained a median dose intensity of 3.77 mg/m2/week. The median patient age in patients receiving HYCAMTIN capsules with BSC and BSC alone was 60 years and 58 years, while the percentage of patients aged greater than or equal to 65 years was 34% and 29%, respectively. The majority of patients were White (99%) and male (73%). In the HYCAMTIN capsules with BSC arm, 68% of patients had extensive disease and 28% had liver metastasis. In the BSC alone arm, 61% had extensive disease and 20% had liver metastases. Eighty percent of patients receiving HYCAMTIN capsules with BSC previously received carboplatin or cisplatin and 77% of patients in the BSC alone arm received prior carboplatin or cisplatin. In the arm receiving HYCAMTIN capsules with BSC, 18% of patients had prior carboplatin and 62% had prior cisplatin. In the BSC-alone arm, 26% of patients had prior carboplatin and 51% had prior cisplatin.
The arm receiving HYCAMTIN capsules with BSC showed a statistically significant improvement in OS compared with the BSC-alone arm (Log-rank P = 0.0104). Efficacy results are shown in Table 3 and Figure 1.
Parameters | Treatment Group | |
HYCAMTIN Capsules with BSC | BSC | |
(N = 71) | (N = 70) | |
Median Overall Survival (months) (95% CI) | 6.0 (4.2, 7.3) | 3.2 (2.6, 4.3) |
Hazard ratio (95% CI) | 0.64 (0.45, 0.90) | |
Log-rank P-value | 0.0104 | |
Figure 1. Kaplan-Meier Curves for Overall Survival in Small Cell Lung Cancer in Study 478
Figure 1. Kaplan-meier Curves For Overall Survival In Small Cell Lung Cancer In Study 478 (Hycamtin Spl Graphic 02)
The 0.25 mg HYCAMTIN capsules are opaque white to yellowish-white imprinted with HYCAMTIN and 0.25 mg and are available in bottles of 10: NDC 66758-101-11.
The 1 mg HYCAMTIN capsules are opaque pink imprinted with HYCAMTIN and 1 mg and are available in bottles of 10: NDC 66758-102-11.
Store refrigerated 2°C to 8°C (36°F to 46°F) protected from light in the original carton.
HYCAMTIN is a cytotoxic drug. Follow applicable special handling and disposable procedures.1
Myelosuppression
Inform patients that HYCAMTIN decreases blood cell counts, such as white blood cells, platelets, and red blood cells. Instruct patients to notify their healthcare provider promptly for fever or other signs of infection [see Warnings and Precautions (5.1)].
Diarrhea
Interstitial Lung Disease (ILD)
Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.3)].
Embryo-Fetal Toxicity
Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with HYCAMTIN capsules [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3)].
Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
Lactation
Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of HYCAMTIN capsules [see Use in Specific Populations (8.2)].
Infertility
Advise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].
Manufactured by:
GlaxoSmithKline Manufacturing S.p.A.
San Polo di Torrile, Parma, Italy for
Sandoz Inc., Princeton, NJ 08540
| This Patient Information has been approved by the U.S. Food and Drug Administration. | ||
| Revised: 9/2023 | ||
PATIENT INFORMATION | ||
What is the most important information I should know about HYCAMTIN? | ||
See “What are the possible side effects of HYCAMTIN?” for more information about side effects. | ||
It is not known if HYCAMTIN is safe and effective in children. | ||
| ||
Before taking HYCAMTIN, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking HYCAMTIN with certain other medicines can affect how HYCAMTIN works causing side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. | ||
How should I take HYCAMTIN?
| ||
What are the possible side effects of HYCAMTIN?
| ||
The most common side effects of HYCAMTIN include: | ||
|
| |
HYCAMTIN may cause short-term and long-term fertility problems in females. This could affect your ability to become pregnant. HYCAMTIN may cause lower sperm count problems in men. This could affect your ability to father a child and cause birth defects. Talk to your healthcare provider about family planning options that might be right for you. These are not all the possible side effects of HYCAMTIN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||
How should I store HYCAMTIN?
Keep HYCAMTIN and all medicines out of the reach of children. | ||
General information about the safe and effective use of HYCAMTIN | ||
GlaxoSmithKline Manufacturing S.p.A. San Polo di Torrile, Parma, Italy for Sandoz Inc., Princeton, NJ 08540 | ||
Principal Display Panel
NDC 66758-101-11
HYCAMTIN®
(topotecan) Capsules
0.25 mg
Rx only
10 Capsules
Sandoz
Point25mgcarton (Point25mgcarton)
Principal Display Panel
NDC 66758-102-11
HYCAMTIN®
(topotecan) Capsules
1 mg
Rx only
10 Capsules
Sandoz
Onemgcarton (Onemgcarton)
* Please review the disclaimer below.
