Topotecan 1 MG Oral Capsule

Details

DRUG INTERACTIONS

7 Topotecan is a substrate for both P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Inhibitors of these transporters increase the systemic exposure to oral topotecan.

Avoid concomitant use of P-gp inhibitors (e.g., amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir, ritonavir, quercetin, quinidine, ranolazine, ticagrelor, verapamil) and BCRP inhibitors (e.g., cyclosporine, eltrombopag) with HYCAMTIN capsules [see Clinical Pharmacology (12.3)].

•Avoid concomitant use of P-gp and BCRP inhibitors with HYCAMTIN.

(7, 12.3)

OVERDOSAGE

10 Overdoses (up to 5-fold of the prescribed dose) occurred in patients treated with HYCAMTIN capsules.

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 oral use [see Adverse Reactions (6.1)].

Mucositis has also been reported in association with overdose.

There is no known antidote for overdosage with HYCAMTIN.

If an overdose is suspected, monitor the patient closely for bone marrow suppression, and institute supportive-care measures (such as the prophylactic use of G-CSF and/or antibiotic therapy) as appropriate.

DESCRIPTION

11 Topotecan hydrochloride is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity.

The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride.

It has the molecular formula C23H23N3O5•HCl and a molecular weight of 457.9.

It is soluble in water and melts with decomposition at 213° to 218°C.

Topotecan hydrochloride has the following structural formula: HYCAMTIN capsules for oral use contain topotecan hydrochloride, the content of which is expressed as topotecan free base.

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.

topotecan hydrochloride chemical structure

CLINICAL STUDIES

14 14.1 Small Cell Lung Cancer The efficacy of HYCAMTIN capsules was studied in 141 patients with relapsed SCLC in a randomized, controlled, open-label trial.

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.

Seventy-one patients were randomized to HYCAMTIN capsules (2.3 mg/m2/day administered for 5 consecutive days repeated every 21 days) and Best Supportive Care (BSC) and 70 patients were randomized to BSC alone.

The primary objective was to compare the overall survival between the treatment arms.

Patients in the arm receiving HYCAMTIN capsules plus 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 the arm receiving HYCAMTIN capsules plus BSC and the BSC-alone treatment arm was 60 years and 58 years while the percentage of patients aged >65 years was 34% and 29%, respectively.

The majority of patients were Caucasian (99.3%) and male (73%).

Eighty percent of patients receiving HYCAMTIN capsules plus BSC previously received carboplatin or cisplatin, and 77% of patients in the BSC-alone arm received prior carboplatin or cisplatin.

The arm receiving HYCAMTIN capsules plus BSC included 68% of patients with extensive disease and 28% with liver metastasis.

In the BSC- alone arm, 61% of patients had extensive disease and 20% had liver metastases.

Both treatment arms recruited 73% males.

In the arm receiving HYCAMTIN capsules plus 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 plus BSC showed a statistically significant improvement in overall survival compared with the BSC-alone arm (Log-rank P = 0.0104).

Survival results are shown in Table 3 and Figure 1.

Table 4.

Overall Survival in Patients With Small Cell Lung Cancer With HYCAMTIN Capsules Plus BSC Compared With BSC Alone Treatment Group HYCAMTIN Capsules + BSC BSC (N = 71) (N = 70) Median (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 BSC = Best Supportive Care.

N = Total number of patients randomized.

CI = Confidence interval.

Figure 1.

Kaplan-Meier Estimates for Survival Figure 1.

Kaplan-Meier Estimates for Survival

HOW SUPPLIED

16 /STORAGE AND HANDLING 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 0007-4205-11.

The 1-mg HYCAMTIN capsules are opaque pink imprinted with HYCAMTIN and 1 mg and are available in bottles of 10: NDC 0007-4207-11.

Store refrigerated 2°C to 8°C (36°F to 46°F).

Store the bottles protected from light in the original outer cartons.

HYCAMTIN is a cytotoxic drug.

Follow applicable special handling and disposable procedures.1

RECENT MAJOR CHANGES

Boxed Warning 06/2014 Dosage and Administration, Dose Modification Guidelines (2.2) 06/2014 Contraindications, Severe Bone Marrow Depression (4) Removed 06/2014 Warnings and Precautions, Embryofetal Toxicity (5.4) 06/2014 Warnings and Precautions, Drug Interactions (5.5) Removed 06/2014

GERIATRIC USE

8.5 Geriatric Use Of the 682 patients with thoracic cancer in 4 clinical trials who received HYCAMTIN capsules, 33% (n = 225) were aged 65 years and older, while 4.8% (n = 33) were aged 75 years and older.

Treatment-related diarrhea was more frequent in patients aged ≥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.

DOSAGE FORMS AND STRENGTHS

3 HYCAMTIN capsules contain topotecan hydrochloride expressed as topotecan free base.

The 0.25-mg capsules are opaque white to yellowish-white and imprinted with HYCAMTIN and 0.25 mg.

The 1-mg capsules are opaque pink and imprinted with HYCAMTIN and 1 mg.

0.25-mg and 1-mg capsules.

(3)

MECHANISM OF ACTION

12.1 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 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.

INDICATIONS AND USAGE

1 HYCAMTIN capsules are indicated for the treatment of relapsed small cell lung cancer in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.

HYCAMTIN is a topoisomerase inhibitor.

HYCAMTIN capsules are indicated for treatment of patients with relapsed small cell lung cancer.

(1)

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category D.

Risk Summary: HYCAMTIN can cause fetal harm when administered to a pregnant woman.

Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to a fetus.

Animal Data: In rabbits, an IV dose of 0.10 mg/kg/day (about equal to the clinical IV dose on a mg/m2 basis) given on days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight.

In the rat, an IV dose of 0.23 mg/kg/day (about equal to the clinical IV dose on a mg/m2 basis) given for 14 days before mating through gestation day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity.

Administration of an IV dose of 0.10 mg/kg/day (about half the clinical IV dose on a mg/m2 basis) to rats on days 6 through 17 of gestation caused an increase in post-implantation mortality.

This dose also caused an increase in total fetal malformations.

The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether topotecan is present in human milk.

Lactating rats excrete high concentrations of topotecan into milk.

Female rats given 4.72 mg/m2 IV (about twice the clinical dose on a mg/m2 basis) excreted topotecan into milk at concentrations up to 48-fold higher than those in plasma.

Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from HYCAMTIN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING: BONE MARROW SUPPRESSION HYCAMTIN® can cause severe myelosuppression.

Administer only to patients with neutrophil counts of ≥1,500 cells/mm3 and platelet counts ≥100,000 cells/mm3.

Monitor blood cell counts.

WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning HYCAMTIN can cause severe myelosuppression.

Administer only to patients with baseline neutrophil counts of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3.

Monitor blood cell counts (5.1).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Bone marrow suppression: Administer HYCAMTIN only to patients with adequate bone marrow reserves.

Monitor peripheral blood counts.

(5.1) Adjust dose as needed.

(2.2) •Diarrhea: Severe diarrhea can occur and may require hospitalization.

(5.2) Withhold for severe diarrhea.

Reduce dose upon recovery.

(2.2) •Interstitial lung disease (ILD): Fatal cases have occurred.

Permanently discontinue for confirmed ILD.

(5.3) •Embryofetal toxicity: Can cause fetal harm.

Advise women of potential risk to the fetus.

(5.4, 8.1) 5.1 Bone Marrow Suppression Bone marrow suppression (primarily neutropenia) is a dose-limiting toxicity of HYCAMTIN.

Neutropenia is not cumulative over time.

The following data on myelosuppression are based on an integrated safety database from 4 thoracic malignancy trials (N = 682) using HYCAMTIN capsules at 2.3 mg/m2/day for 5 consecutive days.

The median day for neutrophil and platelet nadirs occurred on Day 15.

Neutropenia: Grade 4 neutropenia (<500 cells/mm3) occurred in 32% of patients with a median duration of 7 days and was most common during Course 1 of treatment (20% of patients).

Clinical sequelae of neutropenia included infection (17%), febrile neutropenia (4%), sepsis (2%), and septic death (1%).

Pancytopenia has been reported.

Topotecan can cause fatal typhlitis (neutropenic enterocolitis).

Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain [see Dosage and Administration (2.2)].

Thrombocytopenia: Grade 4 thrombocytopenia (<10,000 cells/mm3) occurred in 6% of patients, with a median duration of 3 days.

Anemia: Grade 3 or 4 anemia (<8 g/dL) occurred in 25% of patients.

Administer the first course of HYCAMTIN only to patients with a neutrophil count of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3.

Monitor peripheral blood cell counts frequently during treatment with HYCAMTIN.

Refer to Section 2.2 for dose modification guidelines for hematological toxicities in subsequent courses.

5.2 Diarrhea Diarrhea, including severe and life-threatening diarrhea requiring hospitalization, can occur during treatment with HYCAMTIN capsules.

Diarrhea caused by HYCAMTIN capsules can occur at the same time as drug-induced neutropenia and its sequelae.

In the 682 patients who received HYCAMTIN capsules in the 4 lung cancer trials, the incidence of diarrhea caused by HYCAMTIN capsules was 22%, with 4% Grade 3 and 0.4% Grade 4.The incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia events in the group receiving HYCAMTIN capsules was 5%.

The median time to onset of Grade 2 or worse diarrhea was 9 days in the group receiving HYCAMTIN capsules.

Manage diarrhea caused by HYCAMTIN capsules aggressively.

Do not administer HYCAMTIN capsules to patients with Grade 3 or 4 diarrhea.

Reduce the dose of HYCAMTIN after recovery to Grade 1 or less [see Dosage and Administration (2.2)].

5.3 Interstitial Lung Disease Interstitial lung disease (ILD), including fatalities, has occurred with HYCAMTIN.

Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs and/or colony stimulating factors.

Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue HYCAMTIN if a new diagnosis of ILD is confirmed.

5.4 Embryofetal Toxicity HYCAMTIN can cause fetal harm when administered to a pregnant woman.

Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis.

If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use highly effective contraception during treatment and for at least 1 month after the last dose of HYCAMTIN.

Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking HYCAMTIN [see Use in Specific Populations (8.1, 8.7)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) • Bone Marrow Suppression 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 such as chills, cough, or burning pain on urination.

Advise patients that frequent blood tests will be performed while taking HYCAMTIN to monitor for bone marrow suppression [see Warnings and Precautions (5.1)].

• Embryofetal Toxicity Advise patients on pregnancy planning and prevention.

Advise females of reproductive potential to use highly effective contraception during treatment and for 1 month following treatment with HYCAMTIN [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.7)].

Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 3 months after treatment [see Nonclinical Toxicology (13.1)].

• Nursing Mothers Advise patients to discontinue nursing during treatment with HYCAMTIN [see Use in Specific Populations 8.1, 8.7)].

• Infertility Advise male and female patients of the potential risk for impaired fertility and possible family planning options.

• Diarrhea Inform patients that HYCAMTIN capsules cause diarrhea which may be severe and life-threatening.

Instruct patients how to manage and/or prevent diarrhea and to inform their physician if severe diarrhea occurs during treatment with HYCAMTIN capsules [see Warnings and Precautions (5.2)].

HYCAMTIN is a registered trademark of the GSK group of companies.

HYC:6PI

DOSAGE AND ADMINISTRATION

2 •2.3 mg/m2/day orally once daily for 5 consecutive days repeated every 21 days.

(2) •Renal impairment: Adjust the dose of HYCAMTIN in patients with renal impairment.

(2.2) 2.1 Recommended Dosing The recommended dose of HYCAMTIN capsules is 2.3 mg/m2/day orally once daily for 5 consecutive days repeated every 21 days.

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.

Take HYCAMTIN capsules with or without food.

Swallow capsules whole.

Do not chew, crush, or divide the capsules.

Do not prescribe a replacement dose for emesis.

Diarrhea: Do not administer HYCAMTIN capsules to patients with Grade 3 or 4 diarrhea.

After recovery to Grade 1 or less, reduce the dose of HYCAMTIN by 0.4 mg/m2/day for subsequent courses [see Warnings and Precautions (5.2)].

2.2 Dose Modification Guidelines Hematologic Toxicities: Do not administer subsequent courses of HYCAMTIN capsules until neutrophils recover to greater than 1,000 cells/mm3, platelets recover to greater than 100,000 cells/mm3, hemoglobin levels recover to greater than or equal to 9.0 g/dL (with transfusion if necessary).

• Dose reduce HYCAMTIN capsules by 0.4 mg/m2/day for: neutrophil counts of less than 500 cells/mm3 associated with fever or infection or lasting for 7 days or more; neutrophil counts of 500 to 1,000 cells/mm3 lasting beyond day 21 of the treatment course; platelet counts less than 25,000 cells/mm3.

Renal Impairment: The recommended starting doses of HYCAMTIN capsules in patients with moderate and severe renal impairment are as follows: Table 1.

Dose Reduction Guidelines for Renal Impairment Degree of Renal Impairment Creatinine Clearancea (mL/min) Dose (mg/m2)/day Moderate 30 – 49 1.5b Severe <30 0.6b aCalculated with the Cockroft-Gault method using ideal body weight.

bDose can be increased after the first course by 0.4 mg/m2/day if no severe hematologic or gastrointestinal toxicities occur.