HYCAMTIN

GlaxoSmithKline LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use HYCAMTIN safely and effectively. See full prescribing information for HYCAMTIN. HYCAMTIN (topotecan) CapsulesInitial U.S. Approval: 1996RECENT MAJOR CHANGES Contraindications (4) 10/2011 Warnings and Precautions, Pregnancy (5.4) 10/2011 BOXED WARNINGWARNING: Bone Marrow Suppression See full prescribing information for complete boxed warning HYCAMTIN should be administered only to patients with baseline neutrophil counts of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3. In order to assess the occurrence of bone marrow suppression, blood cell counts should be monitored. INDICATIONS AND USAGEHYCAMTIN is a topoisomerase inhibitor indicated for treatment of patients with relapsed small cell lung cancer. (1)DOSAGE AND ADMINISTRATION •2.3 mg/m2/day orally once daily for 5 consecutive days repeated every 21 days. (2) •See dose modification guidelines for patients with bone marrow toxicity or Grade 3 or 4 diarrhea. (2.3) DOSAGE FORMS AND STRENGTHS0.25 mg and 1 mg capsules. (3)CONTRAINDICATIONS •History of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. (4) •Severe bone marrow depression. (4) WARNINGS AND PRECAUTIONS •Bone marrow suppression. HYCAMTIN should be administered only to patients with adequate bone marrow reserves. Peripheral blood counts should be monitored. (5.1) Dose may need to be adjusted. (2.3) •Topotecan-induced neutropenia can lead to neutropenic colitis. (5.1) •Diarrhea, including severe diarrhea requiring hospitalization, has been reported during treatment with HYCAMTIN capsules. (5.2) Dose may need to be adjusted. (2.3) •HYCAMTIN has been associated with reports of interstitial lung disease, some of which have been fatal. (5.3) •Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) Side EffectsThe most common Grade 3 or 4 hematologic adverse reactions with HYCAMTIN capsules were neutropenia (61%), anemia (25%), and thrombocytopenia (37%). The most common (≥10%) non-hematologic adverse reactions (all grades) were nausea (27%), diarrhea (14%), vomiting (19%), fatigue (11%), and alopecia (10%). To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •Patients should be carefully monitored for adverse reactions when HYCAMTIN capsules are administered with a drug known to inhibit ABCG2 (BCRP) or ABCB1 (P-glycoprotein). (7.1) USE IN SPECIFIC POPULATIONS •Geriatric use: Among patients who received HYCAMTIN capsules in 4 thoracic cancer studies, drug-related diarrhea was more frequent in patients ≥65 years of age (28%) compared to those

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: Bone Marrow Suppression
• 1 HYCAMTIN INDICATIONS AND USAGE
• 2 HYCAMTIN DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dosing
  • 2.2 Adjustment of Dose in Special Populations
  • 2.3 Dose Modification Guidelines
• 3 DOSAGE FORMS AND STRENGTHS
• 4 HYCAMTIN CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Bone Marrow Suppression
  • 5.2 Diarrhea
  • 5.3 Interstitial Lung Disease
  • 5.4 Pregnancy
  • 5.5 Drug Interactions
• 6 HYCAMTIN ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Drugs That Inhibit Drug Efflux Transporters
  • 7.2 Effects of Topotecan on Drug Metabolizing Enzymes
  • 7.3 Effects of Other Drugs on Topotecan Pharmacokinetics
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10 OVERDOSAGE
• 11 HYCAMTIN DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Small Cell Lung Cancer
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Bone Marrow Suppression
  • 17.2 Pregnancy
  • 17.3 Diarrhea
  • 17.4 FDA-Approved Patient Labeling

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The recommended dose of HYCAMTIN capsules is 2.3 mg/m²/day once daily for 5 consecutive days repeated every 21 days. Round the calculated oral daily dose to the nearest 0.25 mg, and prescribe the minimum number of 1 mg and 0.25 mg capsules. The same number of capsules should be prescribed for each of the 5 dosing days.

HYCAMTIN capsules may be taken with or without food. The capsules must be swallowed whole and must not be chewed, crushed, or divided. If your patient vomits after taking the dose of HYCAMTIN, the patient should not take a replacement dose.

2.2 Adjustment of Dose in Special Populations

No dosage adjustment of HYCAMTIN capsules appears to be required for treating patients with mild renal impairment (CLcr = 50-80 mL/min). A dose adjustment of HYCAMTIN capsules to 1.8 mg/m²/day is predicted to adjust the area under the curve (AUC) to the normal range for patients with moderate renal impairment (CLcr = 30-49 mL/min). Insufficient data are available in patients with severe renal impairment (CLcr <30 mL/min) to provide a dosage recommendation for HYCAMTIN capsules [see Use in Specific Populations (8.6)].

2.3 Dose Modification Guidelines

Patients should not be treated with subsequent courses of HYCAMTIN until neutrophils recover to >1,000 cells/mm³, platelets recover to >100,000 cells/mm³, and hemoglobin levels recover to ≥9.0 g/dL (with transfusion if necessary).

For patients who experience severe neutropenia (neutrophils <500 cells/mm³ associated with fever or infection or lasting for 7 days or more) or neutropenia (neutrophils 500 to 1,000 cells/mm³ lasting beyond day 21 of the treatment course), the HYCAMTIN capsules dose should be reduced by 0.4 mg/m²/day for subsequent courses. Doses should be similarly reduced if the platelet count falls below 25,000 cells/mm³.

For patients who experience Grade 3 or 4 diarrhea, the HYCAMTIN capsules dose should be reduced by 0.4 mg/m²/day for subsequent courses [see Warnings and Precautions (5.2)]. Patients with Grade 2 diarrhea may need to follow the same dose modification guidelines.

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

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 studies (N = 682) using HYCAMTIN capsules at 2.3 mg/m²/day for 5 consecutive days. The median day for neutrophil, red blood cell, and platelet nadirs occurred on day 15.

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). Infection, sepsis, and febrile neutropenia occurred in 17%, 2%, and 4% of patients, respectively. Death due to sepsis occurred in 1% of patients. Pancytopenia has been reported.

Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. [See Dosage and Administration (2.3).]

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

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

HYCAMTIN should be administered only in patients with adequate bone marrow reserves, including a baseline neutrophil count of ≥1,500 cells/mm³ and a platelet count ≥100,000 cells/mm³. Frequent monitoring of peripheral blood cell counts should be instituted during treatment with HYCAMTIN.

5.2 Diarrhea

Diarrhea, including severe diarrhea requiring hospitalization, has been reported during treatment with HYCAMTIN capsules. Diarrhea related to HYCAMTIN capsules can occur at the same time as drug-related neutropenia and its sequelae. Communication with patients prior to drug administration regarding these side effects and proactive management of early and all signs and symptoms of diarrhea is important. Treatment-related diarrhea is associated with significant morbidity and may be life-threatening. Should diarrhea occur during treatment with HYCAMTIN capsules, physicians are advised to aggressively manage diarrhea. Clinical guidelines describing the aggressive management of diarrhea include specific recommendations on patient communication and awareness, recognition of early warning signs, use of anti-diarrheals and antibiotics, changes in fluid intake and diet, and need for hospitalization.

Of the 682 patients who received HYCAMTIN capsules in the 4 thoracic cancer studies, the overall incidence of drug-related diarrhea was 22%, including 4% with Grade 3 and 0.4% with Grade 4. Drug-related diarrhea was more frequent in patients ≥65 years of age (28%) compared to those <65 years of age (19%). [See Adverse Reactions (6.1) and Use in Specific Populations (8.5).]

5.3 Interstitial Lung Disease

HYCAMTIN has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions (6.2)]. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and HYCAMTIN should be discontinued if a new diagnosis of ILD is confirmed.

5.4 Pregnancy

Pregnancy Category D

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. There are no adequate and well controlled studies of HYCAMTIN in pregnant women. 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 the fetus [see Use in Specific Populations, Pregnancy (8.1)].

5.5 Drug Interactions

P-glycoprotein inhibitors (e.g., cyclosporine A, elacridar, ketoconazole, ritonavir, and saquinavir) can cause significant increases in topotecan exposure. The concomitant use of P-glycoprotein inhibitors with HYCAMTIN capsules should be avoided. [See Drug Interactions (7.1).]

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

The safety of HYCAMTIN capsules has been evaluated in 682 patients with thoracic cancer (3 recurrent small cell lung cancer [SCLC] studies and 1 recurrent non-small cell lung cancer [NSCLC] study) who received at least one dose of HYCAMTIN capsules. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 describes the hematologic and non-hematologic adverse reactions in recurrent SCLC patients treated with HYCAMTIN capsules plus best supportive care (BSC) and in the overall thoracic cancer patient population.

BSC = Best Supportive Care.

N = total number of patients treated.

Adverse reactions were graded using NCI Common Toxicity Criteria.

Of the 70 patients who received HYCAMTIN capsules plus BSC, the incidence of drug-related diarrhea was 14%, with 4% Grade 3 and 1% Grade 4.

In the 682 patients who received HYCAMTIN capsules in the 4 thoracic cancer studies, the incidence of drug-related diarrhea was 22%, with 4% Grade 3 and 0.4% Grade 4. The overall incidence of drug-related diarrhea was more frequent in patients ≥65 years of age (28%, n = 225) with 10% Grade 1, 9% Grade 2, 7% Grade 3, and 1% Grade 4 compared to those <65 years of age (19%, n = 457) with 7% Grade 1, 9% Grade 2, 3% Grade 3, and 0% Grade 4. The incidence of Grade 3 or 4 diarrhea proximate (within 5 days) to Grade 3 or 4 neutropenia events in the HYCAMTIN capsules treatment group was 5%. The median time to onset of Grade 2 or worse diarrhea was 9 days in the HYCAMTIN capsules group.

In the 682 patients who received HYCAMTIN capsules in the 4 thoracic cancer studies, 39 deaths occurred within 30 days after the last dose of study medication for a reason other than progressive disease; 13 of these deaths were attributed to hematologic toxicity, 5 were attributed to non-hematologic toxicity, and 21 were attributed to other causes. One patient death (68 years of age) was attributed to treatment-related diarrhea and one death (68 years of age) attributed diarrhea as a contributory event; both patients received HYCAMTIN capsules.

In addition to the adverse reactions listed previously, the following adverse reactions have been reported with HYCAMTIN for Injection:

• •Incidence >10%: Febrile neutropenia, abdominal pain, stomatitis, constipation.
• •Incidence 1 to 10%: Sepsis, hypersensitivity (including rash), hyperbilirubinemia, malaise.

6.2 Postmarketing Experience

There is no postmarketing experience with HYCAMTIN capsules. The following adverse reactions have been identified during post-approval use of HYCAMTIN for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Severe bleeding (in association with thrombocytopenia).

Immune system disorders: Allergic manifestations, anaphylactoid reactions.

Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease.

Gastrointestinal disorders: Abdominal pain potentially associated with neutropenic colitis [see Warnings and Precautions (5.1)].

Skin and subcutaneous tissue disorders: Angioedema, severe dermatitis, severe pruritus.

7 DRUG INTERACTIONS

7.1 Drugs That Inhibit Drug Efflux Transporters

Topotecan is a substrate for both ABCB1 [P-glycoprotein (P-gp)] and ABCG2 (BCRP). Elacridar (inhibitor of ABCB1 and ABCG2) administered with HYCAMTIN capsules increased topotecan exposure to approximately 2.5-fold of control. Cyclosporine A (inhibitor of ABCB1, ABCC1 [MRP-1], and CYP3A4) with HYCAMTIN capsules increased topotecan exposure to 2- to 3-fold of control. Patients should be carefully monitored for adverse reactions when HYCAMTIN capsules are administered with a drug known to inhibit these transporters. [See Clinical Pharmacology (12.3).]

7.2 Effects of Topotecan on Drug Metabolizing Enzymes

In vitro inhibition studies using marker substrates known to be metabolized by human cytochromes 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.

7.3 Effects of Other Drugs on Topotecan Pharmacokinetics

The pharmacokinetics of topotecan were generally unchanged when coadministered with ranitidine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D. [See Warnings and Precautions (5.4).]

HYCAMTIN can cause fetal harm when administered to a pregnant woman. 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. An IV dose of 0.10 mg/kg/day (about half the clinical IV dose on a mg/m² basis) given 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.

There are no adequate and well controlled studies of HYCAMTIN in pregnant women. 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 the fetus.

8.3 Nursing Mothers

Rats excrete high concentrations of topotecan into milk. Lactating 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. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HYCAMTIN, discontinue breastfeeding when women are receiving HYCAMTIN.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the 682 patients with thoracic cancer in 4 clinical studies who received HYCAMTIN capsules, 33% (n = 225) were 65 years of age and older, while 4.8% (n = 33) were 75 years of age and older. Treatment-related diarrhea was more frequent in patients ≥65 years of age (28%) compared to those <65 years of age (19%). [See Warnings and Precautions (5.2) and Adverse Reactions (6.1).] Among patients ≥65 years of age, those receiving HYCAMTIN capsules plus BSC showed a survival benefit compared to those receiving BSC alone.

There were no apparent differences in the pharmacokinetics of topotecan in elderly patients with creatinine clearance of ≥60 mL/minute [see Clinical Pharmacology (12.3)].

This drug is known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function [see Dosage and Administration (2.2)].

8.6 Renal Impairment

A cross-study analysis of data collected from 217 patients with advanced solid tumors indicated that exposure (AUC_0−∞) to topotecan lactone, the pharmacologically active moiety, was 10% and 20% higher in patients with mild renal (CLcr = 50-80 mL/min) and moderate renal (CLcr = 30-49 mL/min) impairment, respectively, than in patients with normal renal function (CLcr >80 mL/min) [see Dosage and Administration (2.2)].

8.7 Hepatic Impairment

In a population pharmacokinetic analysis involving oral topotecan administered at doses of 0.15-2.7 mg/m²/day to 118 cancer patients, the pharmacokinetics of total topotecan did not differ significantly based on patient serum bilirubin, ALT, or AST. No dosage adjustment appeared to be required for patients with impaired hepatic function (serum bilirubin of >1.5 mg/dL).

10 OVERDOSAGE

There is no known antidote for overdosage with HYCAMTIN capsules. The primary anticipated complication of overdosage would consist of hematological toxicity. The patient should be observed closely for bone marrow suppression, and supportive measures (such as the prophylactic use of G-CSF and/or antibiotic therapy) should be considered.

11 DESCRIPTION

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: