Topotecan Hydrochloride

Prior to administration of the first course of topotecan hydrochloride, patients must have a baseline neutrophil count of >1,500 cells/mm 3 and a platelet count of >100,000 cells/mm 3. 2.1 Small Cell Lung Cancer

Recommended Dosage

The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed.  The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines

In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage

The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines

Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug.  See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1,000 cells/mm3 with temperature of 38°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.6 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.6 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment

No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.).  Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.).  Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL.  In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL.  Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling

Topotecan hydrochloride is a cytotoxic anticancer drug.  Prepare topotecan hydrochloride under a vertical laminar flow hood while wearing gloves and protective clothing.  If topotecan hydrochloride solution contacts the skin, wash the skin immediately and thoroughly with soap and water.  If topotecan hydrochloride contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs.  Several guidelines on this subject have been published.1-4

Preparation and Administration

Each 4 mg vial of topotecan hydrochloride is reconstituted with 4 mL Sterile Water for Injection.  Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability

Unopened vials of topotecan hydrochloride are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP Controlled Room Temperature] and protected from light in the original package.  Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

Prior to administration of the first course of Topotecan Hydrochloride for Injection, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage:

The recommended dose of Topotecan Hydrochloride for Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines:

In the event of severe neutropenia (defined as 500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 to (1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage:   The recommended dose of Topotecan Hydrochloride for Injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines:   Dosage adjustments for subsequent courses of Topotecan Hydrochloride for Injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0˚C or 100.4˚ F), reduce the dose of Topotecan Hydrochloride for Injection to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Topotecan Hydrochloride for Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Hydrochloride for Injection to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment:  No dosage adjustment of Topotecan Hydrochloride for Injection appears to be required for patients with mild renal impairment (CIcr 40 to 60 mL/min.). Dosage adjustment of Topotecan Hydrochloride for Injection to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Hydrochloride for Injection. [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan Hydrochloride for Injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Topotecan Hydrochloride for Injection after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling: Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for Injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published. 1-4

Preparation and Administration: Each 4-mg vial of Topotecan Hydrochloride for Injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability: Unopened vials of Topotecan Hydrochloride for Injection are stable until the date indicated on the package when stored between 20˚ and 25˚ C (68˚ and 77˚ F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of Topotecan Hydrochloride for Injection diluted for infusion are stable at approximately 20˚ to 25˚ C (68˚ to 77˚ F) and ambient lighting conditions for 24 hours.

Prior to administration of the first course of topotecan hydrochloride, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage:

The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines:

In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage: The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines: Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug. See manufacturer's prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment: No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling: Topotecan hydrochloride is a cytotoxic anticancer drug. Prepare topotecan hydrochloride under a vertical laminar flow hood while wearing gloves and protective clothing. If topotecan hydrochloride solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If topotecan hydrochloride contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4

Preparation and Administration: Each 4-mg vial of topotecan hydrochloride is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability: Unopened vials of topotecan hydrochloride are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

Prior to administration of the first course of topotecan hydrochloride, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage:

The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines:

In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage: The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines: Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug. See manufacturer's prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment: No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling: Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for Injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4

Preparation and Administration: Each 4-mg vial of Topotecan Hydrochloride for Injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability: Unopened vials of Topotecan Hydrochloride for Injection are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of Topotecan Hydrochloride for Injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

Prior to administration of the first course of Topotecan Hydrochloride for Injection, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage

The recommended dose of Topotecan Hydrochloride for Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines

In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage

The recommended dose of Topotecan Hydrochloride for Injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines

Dosage adjustments for subsequent courses of Topotecan Hydrochloride for Injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of Topotecan Hydrochloride for Injection to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Topotecan Hydrochloride for Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Hydrochloride for Injection to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment

No dosage adjustment of Topotecan Hydrochloride for Injection appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of Topotecan Hydrochloride for Injection to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Hydrochloride for Injection [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan Hydrochloride for Injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Topotecan Hydrochloride for Injection after cisplatin discontinuation in patients with cervical cancer.  

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling

Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for Injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4  

Preparation and Administration

Each 4-mg vial of Topotecan Hydrochloride for Injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability

Unopened vials of Topotecan Hydrochloride for Injection are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of Topotecan Hydrochloride for Injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

2.1 Treatment of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]

The recommended regimen is:

• one 5 mg tablet orally, taken daily

or

• one 35 mg tablet orally, taken once-a-week

or

• one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month

or

• one 150 mg tablet orally, taken once-a-month 2.2 Prevention of Postmenopausal Osteoporosis [see Indications and Usage (1.1)]

The recommended regimen is:

• one 5 mg tablet orally, taken daily

or

• one 35 mg tablet orally, taken once-a-week

or

• alternatively, one 75 mg tablet orally, taken on two consecutive days for a total of two tablets each month may be considered

or

• alternatively, one 150 mg tablet orally, taken once-a-month may be considered 2.3 Treatment to Increase Bone Mass in Men With Osteoporosis [see Indications and Usage (1.2)]

The recommended regimen is:

• one 35 mg tablet orally, taken once-a-week 2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis [see Indications and Usage (1.3)]

The recommended regimen is:

• one 5 mg tablet orally, taken daily 2.5 Treatment of Paget’s Disease [see Indications and Usage (1.4)]

The recommended treatment regimen is 30 mg orally once daily for 2 months. Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.

2.6 Important Administration Instructions

Instruct patients to do the following:

• Take risedronate sodium tablets at least 30 minutes before the first food or drink of the day other than water, and before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, [ see Drug Interactions (7.1)]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium. • Swallow risedronate sodium tablets whole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [ see Warnings and Precautions (5.1)]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration. • Do not eat or drink anything except plain water, or take other medications for at least 30 minutes after taking risedronate sodium tablets. 2.7 Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium tablets.

2.8 Administration Instructions for Missed Doses

Instruct patients about missing risedronate sodium tablet doses as follows:

• If a dose of risedronate sodium tablets, 35 mg once-a-week is missed: ∘ Take 1 tablet on the morning after they remember and return to taking 1 tablet once-a-week, as originally scheduled on their chosen day. ∘ Do not take 2 tablets on the same day. • If one or both tablets of risedronate sodium tablets, 75 mg on two consecutive days per month are missed, and the next month’s scheduled doses are more than 7 days away: ∘ If both tablets are missed, take one risedronate sodium tablet, 75 mg in the morning after the day it is remembered and then the other tablet on the next consecutive morning. ∘ If only one risedronate sodium tablet, 75 mg is missed, take the missed tablet in the morning after the day it is remembered. ∘ Return to taking their risedronate sodium tablets, 75 mg on two consecutive days per month as originally scheduled. ∘ Do not take more than two 75 mg tablets within 7 days. • If one or both tablets of risedronate sodium tablets, 75 mg on two consecutive days per month are missed, and the next month's scheduled doses are within 7 days: ∘ Wait until their next month’s scheduled doses and then continue taking risedronate sodium tablets, 75 mg on two consecutive days per month as originally scheduled. • If the dose of risedronate sodium tablets, 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away: ∘ Take the missed tablet in the morning after the day it is remembered and then return to taking their risedronate sodium tablets, 150 mg once-a-month as originally scheduled. ∘ Do not take more than one 150 mg tablet within 7 days. • If the dose of risedronate sodium tablets, 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days: ∘ Wait until their next month’s scheduled dose and then continue taking risedronate sodium tablets, 150 mg once-a-month as originally scheduled.

Prior to administration of the first course of topotecan hydrochloride, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage 

The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed.  The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines

In the event of severe neutropenia (defined as <500 cells/ mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage

The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines

Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug.  See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1,000 cells/mm3 with temperature of 38°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.6 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.6 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment

No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min).  Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min).  Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL.  In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL.  Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling

Topotecan hydrochloride is a cytotoxic anticancer drug.  Prepare topotecan hydrochloride under a vertical laminar flow hood while wearing gloves and protective clothing.  If topotecan hydrochloride solution contacts the skin, wash the skin immediately and thoroughly with soap and water.  If topotecan hydrochloride contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs.  Several guidelines on this subject have been published.1-4

Preparation and Administration

Each 4 mg vial of topotecan hydrochloride is reconstituted with 4 mL Sterile Water for Injection.  Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability

Unopened vials of topotecan hydrochloride are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP Controlled Room Temperature] and protected from light in the original package.  Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

2.1 Small Cell Lung Cancer

Recommended Dosage 

The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed.  The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines

In the event of severe neutropenia (defined as <500 cells/ mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage

The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines

Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug.  See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1,000 cells/mm3 with temperature of 38°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.6 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.6 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment

No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min).  Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min).  Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL.  In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL.  Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling

Topotecan hydrochloride is a cytotoxic anticancer drug.  Prepare topotecan hydrochloride under a vertical laminar flow hood while wearing gloves and protective clothing.  If topotecan hydrochloride solution contacts the skin, wash the skin immediately and thoroughly with soap and water.  If topotecan hydrochloride contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs.  Several guidelines on this subject have been published.1-4

Preparation and Administration

Each 4 mg vial of topotecan hydrochloride is reconstituted with 4 mL Sterile Water for Injection.  Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability

Unopened vials of topotecan hydrochloride are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP Controlled Room Temperature] and protected from light in the original package.  Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see BOXED WARNINGS and WARNINGS). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Patients should be started at the lowest dose for the indication.

1. For treatment of moderate to severe vasomotor symptoms, vulval and vaginal atrophy associated with the menopause, the lowest dose and regimen that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

Attempts to discontinue or taper medication should be made at 3-month to 6-month intervals. The usual initial dosage range is 1 mg to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms. The minimal effective dose for maintenance therapy should be determined by titration. Administration should be cyclic (e.g., 3 weeks on and 1 week off).

2. For treatment of female hypoestrogenism due to hypogonadism, castration or primary ovarian failure.

Treatment is usually initiated with a dose of 1 mg to 2 mg daily of estradiol, adjusted as necessary to control presenting symptoms; the minimal effective dose for maintenance therapy should be determined by titration.

3. For treatment of breast cancer, for palliation only, in appropriately selected women and men with metastatic disease.

Suggested dosage is 10 mg three times daily for a period of at least 3 months.

4. For treatment of advanced androgen-dependent carcinoma of the prostate, for palliation only.

Suggested dosage is 1 mg to 2 mg three times daily. The effectiveness of therapy can be judged by phosphatase determinations as well as by symptomatic improvement of the patient.

5. For prevention of osteoporosis.

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.

The lowest effective dose of estradiol tablets has not been determined.

Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)].

Prior to administration of the first course of topotecan hydrochloride for injection, patients must have a baseline neutrophil count of >1,500 cells/mm

3 and a platelet count of >100,000 cells/mm3.

2.1 Small Cell Lung Cancer

Recommended Dosage:

The recommended dose of topotecan hydrochloride for injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed and median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.
Dosage Modification Guidelines: In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage: The recommended dose of topotecan hydrochloride for injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course). 

Dosage Modification Guidelines: Dosage adjustments for subsequent courses of topotecan hydrochloride for injection in combination with cisplatin are specific for each drug. See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity. 

In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of topotecan hydrochloride for injection to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride for injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride for injection to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment: No dosage adjustment of topotecan hydrochloride for injection appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min.). Dosage adjustment of topotecan hydrochloride for injection to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride for injection [see Use in Specific Populations (8.6) and ClinicalPharmacology (12.3)].

Topotecan hydrochloride for injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride for injection after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Adminstration

Handling: Topotecan hydrochloride for injection is a cytotoxic anticancer drug. Prepare topotecan hydrochloride for injection under a vertical laminar flow hood while wearing gloves and protective clothing. If topotecan hydrochloride for injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If topotecan hydrochloride for injection contacts mucous membranes, flush thoroughly with water. 

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4

Preparation and Administration: Each 4 mg vial of topotecan hydrochloride for injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration. 

Stability: Unopened vials of topotecan hydrochloride for injection are stable until the date indicated on the package when stored at 20°-25°C (68°-77°F); [See USP Controlled Room Temperature] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution. 

Reconstituted vials of topotecan hydrochloride for injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)].

Prior to administration of the first course of Topotecan Hydrochloride for Injection, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Ovarian Cancer and Small Cell Lung Cancer

Recommended Dosage:

  The recommended dose of Topotecan Hydrochloride for Injection is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course.   In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 3 ovarian clinical trials was 9 to 12 weeks, and median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines:

In the event of severe neutropenia (defined as <500 cells/mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. 2.2 Cervical Cancer

Recommended Dosage:

The recommended dose of Topotecan Hydrochloride for Injection is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines: 

Dosage adjustments for subsequent courses of Topotecan Hydrochloride for Injection in combination with cisplatin are specific for each drug. See manufacturer's prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

In the event of severe febrile neutropenia (defined as <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of Topotecan Hydrochloride for Injection to 0.60 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of Topotecan Hydrochloride for Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Hydrochloride for Injection to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses. 2.3 Dosage Adjustment in Specific Populations

Renal Impairment:

No dosage adjustment of Topotecan Hydrochloride for Injection appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min). Dosage adjustment of Topotecan Hydrochloride for Injection to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for Topotecan Hydrochloride for Injection [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan Hydrochloride for Injection in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with Topotecan Hydrochloride for Injection after cisplatin discontinuation in patients with cervical cancer. 

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling

Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for Injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.1-4  

Preparation and Administration

Each 4-mg vial of Topotecan Hydrochloride for Injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability

Unopened vials of Topotecan Hydrochloride for Injection are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of Topotecan Hydrochloride for Injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.