Topotecan injection, powder, lyophilized, for solution

Boxed warning section

WARNING: BONE MARROW SUPPRESSION

See full prescribing information for complete boxed warning.

Topotecan for injection can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts greater than or equal to 1,500 cells/mm 3and platelet count greater than or equal to 100,000/mm 3. Monitor blood cell counts . ( 5.1)

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WARNING: BONE MARROW SUPPRESSION

Topotecan for injection can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts of greater than or equal to 1,500 cells/mm 3and platelet counts greater than or equal to 100,000 cells/mm 3. Monitor blood cell counts [see Warnings and Precautions (5.1)].

Recent major changes

Contraindications, Bone Marrow Depression, removed ( 4) 06/2015

1 indications and usage

Topotecan for injection is a topoisomerase inhibitor indicated for:

  • metastatic carcinoma of the ovary after disease progression on or after initial or subsequent chemotherapy. ( 1.1)
  • small cell lung cancer platinum-sensitive disease in patients who progressed after first-line chemotherapy. ( 1.2)
  • combination therapy with cisplatin for Stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment. ( 1.3)

1.1 ovarian cancer

Topotecan for injection, as a single agent, is indicated for the treatment of patients with metastatic carcinoma of the ovary after disease progression on or after initial or subsequent chemotherapy.

2 dosage and administration

  • Ovarian cancer and small cell lung cancer: 1.5 mg/m 2by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course. ( 2.1, 2.2)
  • Cervical cancer: 0.75 mg/m 2by intravenous infusion over 30 minutes on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m 2on Day 1. ( 2.3)
  • Renal impairment: Dose reduce topotecan for injection in patients with moderate renal impairment (20 to 39 mL/min). ( 2.4)

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

3 dosage forms and strengths

4-mg (free base) lyophilized powder in single-use vial. ( 3)

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For injection: 4-mg (topotecan free base) lyophilized powder in single-use vial for reconstitution; light yellow to greenish cake powder.

4 contraindications

  • History of severe hypersensitivity reactions to topotecan. ( 4)

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Topotecan for injection is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan.

5 warnings and precautions

  • Bone marrow suppression: Administer topotecan for injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. ( 2.4, 5.1)
  • Neutropenic enterocolitis: Fatal typhilitis can occur. ( 5.2)
  • 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, 8.3)
  • Extravasation and tissue injury: Severe cases have been reported. If extravasation occurs, immediately stop administration and institute recommended management procedures. ( 5.5)

5.4 embryofetal toxicity

Based on animal data, topotecan for injection can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose of topotecan for injection. Advise women of the potential risk to a fetus [see Use in Specific Populations ( 8.1, 8.3)].

6 adverse reactions

Ovarian cancer:

  • The most common hematologic adverse reactions were: neutropenia (Grade 4: 80%), anemia (Grade 3/4: 41%), thrombocytopenia (Grade 4: 27 %), and febrile neutropenia (23%). ( 6.1)
  • The most common (>5%) non-hematologic adverse reactions (all grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. ( 6.1)

Small cell lung cancer:

  • The most common hematologic adverse reactions were: neutropenia (Grade 4: 70%), anemia (Grade 3/4: 42%), thrombocytopenia (Grade 4: 29%), and febrile neutropenia (28%).
  • The most common (>5%) non-hematologic adverse reactions (all grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue.

Cervical cancer (topotecan for injection plus cisplatin):

  • The most common hematologic adverse reactions were: neutropenia (Grade 3/4: 74%), anemia (Grade 3/4: 40%), and thrombocytopenia (Grade 3/4: 33 %). ( 6.1)
  • The most common (>25% and greater than or equal to 2% more than cisplatin alone) non-hematologic adverse reactions (all grades) were: pain, vomiting, and infection/febrile neutropenia. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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The following serious adverse reactions are described below and elsewhere in the labeling:

6.1 clinical trials experience

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.

Ovarian Cancer

Table 1 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/paclitaxel comparator trial in ovarian cancer.

Table 1. Adverse Reactions Experienced by 5% of Ovarian Cancer Patients Randomized to Receive Topotecan for Injection or Paclitaxel

a Death related to sepsis occurred in 2% of patients receiving topotecan for injection and 0% of patients receiving paclitaxel.

bPain includes body pain, skeletal pain, and back pain.

Adverse Reaction
Topotecan for Injection
( n = 112 )
Paclitaxel
( n = 114 )
Hematologic Grade 3 / 4
%
%
Grade4neutropenia(<500cells/mm 3)
80
21
Grade3/4anemia(Hgb<8g/dL)
41
6
Grade4thrombocytopenia(<25,000plts/mm 3)
27
3
Febrileneutropenia
23
4
Non - hematologic Grade 3 / 4
%
%
Infections and infestations
Sepsis a
5
2
Respiratory , thoracic , and mediastinal disorders
Dyspnea

6

5
Gastrointestinal disorders
Abdominalpain
Constipation
Diarrhea
Intestinalobstruction
Nausea
Vomiting
5
5
6
5
10
10
4

1
4
2
3
General disorders and administrative site conditions
Fatigue
Asthenia
Pain b
7
5
5
6
3
7

Small Cell Lung Cancer

Table 2 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV (cyclophosphamide-doxorubicin-vincristine) comparator trial in small cell lung cancer.

Table 2. Adverse Reactions Experienced by 5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan for Injection or CAV

a Death related to sepsis occurred in 3% of patients receiving topotecan for injection and 1% of patients receiving CAV.

b Pain includes body pain, skeletal pain, and back pain.

Adverse Reaction

Topotecan
for Injection
( n = 107 )
CAV
( n = 104 )
Hematologic Grade 3 / 4
%
%
Grade4neutropenia
(<500cells/mm 3)
70
72
Grade3/4anemia
(Hgb<8g/dL)
42
20
Grade4thrombocytopenia
(<25,000plts/mm 3)
29
5
Febrileneutropenia
28
26
Non - hematologic Grade 3 / 4
%
%
Infections and infestations


Sepsis a
5
5
Respiratory , thoracic , and mediastinal disorders


Dyspnea
9
14
Pneumonia
8
6
Gastrointestinal disorders


Abdominalpain
6
4
Nausea
8
6
General disorders and administrative site conditions


Fatigue
6
10
Asthenia
9
7
Pain b
5
7

Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer Patients Receiving topotecan for injection :Based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer treated with topotecan for injection, Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Grade 3/4 elevations occurred in 4%. Grade 3/4 elevated bilirubin occurred in less than 2% of patients.

Cervical Cancer

In the comparative trial with topotecan for injection plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer.

Table 3. Adverse Reactions Experienced by 5% of Patients with Cervical Cancer Randomized to Receive Topotecan for Injection plus Cisplatin or Cisplatin Monotherapy (Between Arm Difference 2%) a

a Includes patients who were eligible and treated.

b Data were collected using NCI Common Toxicity Criteria, v. 2.0.

c Grades 1 through 4 only. There were 3 patients who experienced deaths with investigator-designated attribution. The first patient experienced a Grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related.

dConstitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss.

e Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain.

f High-level terms were included if the between-arm difference was 10%.

Adverse Reaction
Topotecan for Injection plus Cisplatin
( n = 140 )
%
Cisplatin
( n = 144 )
%
Hematologic


Neutropenia
Grade3(<1,000-500cells/mm 3)
Grade4(<500cells/mm 3)
26
48
1
1
Anemia
Grade3(Hgb<8-6.5g/dL)
Grade4(Hgb<6.5g/dL)
34
6
19
3
Thrombocytopenia
Grade3(<50,000-10,000cells/mm 3)
Grade4(<10,000cells/mm 3)
26
7
3

Non - hematologic b , c


General disorders and administrative site conditions
Constitutional d
Pain e
69
59
62
50
Gastrointestinal disorders
Vomiting
Stomatitis-pharyngitis
Other
40
6
63
37

56
Dermatology f
48
20
Infection - febrileneutropenia f
28
18
Cardiovascular f
25
15

7 drug interactions

  • Do not initiate G-CSF until 24 hours after completion of treatment with topotecan for injection. Concomitant administration can prolong duration of neutropenia.( 7)

7.1 g csf

Concomitant administration with GCSF can prolong the duration of neutropenia. If GCSF is used, it should be started no sooner than 24 hours following the last dose of topotecan for injection.

8 use in specific populations

  • Lactation: Discontinue breastfeeding. ( 8.2)

8.1 pregnancy

Risk Summary

Based on animal data, topotecan for injection can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose [see Data].There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown; however, the background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data:In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m 2basis) given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose on a mg/m 2basis) given for 14 days before mating through gestation Day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. Administration of an intravenous dose of 0.10 mg/kg/day (about half the clinical dose on a mg/m 2basis) 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.

8.4 pediatric use

Safety and effectiveness in pediatric patients have not been established.

10 overdosage

Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. 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 topotecan for injection for intravenous use [see Adverse Reactions ( 6.1, 6.2].In addition, elevated hepatic enzymes and mucositis have been reported following overdose. One patient received a single dose of 40 mg/m 2of intravenous topotecan and developed gastrointestinal toxicity, skin toxicity, and myelosuppresion leading to septic shock. Another patient received a single dose of 35 mg/m 2and experienced severe, reversible neutropenia.

There is no known antidote for overdosage with topotecan for injection. If an overdose is suspected, monitor the patient for bone marrow suppression and institute supportive-care measures (such as prophylactic use of G-CSF and antibiotic therapy) as appropriate.

11 description

Topotecan 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-1 H-pyrano[3',4':6,7]indolizino[1,2- b]quinoline-3,14-(4 H,12 H)-dione. 1.25 hydrochloride. It has the molecular formula C 23H 23N 3O 51.25HCl and a molecular weight of 467.02. It is soluble in water and melts with decomposition at 213 to 218C.

Topotecan hydrochloride has the following structural formula:

Structure

Topotecan for injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish cake powder available in single-dose vials. Each vial contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base. The reconstituted solution ranges in color from yellow to yellow-green and is intended for administration by intravenous infusion.

Inactive ingredients are mannitol, 48 mg, and tartaric acid, 20 mg. Hydrochloric acid and sodium hydroxide may be used to adjust the pH. The solution pH ranges from 2.5 to 3.5.

12 clinical pharmacology

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 religation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

12.3 pharmacokinetics

Following administration of topotecan for injection at doses of 0.5 to 1.5 mg/m 2administered as a 30-minute infusion to cancer patients, topotecan exhibited multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional.

Distribution

Binding of topotecan to plasma proteins is approximately 35%.

Metabolism

Topotecan undergoes a reversible pH-dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitrostudies in human liver microsomes indicate topotecan is metabolized to an N-demethylated metabolite. The mean metabolite:parent AUC ratio was about 3% for total topotecan and topotecan lactone following IV administration.

Excretion

Renal clearance is the primary route of topotecan elimination.

In a mass balance/excretion trial in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4% 2.3% of the administered IV dose. Mean values of 50.8% 2.9% as total topotecan and 3.1% 1.0% as N-desmethyl topotecan were excreted in the urine following IV administration. Fecal elimination of total topotecan accounted for 17.9% 3.6% while fecal elimination of N-desmethyl topotecan was 1.7% 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.

Specific Populations

Gender:Plasma clearance of topotecan lactone in male patients was approximately 24% higher than that in female patients, largely reflecting difference in body size.

Age:Population pharmacokinetic analysis in female patients did not identify age as a significant factor. Decreased renal clearance, which is common in the elderly, is a more important determinant of topotecan clearance [see Dosage and Administration (2.4), Use in Specific Populations (8.5)].

Renal Impairment:In patients with mild renal impairment (Clcr = 40 to 60 mL/min), plasma clearance of topotecan lactone was decreased by 33% compared with patients with normal renal function (Clcr greater than 60 mL/min). In patients with moderate renal impairment (Clcr = 20 to 39 mL/min), plasma clearance of topotecan lactone was reduced by 65% compared with patients with normal renal function. Dosage adjustment is recommended for patients with moderate renal impairment. No dosage adjustment is required in patients with mild renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)].

Hepatic Impairment:Plasma clearance of topotecan with hepatic impairment (serum bilirubin levels between 1.7 and 15.0 mg/dL) was decreased by 33% compared with patients with normal hepatic function (serum bilirubin levels less than 1.7 mg/dL).

Drug Interactions

Effects of Topotecan on Drug-Metabolizing Enzymes: In vitroinhibition studies using marker substrates for human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities of these enzymes were not altered by topotecan.

Cisplatin:Administration of cisplatin (60 or 75 mg/m 2on Day 1) before topotecan (0.75 mg/m 2/day on Days 1 to 5) in 9 patients with ovarian cancer had no significant effect on the C maxand AUC of total topotecan.

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

13 nonclinical toxicology

14 clinical studies

15 references

  1. "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 how supplied/storage and handling

16.1 how supplied

Topotecan for injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish cake powder. Topotecan for injectionis supplied in 4-mg (free base) single-dose vials.

NDC 50742-404-01 (package of 1)

16.2 storage and handling

Store at 20 to 25C (68 and 77F) [see USP Controlled Room Temperature].

Protect vials from light in the original cartons. Handle and dispose of topotecan for injection consistent with recommendations for the handling and disposal of hazardous drugs 1.

17 patient counseling information

  • Bone Marrow Suppression

Inform patients that topotecan for injection decreases blood cell counts such as white blood cells, platelets, and red blood cells. Advise patients to notify their healthcare provider promptly for fever, other signs of infection (e.g., chills, cough, or burning pain on urination), or bleeding. Inform patients that frequent blood tests will be performed while taking topotecan for injection to monitor for the occurrence of bone marrow suppression.

  • Embryofetal Toxicity

Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with topotecan for injection. Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the last dose of topotecan for injection. Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of topotecan for injection [see Warnings and Precautions (5.4), Use in Specific Populations ( 8.1, 8.3].

  • Lactation

Advise nursing mothers to discontinue breastfeeding during treatment with topotecan for injection [see Use in Specific Populations (8.2)].

  • Infertility

Advise male and female patients of the potential risk for impaired fertility and possible family planning options [see Use in Specific Populations (8.3)].

  • Asthenia and Fatigue

Advise patients that topotecan for injection may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.

Manufactured for:

Ingenus Pharmaceuticals, LLC

4190 Millenia Boulevard, Orlando,

FL 32839-6408.

Customer toll free number: 1-877-748-1970

Manufactured by:

Ingensu Pharamceuticals, GmbH

Via Cadepiano 24, Barbengo,

Ticino 6917, Switzerland

Revised:12/2016

Ingredients and appearance - Product information

Topotecan injection, powder, lyophilized, for solution- Topotecan

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 50742-404
Route of Administration Intravenous

Active Ingredient/Active Moiety

Ingredient Name Strength
Topotecan hydrochloride ( UNII: 956S425ZCY)( Topotecan - UNII: 7M7YKX2N15 ) 4 mgin 4 mL

Inactive Ingredients

Ingredient Name Code
Mannitol ( UNII: 3OWL53L36A)
Tartaric acid ( UNII: W4888I119H)
Sodium hydroxide ( UNII: 55X04QC32I)
Hydrochloric acid ( UNII: QTT17582CB)

Product Characteristics

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA206962 USA

Labeler - Ingenus Pharmaceuticals, LLC( 833250017)

Establishment

Name ID/FEI Business Operations
Ingenus Pharmaceuticals, LLC 833250017 analysis( 50742-404), label( 50742-404), manufacture( 50742-404), pack( 50742-404), sterilize( 50742-404)

Package label.principal display panel

Vial label Carton label