Topotecan Hydrochloride (Page 2 of 6)

6 ADVERSE REACTIONS

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

• Myelosuppression [see Warnings and Precautions (5.1)]
• Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.2)]
• Extravasation and Tissue Injury [see Warnings and Precautions (5.3)]

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.

The data in Warnings and Precautions reflect exposure to topotecan hydrochloride for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received topotecan hydrochloride for injection 1.5 mg/m² by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients with cervical cancer received topotecan hydrochloride for injection 0.75 mg/m² by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m² by intravenous infusion on Day 1, of a 21-day cycle.

Ovarian Cancer

The safety of topotecan hydrochloride for injection was evaluated in a randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039) [see Clinical Studies (14.1)]. Table 1 shows the incidence of Grade 3 and 4 hematologic and non-hematologic adverse reactions that occurred in patients receiving topotecan hydrochloride for injection.

Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Ovarian Cancer in Study 039

	Topotecan Hydrochloride for Injection	Paclitaxel
Adverse Reaction	(n = 112)	(n = 114)
	G r ade 3-4 (%)	G r ade 3-4 (%)
Hematologic
Grade 4 neutropenia (< 500/mm3)	80	21
Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm3)	41 27	6 3
Febrile neutropenia	23	4
Non-Hematologic
Infections
Sepsisa	5	2
Respiratory, thoracic, and mediastinal
Dyspnea	6	5
Gastrointestinal
Vomiting	10	3
Nausea	10	2
Diarrhea	6	1
Abdominal pain	5	4
Intestinal obstruction	5	4
Constipation	5	0
General and administrative site conditions
Fatigue	7	6
Painb	5	7
Asthenia	5	3
a Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride and 0% of patients receiving paclitaxel.
b Pain includes body pain, skeletal pain, and back pain.

Small Cell Lung Cancer (SCLC)

The safety of topotecan hydrochloride for injection was evaluated in randomized, comparative trial in patients with recurrent or progressive SCLC (Study 090) [see Clinical Studies (14.2)]. Table 2 shows the Grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with SCLC.

Table 2. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Small Cell Lung Cancer in Study 090

A dverse Reactions	Topotecan Hydrochloride for Injection (n = 107)	CAV c ( n = 104)
	G r ade 3-4 (%)	G r ade 3-4 (%)
Hematologic
Grade 4 neutropenia (< 500/mm3)	70	72
Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm3)	42 29	20 5
Febrile neutropenia	28	26
N on-Hematologic
Infections Sepsisa	5	5
Re spiratory, thoracic, and mediastinal	9	14
Dyspnea
Pneumonia	8	6
G astrointestinal	8	6
Nausea
Abdominal pain	6	4
G e neral and administrative site conditions	9	7
Asthenia
Fatigue	6	10
Painb	5	7

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

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

^c CAV = cyclophosphamide, doxorubicin and vincristine.

Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer (SCLC)

Based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with topotecan hydrochloride for injection, Grade 3 or 4 increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2%.

Cervical Cancer

The safety of topotecan hydrochloride for injection was evaluated in a comparative trial of topotecan hydrochloride with cisplatin versus cisplatin as a single agent in patients with cervical cancer (Study GOG 0179). Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer.

Table 3. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Cervical Cancer (Between-Arm Difference ≥ 2%)^a in Study GOG 0179

A dverse Reaction	Topotecan Hydrochloride for Injection with Cisplatin ( n = 140) %	C isplatin n = 144) %
Hematologic
Neutropenia	26	1
Grade 3 (< 1,000 to 500/mm3)
Grade 4 (< 500/mm3)	48	1
Anemia	34	19
Grade 3 (Hgb < 8 to 6.5 g/dL)
Grade 4 (Hgb < 6.5 g/dL)	6	3
Thrombocytopenia	26	3
Grade 3 (< 50,000 to 10,000/mm3)
Grade 4 (< 10,000/mm3)	7	0
N on-Hematologic b ,c
G e neral and administrative site conditions	69	62
Constitutionald
Paine	59	50
G astrointestinal	40	37
Vomiting
Stomatitis-pharyngitis	6	0
Other	63	56
De r m a t ology f	48	20
Infection Febrile neutropeniaf	28	18
C ardiovascular f	25	15

^a Includes patients who were eligible and treated.

^b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 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.

^d Constitutional 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%.