TEMOZOLOMIDE- temozolomide capsule 
Amneal Pharmaceuticals LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TEMOZOLOMIDE CAPSULES safely and effectively. See full prescribing information for TEMOZOLOMIDE CAPSULES.   

TEMOZOLOMIDE capsules for oral use
Initial U.S. Approval: 1999

INDICATIONS AND USAGE

Temozolomide capsules are an alkylating drug indicated for the treatment of adult patients with:

  • Newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and then as maintenance treatment. (1.1)
  • Refractory anaplastic astrocytoma patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. (1.2)

DOSAGE AND ADMINISTRATION

  • Newly Diagnosed GBM: 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1 to 5 of a 28-day cycle of temozolomide capsules for 6 cycles. (2.1)
  • Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. (2.1)

DOSAGE FORMS AND STRENGTHS

  • 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg capsules. (3)

CONTRAINDICATIONS

  • Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC). (4.1)

WARNINGS AND PRECAUTIONS

  • Myelosuppression - monitor Absolute Neutrophil Count (ANC) and platelet count prior to dosing and throughout treatment. Geriatric patients and women have a higher risk of developing myelosuppression. (5.1)
  • Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. (5.2)
  • Pneumocystis pneumonia (PCP) – PCP prophylaxis required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen for the treatment of newly diagnosed glioblastoma multiforme. (5.3)
  • All patients, particularly those receiving steroids, should be observed closely for the development of lymphopenia and PCP. (5.4)
  • Complete blood counts should be obtained throughout the treatment course as specified. (5.4)
  • Hepatotoxicity - fatal and severe hepatotoxicity have been reported. Perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide. (5.5)  
  • Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving temozolomide. (5.6) 

ADVERSE REACTIONS

  • The most common adverse reactions (≥ 10% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, coordination abnormal, viral infection, amnesia, and insomnia. (6.1)
  • The most common Grade 3 to 4 hematologic laboratory abnormalities (≥10% incidence) that have developed during treatment with temozolomide are: lymphopenia, thrombocytopenia, neutropenia, and leukopenia. (6.1)
  • Allergic reactions have also been reported. (6)

    To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  •  Valproic acid: decreases oral clearance of temozolomide. (7.1)

USE IN SPECIFIC POPULATIONS

  • Nursing mothers: Not recommended. (8.3)
  • Pediatric use: No established use. (8.4)
  • Hepatic/Renal Impairment: Caution should be exercised when temozolomide is administered to patients with severe renal or hepatic impairment. (8.6, 8.7)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1  INDICATIONS AND USAGE

1.1 Newly Diagnosed Glioblastoma Multiforme

1.2 Refractory Anaplastic Astrocytoma

2  DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing and Dose Modification Guidelines

2.2 Preparation and Administration

3  DOSAGE FORMS AND STRENGTHS

4  CONTRAINDICATIONS

4.1 Hypersensitivity

5  WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

5.2 Myelodysplastic Syndrome

5.3 Pneumocystis Pneumonia

5.4 Laboratory Tests

5.5 Hepatotoxicity

5.6  Use in Pregnancy

6  ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7  DRUG INTERACTIONS

7.1 Valproic Acid

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  DESCRIPTION

12  CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14  CLINICAL STUDIES

14.1 Newly Diagnosed Glioblastoma Multiforme

14.2 Refractory Anaplastic Astrocytoma

15  REFERENCES

16  HOW SUPPLIED/STORAGE AND HANDLING

16.1 Safe Handling and Disposal

16.2 How Supplied

16.3 Storage

17  PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1  INDICATIONS AND USAGE

1.1 Newly Diagnosed Glioblastoma Multiforme

Temozolomide capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

1.2 Refractory Anaplastic Astrocytoma

Temozolomide capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

2  DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing and Dose Modification Guidelines

Dosage of temozolomide capsules must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For temozolomide capsules dosage calculations based on body surface area (BSA) see Table 5. For suggested capsule combinations on a daily dose see Table 6.

Patients with Newly Diagnosed High Grade Glioma: Concomitant Phase: Temozolomide capsules are administered at 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance temozolomide capsules for 6 cycles. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The temozolomide capsules dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count greater than or equal to 1.5 x 109 /L, platelet count  greater than or equal to 100 x 109/L, common toxicity criteria (CTC) nonhematological toxicity  less than or equal to Grade 1 (except for alopecia, nausea, and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. Pneumocystis pneumonia (PCP) prophylaxis is required during the concomitant administration of temozolomide capsules and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade  less than or equal to 1).

TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide

Toxicity

TMZ Interruption*

TMZ Discontinuation

Absolute Neutrophil Count

greater than or equal to 0.5 and less than 1.5 x 109/L

less than 0.5 x 109/L

Platelet Count

greater than or equal to 10 and less than 100 x 109/L

less than 10 x 109/L

CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting)

CTC Grade 2

CTC Grade 3 or 4

*Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count  greater than or equal to 1.5 x 109/L; platelet count  greater than or equal to 100 x 109/L; CTC nonhematological toxicity  less than or equal to Grade 1 (except for alopecia, nausea, vomiting). TMZ=temozolomide; CTC=Common Toxicity Criteria.

Maintenance Phase:

Cycle 1: Four weeks after completing the  temozolomide capsules+RT phase, temozolomide capsules are administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment.

Cycles 2 to 6: At the start of Cycle 2, the dose can be escalated to 200 mg/m2, if the CTC nonhematologic toxicity for Cycle 1 is Grade less than or equal to 2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is greater than or equal to 1.5 x 109/L, and the platelet count is greater than or equal to 100 x 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.

 

Dose Reduction or Discontinuation During Maintenance: Dose reductions during the maintenance phase should be applied according to Tables 2 and 3.

During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of temozolomide capsules) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1,500/μL) and the platelet count exceeds 100 x 109/L (100,000/μL). The next cycle of temozolomide capsules should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3.

TABLE 2: Temozolomide Dose Levels for Maintenance Treatment

Dose Level

Dose (mg/m2/day)

Remarks

-1

100

Reduction for prior toxicity

0

150

Dose during Cycle 1

1

200

Dose during Cycles 2 to 6 in absence of toxicity

TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment

Toxicity

Reduce TMZ by 1 Dose Level*

Discontinue TMZ

Absolute Neutrophil Count

less than 1 x 109/L

See footnote

Platelet Count

less than 50 x 109/L

See footnote

CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting)

CTC Grade 3

CTC Grade 4

*TMZ dose levels are listed in Table 2.

TMZ is to be discontinued if dose reduction to less than 100 mg/m2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. TMZ=temozolomide; CTC=Common Toxicity Criteria.

Patients with Refractory Anaplastic Astrocytoma: For adults the initial dose is 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are  greater than or equal to 1.5 x 109/L (1,500/μL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are  greater than or equal to 100 x 109/L (100,000/μL), the temozolomide capsules dose may be increased to 200 mg/m2/day for 5 consecutive days per 28-day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1,500/μL) and the platelet count exceeds 100 x 109/L (100,000/μL). The next cycle of temozolomide capsules should not be started until the ANC and platelet count exceed these levels. If the ANC falls to less than 1 x 109/L (1,000/μL) or the platelet count is less than 50 x 109/L (50,000/μL) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see Table 4). Temozolomide capsules therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known.

TABLE 4: Dosing Modification Table

table 4

TABLE 5: Daily Dose Calculations by Body Surface Area (BSA)

Total BSA
(m
2)

75 mg/m2
(mg daily)

150 mg/m2
(mg daily)

200 mg/m2
(mg daily)

1

75

150

200

1.1

82.5

165

220

1.2

90

180

240

1.3

97.5

195

260

1.4

105

210

280

1.5

112.5

225

300

1.6

120

240

320

1.7

127.5

255

340

1.8

135

270

360

1.9

142.5

285

380

2

150

300

400

2.1

157.5

315

420

2.2

165

330

440

2.3

172.5

345

460

2.4

180

360

480

2.5

187.5

375

500

TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults

Number of Daily Capsules by Strength (mg)

Total Daily Dose (mg)

250 mg

180 mg

140 mg

100 mg

20 mg

5 mg

75

0

0

0

0

3

3

82.5

0

0

0

0

4

0

90

0

0

0

0

4

2

97.5

0

0

0

1

0

0

105

0

0

0

1

0

1

112.5

0

0

0

1

0

2

120

0

0

0

1

1

0

127.5

0

0

0

1

1

1

135

0

0

0

1

1

3

142.5

0

0

1

0

0

0

150

0

0

1

0

0

2

157.5

0

0

1

0

1

0

165

0

0

1

0

1

1

172.5

0

0

1

0

1

2

180

0

1

0

0

0

0

187.5

0

1

0

0

0

1

195

0

1

0

0

0

3

200

0

1

0

0

1

0

210

0

0

0

2

0

2

220

0

0

0

2

1

0

225

0

0

0

2

1

1

240

0

0

1

1

0

0

255

1

0

0

0

0

1

260

1

0

0

0

0

2

270

1

0

0

0

1

0

280

0

0

2

0

0

0

285

0

0

2

0

0

1

300

0

0

0

3

0

0

315

0

0

0

3

0

3

320

0

1

1

0

0

0

330

0

1

1

0

0

2

340

0

1

1

0

1

0

345

0

1

1

0

1

1

360

0

2

0

0

0

0

375

0

2

0

0

0

3

380

0

1

0

2

0

0

400

0

0

0

4

0

0

420

0

0

3

0

0

0

440

0

0

3

0

1

0

460

0

2

0

1

0

0

480

0

1

0

3

0

0

500

2

0

0

0

0

0

2.2 Preparation and Administration

Temozolomide Capsules: In clinical trials, temozolomide capsules were administered under both fasting and nonfasting conditions; however, absorption is affected by food [see Clinical Pharmacology (12.3)], and consistency of administration with respect to food is recommended. There are no dietary restrictions with temozolomide capsules. To reduce nausea and vomiting, temozolomide capsules should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of temozolomide capsules.

Temozolomide capsules should not be opened or chewed. They should be swallowed whole with a glass of water.

If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see How Supplied/Storage and Handling (16.1)].

3  DOSAGE FORMS AND STRENGTHS

4  CONTRAINDICATIONS

4.1 Hypersensitivity

Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components. Temozolomide is also contraindicated in patients who have a history of hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).

5  WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, patients must have an absolute neutrophil count (ANC)  greater than or equal to 1.5 x 109/L and a platelet count  greater than or equal to 100 x 109/L. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L and platelet count exceeds 100 x 109/L. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.

5.2 Myelodysplastic Syndrome

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.

5.3 Pneumocystis Pneumonia

For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis pneumonia (PCP) is required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen.

There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.

5.4 Laboratory Tests

For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment.

For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 x 109/L and the platelet count falls below 100 x 109/L [see Dosage and Administration (2.1)].

5.5 Hepatotoxicity

Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.

5.6  Use in Pregnancy

Temozolomide can cause fetal harm when administered to a pregnant woman. Administration of temozolomide to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m2), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species [see Use in Specific Populations (8.1)].

6  ADVERSE REACTIONS

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed Glioblastoma Multiforme: During the concomitant phase (temozolomide+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the temozolomide+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation (see Table 7). Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide.

TABLE 7: Number (%) of Patients with Adverse Reactions: All and Severe/Life Threatening (Incidence of 5% or Greater)

   Concomitant Phase
RT Alone
(n=285)
 Concomitant Phase
RT+TMZ
(n=288)*
 Maintenance Phase
TMZ
(n=224)
  All Grade ≥ 3 All Grade ≥ 3 All Grade ≥ 3
 Subjects Reporting any Adverse Reaction 258 (91) 74 (26) 266 (92) 80 (28) 206 (92) 82 (37)
 Body as a Whole - General Disorders            
 Anorexia 25 (9) 1 (<1) 56 (19) 2 (1) 61 (27) 3 (1)
 Dizziness 10 (4) 0  12 (4) 2 (1) 12 (5) 0 
 Fatigue 139 (49) 15 (5) 156 (54) 19 (7) 137 (61) 20 (9)
 Headache 49 (17) 11 (4) 56 (19) 5 (2) 51 (23) 9 (4)
 Weakness 9 (3) 3 (1) 10 (3) 5 (2) 16 (7) 4 (2)
 Central and Peripheral Nervous System Disorders            
 Confusion 12 (4) 6 (2) 11 (4) 4 (1) 12 (5) 4 (2)
 Convulsions 20 (7) 9 (3) 17 (6) 10 (3) 25 (11) 7 (3)
 Memory Impairment 12 (4) 1 (<1) 8 (3) 1 (<1) 16 (7) 2 (1)
 Disorders of the Eye            
 Vision Blurred 25 (9) 4 (1) 26 (9) 2 (1) 17 (8) 0 
 Disorders of the Immune System            
 Allergic Reaction 7 (2) 1 (<1) 13 (5) 0  6 (3) 0 
 Gastrointestinal System Disorders            
 Abdominal Pain 2 (1) 0  7 (2) 1 (<1) 11 (5) 1 (<1)
 Constipation 18 (6) 0  53 (18) 3 (1) 49 (22) 0 
 Diarrhea 9 (3) 0  18 (6) 0  23 (10) 2 (1)
 Nausea 45 (16) 1 (<1) 105 (36) 2 (1) 110 (49) 3 (1)
 Stomatitis 14 (5) 1 (<1) 19 (7) 0  20 (9) 3 (1)
 Vomiting 16 (6) 1 (<1) 57 (20) 1 (<1) 66 (29) 4 (2)
 Injury and Poisoning            
 Radiation Injury NOS 11 (4) 1 (<1) 20 (7) 0  5 (2) 0 
 Musculoskeletal System Disorders            
 Arthralgia 2 (1) 0  7 (2) 1 (<1) 14 (6) 0 
 Platelet, Bleeding and Clotting Disorders            
 Thrombocytopenia 3 (1) 0  11 (4) 8 (3) 19 (8) 8 (4)
 Psychiatric Disorders            
 Insomnia 9 (3) 1 (<1) 14 (5) 0  9 (4) 0 
 Respiratory System Disorders            
 Coughing 3 (1) 0  15 (5) 2 (1) 19 (8) 1 (<1)
 Dyspnea 9 (3) 4 (1) 11 (4) 5 (2) 12 (5) 1 (<1)
 Skin and Subcutaneous Tissue Disorders            
 Alopecia 179 (63) 0  199 (69) 0  124 (55) 0 
 Dry Skin 6 (2) 0  7 (2) 0  11 (5) 1 (<1)
 Erythema 15 (5) 0  14 (5) 0  2 (1) 0 
 Pruritus 4 (1) 0  11 (4) 0  11 (5) 0 
 Rash 42 (15) 0  56 (19) 3 (1) 29 (13) 3 (1)
 Special Senses Other, Disorders            
 Taste Perversion 6 (2) 0  18 (6) 0  11 (5) 0 

*One patient who was randomized to RT only arm received RT+temozolomide. RT+TMZ=radiotherapy plus temozolomide; NOS=not otherwise specified.

Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥ 3 column.

Myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, was observed. When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic reactions, were observed in 14% of the patients treated with temozolomide.

Refractory Anaplastic Astrocytoma: Tables 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients’ underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC Grade 3 or 4) was 10% and 6%, respectively. Myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse reaction. It usually occurred within the first few cycles of therapy and was not cumulative.

Myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. Less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression.

In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC less than 500 cells/μL) and thrombocytopenia (less than 20,000 cells/μL) in women than men in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively).

In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported.

TABLE 8: Adverse Reactions in the Anaplastic Astrocytoma Trial in Adults (≥ 5%)

  No. (%) of Temozolomide Patients
(N=158)
  All Reactions Grade 3/4
 Any Adverse Reaction  153 (97) 79 (50)
 Body as a Whole   
 Headache  65 (41) 10 (6)
 Fatigue  54 (34) 7 (4)
 Asthenia  20 (13) 9 (6)
 Fever  21 (13) 3 (2)
 Back pain  12 (8) 4 (3)
 Cardiovascular   
 Edema peripheral  17 (11) 1 (1)
 Central and Peripheral Nervous System   
 Convulsions  36 (23) 8 (5)
 Hemiparesis  29 (18) 10 (6)
 Dizziness  19 (12) 1 (1)
 Coordination abnormal  17 (11) 2 (1)
 Amnesia  16 (10) 6 (4)
 Insomnia  16 (10) 0
 Paresthesia  15 (9) 1 (1)
 Somnolence  15 (9) 5 (3)
 Paresis  13 (8) 4 (3)
 Urinary incontinence  13 (8) 3 (2)
 Ataxia  12 (8) 3 (2)
 Dysphasia  11 (7) 1 (1)
 Convulsions local  9 (6) 0
 Gait abnormal  9 (6) 1 (1)
 Confusion  8 (5) 0
 Endocrine   
 Adrenal hypercorticism  13 (8) 0
 Gastrointestinal System   
 Nausea  84 (53) 16 (10)
 Vomiting  66 (42) 10 (6)
 Constipation  52 (33) 1 (1)
 Diarrhea  25 (16) 3 (2)
 Abdominal pain  14 (9) 2 (1)
 Anorexia  14 (9) 1 (1)
 Metabolic   
 Weight increase  8 (5) 0
 Musculoskeletal System   
 Myalgia  8 (5) 
 Psychiatric Disorders   
 Anxiety  11 (7) 1 (1)
 Depression  10 (6) 0
 Reproductive Disorders   
 Breast pain, female  4 (6) 
 Resistance Mechanism Disorders   
 Infection viral  17 (11) 0
 Respiratory System   
 Upper respiratory tract infection  13 (8) 0
 Pharyngitis  12 (8) 0
 Sinusitis  10 (6) 0
 Coughing  8 (5) 0
 Skin and Appendages   
 Rash  13 (8) 0
 Pruritus  12 (8) 2 (1)
 Urinary System   
 Urinary tract infection  12 (8) 0
 Micturition increased frequency  9 (6) 0
 Vision   
 Diplopia  8 (5) 0
 Vision abnormal*  8 (5) 

*Blurred vision; visual deficit; vision changes; vision troubles

TABLE 9: Adverse Hematologic Effects (Grade 3 to 4) in the Anaplastic Astrocytoma Trial in Adults

  Temozolomide*
 Hemoglobin  7/158 (4%)
 Lymphopenia  83/152 (55%)
 Neutrophils  20/142 (14%)
 Platelets  29/156 (19%)
 WBC  18/158 (11%)

*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment.

Temozolomide for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) as the corresponding temozolomide capsules. Adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the temozolomide capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of temozolomide. 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 the drug exposure.

Dermatologic disorders:  Toxic epidermal necrolysis and Stevens-Johnson syndrome.

Immune system disorders:  Allergic reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge.

Hematopoietic disorders:  Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes [see Warnings and Precautions (5.1)].

Hepatobiliary disorders:  Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis [see Warnings and Precautions (5.5)].

Infections and infestations: Serious opportunistic infections, including some cases with fatal outcomes, can occur with bacterial, viral (primary and reactivated), fungal, and protozoan organisms.

Pulmonary disorders:  Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis.

Endocrine disorders: Diabetes insipidus.

7  DRUG INTERACTIONS

7.1 Valproic Acid

Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known [see Clinical Pharmacology (12.3)].

8  USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D. See Warnings and Precautions section.

Temozolomide can cause fetal harm when administered to a pregnant woman. Five consecutive days of oral temozolomide administration of 0.38 and 0.75 times the highest recommended human dose (75 and 150 mg/m2) in rats and rabbits, respectively, during the period of organogenesis caused numerous malformations of the external and internal soft tissues and skeleton in both species. Doses equivalent to 0.75 times the highest recommended human dose (150 mg/m2) caused embryolethality in rats and rabbits as indicated by increased resorptions. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide.

8.3 Nursing Mothers

It is not known whether this 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 and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of temozolomide to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Temozolomide capsules have been studied in 2 open-label studies in pediatric patients (aged 3 to 18 years) at a dose of 160 to 200 mg/m2 daily for 5 days every 28 days. In one trial, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had recurrence following surgery and radiation therapy, while 31% also had disease progression following chemotherapy. In a second study conducted by the Children’s Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9). The temozolomide toxicity profile in pediatric patients is similar to adults. Table 10 shows the adverse reactions in 122 children in the COG study.

TABLE 10: Adverse Reactions Reported in the Pediatric Cooperative Group Trial (≥10%)

   No. (%) of Temozolomide Patients
(N=122)*
 Body System/Organ Class
          Adverse Reaction
 All Reactions Grade 3/4
 Subjects Reporting an AE 107 (88) 69 (57)
 Body as a Whole  
 Central and Peripheral Nervous System  
 Central cerebral CNS cortex 22 (18) 13 (11)
 Gastrointestinal System  
 Nausea 56 (46) 5 (4)
 Vomiting 62 (51) 4 (3)
 Platelet, Bleeding and Clotting  
 Thrombocytopenia 71 (58) 31 (25)
 Red Blood Cell Disorders  
 Decreased Hemoglobin 62 (51) 7 (6)
 White Cell and RES Disorders  
 Decreased WBC 71 (58) 21 (17)
 Lymphopenia 73 (60) 48 (39)
 Neutropenia 62 (51) 24 (20)

*These various tumors included the following: PNET-medulloblastoma, glioblastoma, low grade astrocytoma, brain stem tumor, ependymoma, mixed glioma, oligodendroglioma, neuroblastoma, Ewing's sarcoma, pineoblastoma, alveolar soft part sarcoma, neurofibrosarcoma, optic glioma, and osteosarcoma.

8.5 Geriatric Use

Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, P=0.31 and 2/10; 20%, P=0.09, respectively) in the first cycle of therapy than patients under 70 years of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (< 65 years) vs. older (≥ 65 years).

8.6 Renal Impairment

Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

10  OVERDOSAGE

Doses of 500 mg, 750 mg, 1,000 mg, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2,000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.

11  DESCRIPTION

Temozolomide capsules contain temozolomide, USP, an imidazotetrazine derivative. The chemical name of temozolomide, USP is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1d]-as-tetrazine-8-carboxamide. The structural formula is:

f696f63e-figure-02

The material is a white to light tan/light pink powder with a molecular formula of C6H6N6O2 and a molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at pH >7; hence temozolomide, USP can be administered orally and intravenously. The prodrug, temozolomide, USP, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.

Temozolomide Capsules:

Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide, USP.

The inactive ingredients for temozolomide capsules are as follows: colloidal silicon dioxide, ethyl alcohol, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid.

The body of the capsules are made of gelatin and titanium dioxide, and are white opaque color. The cap is also made of gelatin, and the colors vary based on the dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains alcohol, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol and shellac.

Temozolomide Capsules 5 mg: The green cap contains FD&C Blue #2, gelatin, titanium dioxide and yellow iron oxide.

Temozolomide Capsules 20 mg: The yellow cap contains D&C Yellow #10, FD&C Yellow #6, gelatin and titanium dioxide.

Temozolomide Capsules 100 mg: The pink cap contains FD&C Blue #1, FD&C Red #3, FD&C Red #40, gelatin and titanium dioxide.

Temozolomide Capsules 140 mg: The blue cap contains FD&C Blue #1, gelatin and titanium dioxide.

Temozolomide Capsules 180 mg: The red cap contains FD&C Blue #1, FD&C Red #40, gelatin and titanium dioxide.

Temozolomide Capsules 250 mg: The white cap contains gelatin and titanium dioxide.

12  CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.

12.3 Pharmacokinetics

Absorption: Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1 to 2.25 hours) when temozolomide was administered after a modified high-fat breakfast.

A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m2 temozolomide for injection administered over 90 minutes is bioequivalent to 150 mg/m2 temozolomide oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg·hr/mL and 891 ng·hr/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg·hr/mL and 864 ng·hr/mL, respectively.

Distribution: Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.

Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.

Excretion: About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m2. Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m2/day.

Effect of Age: A population pharmacokinetic analysis indicated that age (range: 19 to 78 years) has no influence on the pharmacokinetics of temozolomide.

Effect of Gender: A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men.

Effect of Race: The effect of race on the pharmacokinetics of temozolomide has not been studied.

Tobacco Use: A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers.

Effect of Renal Impairment: A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr <36 mL/min/m2). Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Use in Special Populations (8.6)]. Temozolomide has not been studied in patients on dialysis.

Effect of Hepatic Impairment: A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child-Pugh Class I - II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

Effect of Other Drugs on Temozolomide Pharmacokinetics: In a multiple-dose study, administration of temozolomide capsules with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC.

A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5% [see Drug Interactions (7.1)].

A population analysis did not demonstrate any influence of co-administered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25 to 125 mg/m2) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses 0.5 times the maximum daily dose. Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose.

Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation. Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation.

Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m2) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m2).

13.2 Animal Toxicology and/or Pharmacology

Toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 0.63 times the maximum recommended human dose (125 mg/m2). These changes were most commonly seen at doses where mortality was observed.

14  CLINICAL STUDIES

14.1 Newly Diagnosed Glioblastoma Multiforme

Five hundred and seventy-three patients were randomized to receive either temozolomide (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the temozolomide+RT arm received concomitant temozolomide (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of temozolomide alone (150 or 200 mg/m2) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2- to 3- cm margin. Pneumocystis pneumonia (PCP) prophylaxis was required during the TMZ + RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1.

At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the  temozolomide+RT arm.

The addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed GBM showed a statistically significant improvement in overall survival compared to radiotherapy alone (Figure 1). The hazard ratio (HR) for overall survival was 0.63 (95% CI for HR=0.52 to 0.75) with a log-rank P<0.0001 in favor of the temozolomide arm. The median survival was increased by 2.5 months in the temozolomide arm.

FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population)

f696f63e-figure-03

14.2 Refractory Anaplastic Astrocytoma

A single-arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline Karnofsky performance status of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine, and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Median age of this subgroup of 54 patients was 42 years (19 to 76). Sixty-five percent were male. Seventy-two percent of patients had a KPS of >80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first relapse was 13.8 months (4.2 to 75.4).

Temozolomide capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m2/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was greater than or equal to 1.5 x 109/L (1,500/μL) and the nadir and Day 29, Day 1 of next cycle platelet count was greater than or equal to 100 x 109/L (100,000/μL), the temozolomide dose was increased to 200 mg/m2/day for the first 5 consecutive days of a 28-day cycle.

In the refractory anaplastic astrocytoma population, the overall tumor response rate (CR + PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range: 16 to 114 weeks) and the median duration of complete responses was 64 weeks (range: 52 to 114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31% to 58%) and progression-free survival at 12 months was 29% (95% CI: 16% to 42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62% to 86%) and 12-month overall survival was 65% (95% CI: 52% to 78%). Median overall survival was 15.9 months.

15  REFERENCES

  1. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
  2. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.
  3. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.[3]
  4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology.

16  HOW SUPPLIED/STORAGE AND HANDLING

16.1 Safe Handling and Disposal

Care should be exercised in the handling and preparation of temozolomide, USP. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the contents to avoid inhalation or contact with the skin or mucous membranes. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the capsules. Procedures for proper handling and disposal of anticancer drugs should be considered1-4. Several guidelines on this subject have been published.

16.2 How Supplied

Temozolomide capsules, 5 mg, are supplied as size “3” hard gelatin capsules with green opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “801” with black ink. They are available as follows:

Bottles of 5: NDC 65162-801-51

Bottles of 14: NDC 65162-801-14

Temozolomide capsules, 20 mg, are supplied as size “2” hard gelatin capsules with yellow opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “802” with black ink. They are available as follows:

Bottles of 5: NDC 65162-802-51

Bottles of 14: NDC 65162-802-14

Temozolomide capsules, 100 mg, are supplied as size “1” hard gelatin capsules with pink opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “803” with black ink. They are available as follows:

Bottles of 5: NDC 65162-803-51

Bottles of 14: NDC 65162-803-14

Temozolomide capsules, 140 mg, are supplied as size “0” hard gelatin capsules with blue opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “804” with black ink.

They are available as follows:

Bottles of 5: NDC 65162-804-51

Bottles of 14: NDC 65162-804-14

Temozolomide capsules, 180 mg, are supplied as size “0” hard gelatin capsules with red opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “805” with black ink.

They are available as follows:

Bottles of 5: NDC 65162-805-51

Bottles of 14: NDC 65162-805-14

Temozolomide capsules, 250 mg, are supplied as size “0” hard gelatin capsules with white opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “806” with black ink.

They are available as follows:

Bottles of 5: NDC 65162-806-51

16.3 Storage

Store temozolomide capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17  PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Physicians should discuss the following with their patients:

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 12-2017-06

PATIENT INFORMATION

Temozolomide (TEM-oh-ZOE-loe-mide) Capsules

What is the most important information I should know about temozolomide capsules?

See the section “What are the possible side effects of temozolomide capsules?” for more information about side effects.

What are temozolomide capsules?

Temozolomide capsules are a prescription medicine used to treat adults with certain brain cancer tumors. Temozolomide capsules blocks cell growth, especially cells that grow fast, such as cancer cells. Temozolomide capsules may decrease the size of certain brain tumors in some patients.

It is not known if temozolomide capsules are safe and effective in children.

Who should not take temozolomide capsules?

Do not take temozolomide capsules if you:

What should I tell my doctor before taking temozolomide capsules?

Tell your doctor about all your medical conditions, including if you:

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take a medicine that contains valproic acid (Stavzor®, Depakene®).

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take temozolomide capsules?

Temozolomide capsules may be taken by mouth as a capsule at home.

There are two common dosing schedules for taking temozolomide capsules.

Temozolomide Capsules:

What should I avoid while taking temozolomide capsules?

What are the possible side effects of temozolomide capsules?

Temozolomide capsules can cause serious side effects.

Your doctor will check your blood regularly while you are taking temozolomide capsules to see if these side effects are happening. Your doctor may need to change the dose of temozolomide capsules or when you get it depending on your blood cell counts. People who are age 70 or older and women may be more likely to have their blood cells affected.

Common side effects with temozolomide capsules include:

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects with temozolomide capsules. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store temozolomide capsules?

General information about temozolomide capsules.

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use temozolomide capsules for a condition for which it was not prescribed. Do not give temozolomide capsules to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about temozolomide capsules. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about temozolomide capsules that is written for health professionals.

For more information, go to www.amneal.com or call 1-877-835-5472.

How are temozolomide capsules supplied?

Temozolomide capsules contain a white capsule body with a color cap and the colors vary based on the dosage strength. The capsules are available in six different strengths.

Temozolomide Capsule Strength                    Color

5 mg                                                                Green Cap

20 mg                                                              Yellow Cap

100 mg                                                            Pink Cap

140 mg                                                            Blue Cap

180 mg                                                            Red Cap

250 mg                                                            White Cap

What are the ingredients in temozolomide capsules?

Active ingredient: temozolomide, USP.

Inactive ingredients: colloidal silicon dioxide, ethyl alcohol, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid.

The body of the capsules are made of gelatin and titanium dioxide and are opaque white. The cap is also made of gelatin, and the colors vary based on the dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains alcohol, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol and shellac.

Temozolomide Capsules 5 mg: The green cap contains FD&C Blue #2, gelatin, titanium dioxide and yellow iron oxide.

Temozolomide Capsules 20 mg: The yellow cap contains D&C Yellow #10, FD&C Yellow #6, gelatin and titanium dioxide.

Temozolomide Capsules 100 mg: The pink cap contains FD&C Blue #1, FD&C Red #3, FD&C Red #40, gelatin and titanium dioxide.

Temozolomide Capsules 140 mg: The blue cap contains FD&C Blue #1, gelatin and titanium dioxide.

Temozolomide Capsules 180 mg: The red cap contains FD&C Blue #1, FD&C Red #40, gelatin and titanium dioxide.

Temozolomide Capsules 250 mg: The white cap contains gelatin and titanium dioxide.

*The trademarks depicted herein are owned by their respective companies.

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 12-2017-03

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

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TEMOZOLOMIDE 
temozolomide capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:65162-801
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TEMOZOLOMIDE (UNII: YF1K15M17Y) (TEMOZOLOMIDE - UNII:YF1K15M17Y) TEMOZOLOMIDE5 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
ALCOHOL (UNII: 3K9958V90M)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
TARTARIC ACID (UNII: W4888I119H)  
GELATIN (UNII: 2G86QN327L)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
FD&C RED NO. 40 (UNII: WZB9127XOA)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
SHELLAC (UNII: 46N107B71O)  
FERRIC OXIDE YELLOW (UNII: EX438O2MRT)  
Product Characteristics
ColorWHITE (opaque) , GREEN (opaque) Scoreno score
ShapeCAPSULESize16mm
FlavorImprint Code AMNEAL;801
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:65162-801-141 in 1 CARTON04/03/2015
114 in 1 BOTTLE; Type 0: Not a Combination Product
2NDC:65162-801-511 in 1 CARTON04/03/2015
25 in 1 BOTTLE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20369104/03/2015
TEMOZOLOMIDE 
temozolomide capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:65162-802
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TEMOZOLOMIDE (UNII: YF1K15M17Y) (TEMOZOLOMIDE - UNII:YF1K15M17Y) TEMOZOLOMIDE20 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
TARTARIC ACID (UNII: W4888I119H)  
GELATIN (UNII: 2G86QN327L)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
ALCOHOL (UNII: 3K9958V90M)  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
FD&C RED NO. 40 (UNII: WZB9127XOA)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
SHELLAC (UNII: 46N107B71O)  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8)  
Product Characteristics
ColorYELLOW (opaque) , WHITE (opaque) Scoreno score
ShapeCAPSULESize18mm
FlavorImprint Code AMNEAL;802
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:65162-802-511 in 1 CARTON04/03/2015
15 in 1 BOTTLE; Type 0: Not a Combination Product
2NDC:65162-802-141 in 1 CARTON04/03/2015
214 in 1 BOTTLE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20369104/03/2015
TEMOZOLOMIDE 
temozolomide capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:65162-803
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TEMOZOLOMIDE (UNII: YF1K15M17Y) (TEMOZOLOMIDE - UNII:YF1K15M17Y) TEMOZOLOMIDE100 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
TARTARIC ACID (UNII: W4888I119H)  
GELATIN (UNII: 2G86QN327L)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
ALCOHOL (UNII: 3K9958V90M)  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
FD&C RED NO. 40 (UNII: WZB9127XOA)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
SHELLAC (UNII: 46N107B71O)  
FD&C RED NO. 3 (UNII: PN2ZH5LOQY)  
Product Characteristics
ColorWHITE (opaque) , PINK (opaque) Scoreno score
ShapeCAPSULESize19mm
FlavorImprint Code AMNEAL;803
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:65162-803-511 in 1 CARTON04/03/2015
15 in 1 BOTTLE; Type 0: Not a Combination Product
2NDC:65162-803-141 in 1 CARTON04/03/2015
214 in 1 BOTTLE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20369104/03/2015
TEMOZOLOMIDE 
temozolomide capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:65162-804
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TEMOZOLOMIDE (UNII: YF1K15M17Y) (TEMOZOLOMIDE - UNII:YF1K15M17Y) TEMOZOLOMIDE140 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
TARTARIC ACID (UNII: W4888I119H)  
GELATIN (UNII: 2G86QN327L)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
ALCOHOL (UNII: 3K9958V90M)  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
FD&C RED NO. 40 (UNII: WZB9127XOA)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
SHELLAC (UNII: 46N107B71O)  
Product Characteristics
ColorWHITE (opaque) , BLUE (opaque) Scoreno score
ShapeCAPSULESize22mm
FlavorImprint Code AMNEAL;804
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:65162-804-511 in 1 CARTON04/03/2015
15 in 1 BOTTLE; Type 0: Not a Combination Product
2NDC:65162-804-141 in 1 CARTON04/03/2015
214 in 1 BOTTLE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20369104/03/2015
TEMOZOLOMIDE 
temozolomide capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:65162-805
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TEMOZOLOMIDE (UNII: YF1K15M17Y) (TEMOZOLOMIDE - UNII:YF1K15M17Y) TEMOZOLOMIDE180 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
TARTARIC ACID (UNII: W4888I119H)  
GELATIN (UNII: 2G86QN327L)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
ALCOHOL (UNII: 3K9958V90M)  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
FD&C RED NO. 40 (UNII: WZB9127XOA)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
SHELLAC (UNII: 46N107B71O)  
Product Characteristics
ColorWHITE (opaque) , RED (opaque) Scoreno score
ShapeCAPSULESize22mm
FlavorImprint Code AMNEAL;805
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:65162-805-511 in 1 CARTON04/03/2015
15 in 1 BOTTLE; Type 0: Not a Combination Product
2NDC:65162-805-141 in 1 CARTON04/03/2015
214 in 1 BOTTLE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20369104/03/2015
TEMOZOLOMIDE 
temozolomide capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:65162-806
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
TEMOZOLOMIDE (UNII: YF1K15M17Y) (TEMOZOLOMIDE - UNII:YF1K15M17Y) TEMOZOLOMIDE250 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
TARTARIC ACID (UNII: W4888I119H)  
GELATIN (UNII: 2G86QN327L)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
ALCOHOL (UNII: 3K9958V90M)  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
FD&C RED NO. 40 (UNII: WZB9127XOA)  
FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)  
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
SHELLAC (UNII: 46N107B71O)  
Product Characteristics
ColorWHITE (opaque) Scoreno score
ShapeCAPSULESize22mm
FlavorImprint Code AMNEAL;806
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:65162-806-511 in 1 CARTON04/03/2015
15 in 1 BOTTLE; Type 0: Not a Combination Product
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA20369104/03/2015
Labeler - Amneal Pharmaceuticals LLC (123797875)
Establishment
NameAddressID/FEIBusiness Operations
Amneal Pharmaceuticals of New York, LLC123797875ANALYSIS(65162-801, 65162-802, 65162-803, 65162-804, 65162-805, 65162-806) , LABEL(65162-801, 65162-802, 65162-803, 65162-804, 65162-805, 65162-806) , MANUFACTURE(65162-801, 65162-802, 65162-803, 65162-804, 65162-805, 65162-806) , PACK(65162-801, 65162-802, 65162-803, 65162-804, 65162-805, 65162-806)

Revised: 12/2019
Document Id: 974752b1-4653-4d40-b5fd-34d5cb37a684
Set id: 6c8529ec-8936-4fec-a1a5-2b285c7e4859
Version: 19
Effective Time: 20191227
 
Amneal Pharmaceuticals LLC