Temozolomide

RECENT MAJOR CHANGES Indications and Usage ( 1.2 ) 9/2023 Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.4 ) 9/2023 Contraindications ( 4 ) 9/2023 Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.5 , 5.6 ) 9/2023

1. INDICATIONS AND USAGE TEMOZOLOMIDE Capsules, USP are an alkylating drug indicated for the treatment of adult patients with: • Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. ( 1.1 ) • Refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. ( 1.2 ) 1.1 Newly Diagnosed Glioblastoma TEMOZOLOMIDE Capsules, USP is indicated for the treatment of adult patients with newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. 1.2 Refractory Anaplastic Astrocytoma TEMOZOLOMIDE Capsules , USP is indicated for the treatment of adult patients with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

2 DOSAGE AND ADMINISTRATION • Newly Diagnosed Glioblastoma: o 75 mg/m 2 once daily for 42 to 49 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m 2 once daily for Days 1 to 5 of each 28-day cycle for 6 cycles. May increase maintenance dose to 200 mg/m 2 for Cycles 2 to 6 based on toxicity. ( 2.1 ) o Provide Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less. ( 2.1 ) • Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma: Beginning 4 weeks after the end of radiotherapy, administer temozolomide capsules orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles. The recommended dosage for Cycle 1 is 150 mg/m 2 per day and for Cycles 2 to 12 is 200 mg/m 2 if patient experienced no or minimal toxicity in Cycle 1. ( 2.2 ) • Refractory Anaplastic Astrocytoma: Initial dose of 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. ( 2.2 ) 2.1 Monitoring to Inform Dosage and Administration Prior to dosing, withhold temozolomide capsules until patients have an absolute neutrophil count (ANC) of 1.5 x 10 9 /L or greater and a platelet count of 100 x 10 9 /L or greater. For concomitant radiotherapy, obtain a complete blood count prior to initiation of treatment and weekly during treatment. For the 28-day treatment cycles, obtain a complete blood count prior to treatment on Day 1 and on Day 22 of each cycle. Perform complete blood counts weekly until recovery if the ANC falls below 1.5 x 10 9 /L and the platelet count falls below 100 x 10 9 /L. For concomitant use with focal radiotherapy, obtain a complete blood count weekly and as clinically indicated. 2.2 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administertemozolomide capsules either orally or intravenously once daily for 42 to 49 consecutive days during the concomitant use phase withfocalradiotherapy, and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance use phase. Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant use phase and continue in patients who develop lymphopenia untilresolutionto Grade 1 or less [see Warnings and Precautions (5.3) ] . ConcomitantUse Phase: The recommended dosage of temozolomide capsules is 75 mg/m 2 either orally or intravenously once daily for 42 to 49 days in combination with focalradiotherapy. Focal radiotherapy includes the tumor bed or resection site with a 2 to 3 cm margin. Otheradministration schedules have been used. Obtaina complete blood count weekly. The recommended dosage modifications due to adverse reactions during concomitant use phase areprovided in Table 1 . TABLE 1:Dosage Modifications Due to Adverse Reactions During Concomitant Use Phase AdverseReaction Interruption Discontinuation AbsoluteNeutrophil Count Withhold temozolomide capsules if ANC is greater than or equal to 0.5 x 10 9 /L and less than 1.5 x 10 9 /L. Resume temozolomide capsules at the same dose when ANC is greater than or equal to 1.5 x 10 9 /L. Discontinue temozolomide capsules if ANC is less than 0.5 x 10 9 /L. PlateletCount Withhold temozolomide capsules if platelet count is greater than or equal to 10 x 10 9 /L and less than 100 x 10 9 /L. Resume temozolomide capsules at the same dose when platelet count is greater than or equal to 100 x 10 9 /L. Discontinue temozolomide capsules if platelet count is less than 10 x 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold temozolomide capsules if Grade 2 adverse reaction occurs. Resume temozolomide capsules at the same dose when resolution to Grade 1 or less. Discontinue temozolomide capsules if Grade 3 or 4 adverse reaction occurs. Single Agent Maintenance Use Phase: Beginning 4 weeks after concomitant use phase completion, administer temozolomide capsules either orally or intravenously once daily on Days 1 to5of each 28-day cycle fo …

3 DOSAGE FORMS AND STRENGTHS Temozolomide capsules, USP are available in 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg strengths. The capsules contain a white capsule body with a color cap, and the colors vary based on the dosage strength. 5 mg: Opaque green cap and opaque white body, hard gelatin capsules imprinted with ‘13’ on cap and ‘H’ on body, filled with off-white to pink or tan color granular powder. 20 mg: Opaque yellow cap and opaque white body, hard gelatin capsules imprinted with ‘14’ on cap and ‘H’ on body, filled with off-white to pink or tan color granular powder. 100 mg: Opaque pink cap and opaque white body, hard gelatin capsules imprinted with ‘15’ on cap and ‘H’ on body, filled with off-white to pink or tan color granular powder. 140 mg: Opaque blue cap and opaque white body, hard gelatin capsules imprinted with ‘16’ on cap and ‘H’ on body, filled with off-white to pink or tan color granular powder. 180 mg: Opaque orange cap and opaque white body, hard gelatin capsules imprinted with ‘17’ on cap and ‘H’ on body, filled with off-white to pink or tan color granular powder. 250 mg: Opaque white cap and opaque white body, hard gelatin capsules imprinted with ‘18’ on cap and ‘H’ on body, filled with off-white to pink or tan color granular powder. • Capsules: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. ( 3 )

4 CONTRAINDICATIONS Temozolomide capsules, USP is contraindicated in patients with a history of hypersensitivity reactions to: temozolomide or any other ingredients in Temozolomide capsules, USP; and dacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3­-methyltriazen-1-yl)-imidazole-4-carboxamide. Reactions to Temozolomide have included anaphylaxis [see Adverse Reactions (6.2) ]. History of hypersensitivity to temozolomide or any other ingredients in Temozolomide capsules, USP and dacarbazine. ( 4.1 )

6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions ( 5.1 )]. • Myelodysplastic Syndrome and Secondary Malignancies [see Warnings and Precautions ( 5.2 )]. • Pneumocystis Pneumonia [see Warnings and Precautions ( 5.3 )]. • Hepatotoxicity [see Warnings and Precautions ( 5.4 )]. The most common adverse reactions (≥ 20% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥ 10% incidence) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes.( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-051 [see Clinical Studies ( 14.1 )]. 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%). The most common adverse reactions (≥20%) across the cumulative TEMOZOLOMIDE experience were alopecia, fatigue, nausea, and vomiting. Table 3 summarizes the adverse reactions in Newly Diagnosed Glioblastoma Trial. Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of TEMOZOLOMIDE. TABLE 3: Adverse Reactions (≥5%) in Patients Receiving TEMOZOLOMIDE in Newly Diagnosed Glioblastoma Trial Adverse Reactions Concomitant Phase Maintenance Phase Radiation Therapy and TEMOZOLAMIDE N=288* Radiation Therapy Alone N=285 TEMOZOLOMIDE N=224 All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Skin and Subcutaneous Tissue Alopecia 69 63 55 Rash 19 1 15 13 1 Dry Skin 2 2 5 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. Adverse reactions with TEMOZOLOMIDE for injection Adverse reactions that were reported in 35 patients who received TEMOZOLOMIDE for injection that were not reported in patients who received TEMOZOLOMIDE capsules were pain, irritation, pruritus, warmth, swelling, and erythema at infusion site; petechiae; and hematoma. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval 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: Toxic epidermal necrolysis and Stevens-Johnson syndrome Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMOZOLOMIDE and, in some cases, recurred upon rechallenge. Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary : Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine : Diabete …

8. USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] TEMOZOLOMIDE can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to TEMOZOLOMIDE during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of TEMOZOLOMIDE to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions. 8.2 Lactation There are no data on the presence of TEMOZOLOMIDE or its metabolites in human milk, the effects on a breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions, including myelosuppression from temozolomide in the breastfed children, advise women not to breastfeed during treatment with TEMOZOLOMIDE and for at least 1 week after the last dose. 8.3 Females and Males of Reproductive Potential TEMOZOLOMIDE can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) ]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TEMOZOLOMIDE [see Use in Specific Populations ( 8.1 )] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TEMOZOLOMIDE and for at least 6 months after the last dose. Males Because of the potential for embryofetal toxicity and genotoxic effects on sperm cells, advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with TEMOZOLOMIDE and for at least 3 months after the final dose [see Use in Specific Populations ( 8.1 ), Nonclinical Toxicology ( 13.1 )]. Advise male patients not to donate semen during treatment with TEMOZOLOMIDE and for at least 3 months after the final dose. Infertility TEMOZOLOMIDE may impair male fertility [ see Nonclinical Toxicology ( 13.1 )]. Limited data from male patients show changes in sperm parameters during treatment with TEMOZOLOMIDE; however, no information is available on the duration or reversibility of these changes. 8.4 Pediatric Use Safety and effectiveness of TEMOZOLOMIDE have not been established in pediatric patients. Safety and effectiveness of TEMOZOLOMIDE capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to 18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. 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 adverse reaction profile in pediatric …

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 DNA alkylation, mainly at the O 6 and N 7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death.

12.2 Pharmacodynamics Temozolomide exposure-response relationships and the time course of pharmacodynamic response are unknown.

11 DESCRIPTION Temozolomide is an alkylating drug. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]- as -tetrazine­-8-carboxamide. The structural formula of temozolomide is: The material is a white to light tan/light pink powder with a molecular formula of C 6 H 6 N 6 O 2 and a molecular weight of 194.15. The molecule is stable at acidic pH (7; hence Temozolomide capsules, USP can be administered orally. The prodrug, temozolomide, 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, USP: Temozolomide capsules, USP for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients are as follows: Temozolomide capsules, USP, 5 mg: lactose anhydrous (103.52 mg), colloidal silicon dioxide (0.180 mg), sodium starch glycolate (5.650 mg), tartaric acid (2.260 mg), and stearic acid (3.390 mg). Temozolomide capsules, USP, 20 mg: lactose anhydrous (179.0 mg), colloidal silicon dioxide (0.320 mg), sodium starch glycolate (10.350 mg), tartaric acid (4.140 mg), and stearic acid (6.210 mg). Temozolomide capsules, USP, 100 mg: lactose anhydrous (73.0 mg), colloidal silicon dioxide (0.280 mg), sodium starch glycolate (9.00 mg), tartaric acid (3.60 mg), and stearic acid (5.40 mg). Temozolomide capsules, USP, 140 mg: lactose anhydrous (102.2 mg), colloidal silicon dioxide (0.390 mg), sodium starch glycolate (12.60 mg), tartaric acid (5.040 mg), and stearic acid (7.560 mg). Temozolomide capsules, USP, 180 mg: lactose anhydrous (131.4 mg), colloidal silicon dioxide (0.500 mg), sodium starch glycolate (16.20 mg), tartaric acid (6.480 mg), and stearic acid (9.720 mg). Temozolomide capsules, USP, 250 mg: lactose anhydrous (182.5 mg), colloidal silicon dioxide (0.700 mg), sodium starch glycolate (22.50 mg), tartaric acid (9.000 mg), and stearic acid (13.50 mg). The body of the capsules for 5 mg, 20 mg, 140 mg, 180 mg and 250 mg strengths is made of gelatin, and titanium dioxide and is white opaque. The body of the capsules for 100 mg strengths is made of gelatin, titanium dioxide and ferric oxide yellow and is buff opaque. 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 shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and Black Iron Oxide. Temozolomide capsules, USP, 5 mg: The green opaque cap contains gelatin, titanium dioxide, FDA/E172 yellow iron oxide, and FD&C Blue #2. Temozolomide capsules, USP, 20 mg: The rich yellow opaque cap contains gelatin, titanium dioxide, and FDA/E172 yellow iron oxide. Temozolomide capsules, USP, 100 mg: The peach opaque cap contains gelatin, titanium dioxide, ferric oxide yellow, and ferric oxide red. Temozolomide capsules, USP, 140 mg: The blue opaque cap contains gelatin, titanium dioxide, and FD&C Blue#2. Temozolomide capsules, USP, 180 mg: The red opaque cap contains gelatin, titanium dioxide, and ferric oxide red. Temozolomide capsules, USP, 250 mg: The white opaque cap contains gelatin, and titanium dioxide. structure

10. OVERDOSAGE Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 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 myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, monitor complete blood count and provide supportive measures as necessary.

16 HOW SUPPLIED/STORAGE AND HANDLING Temozolomide is a hazardous drug. Follow applicable special handling and disposal procedures.1 Temozolomide capsules, USP are supplied in amber glass bottles with child-resistant caps or child-resistant blister packs containing the following capsule strengths: 5 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “5 mg” on body and “890” on cap in green ink, containing white to light tan/light pink powder and are supplied as: Bottles of 5 with Child Resistant Cap..................NDC 47335-890-80 Bottles of 14 with Child Resistant Cap.................NDC 47335-890-21 Bottles of 20 with Child Resistant Cap................NDC 47335-890-87 Unit-dose blister pack of 5 (1 × 5).............................NDC 47335-890-74 Unit-dose blister pack of 15 (3 x 5)...........................NDC 47335-890-72 Unit-dose blister pack of 20 (4 × 5)...........................NDC 47335-890-75 20 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “20 mg” on body and “891” on cap in yellow ink, containing white to light tan/light pink powder and are supplied as: Bottles of 5 with Child Resistant Cap..................NDC 47335-891-80 Bottles of 14 with Child Resistant Cap.................NDC 47335-891-21 Bottles of 20 with Child Resistant Cap................NDC 47335-891-87 Unit-dose blister pack of 5 (1 × 5) ...........................NDC 47335-891-74 Unit-dose blister pack of 15 (3 x 5)..........................NDC 47335-891-72 Unit-dose blister pack of 20 (4 × 5) .........................NDC 47335-891-75 100 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “100 mg” on body and “892” on cap in pink ink, containing white to light tan/light pink powder and are supplied as: Bottles of 5 with Child Resistant Cap..................NDC 47335-892-80 Bottles of 14 with Child Resistant Cap.................NDC 47335-892-21 Bottles of 20 with Child Resistant Cap................NDC 47335-892-87 Unit-dose blister pack of 5 (1 × 5) ...........................NDC 47335-892-74 Unit-dose blister pack of 15 (3 x 5)..........................NDC 47335-892-72 Unit-dose blister pack of 20 (4 × 5)..........................NDC 47335-892-75 140 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “140 mg” on body and “929” on cap in blue ink, containing white to light tan/light pink powder and are supplied as: Bottles of 5 with Child Resistant Cap..................NDC 47335-929-80 Bottles of 14 with Child Resistant Cap.................NDC 47335-929-21 Bottles of 20 with Child Resistant Cap................NDC 47335-929-87 Unit-dose blister pack of 5 (1 × 5) ...........................NDC 47335-929-74 Unit-dose blister pack of 15 (3 x 5)..........................NDC 47335-929-72 Unit-dose blister pack of 20 (4 × 5)..........................NDC 47335-929-75 180 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “180 mg” on body and “930” on cap in reddish brown ink, containing white to light tan/light pink powder and are supplied as: Bottles of 5 with Child Resistant Cap..................NDC 47335-930-80 Bottles of 14 with Child Resistant Cap................ NDC 47335-930-21 Bottles of 20 with Child Resistant Cap................NDC 47335-930-87 Unit-dose blister pack of 5 (1 × 5) ...........................NDC 47335-930-74 Unit-dose blister pack of 15 (3 x 5)..........................NDC 47335-930-72 Unit-dose blister pack of 20 (4 × 5) .........................NDC 47335-930-75 250 mg hard gelatin capsules have white opaque caps and bodies, imprinted with band and the dosage strength “250 mg” on body and “893” on cap in black ink, containing white to light tan/light pink powder and are supplied as: Bottles of 5 with Child Resistant Cap......................NDC 47335-893-80 Bottles …