NDC 0085-1417 Temodar

Temozolomide

NDC Product Code 0085-1417

NDC CODE: 0085-1417

Proprietary Name: Temodar What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Temozolomide What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat certain types of brain cancer. Temozolomide belongs to a class of drugs known as alkylating agents. It works by slowing or stopping the growth of cancer cells.

Product Characteristics

Color(s):
GREEN (C48329)
WHITE (C48325)
YELLOW (C48330)
PINK (C48328)
BLUE (C48333)
ORANGE (C48331)
Shape: CAPSULE (C48336)
Size(s):
16 MM
17 MM
19 MM
20 MM
21 MM
Imprint(s):
TEMODAR;5;MG
TEMODAR;20;MG
TEMODAR;100;MG
TEMODAR;140;MG
TEMODAR;180;MG
TEMODAR;250;MG
Score: 1

NDC Code Structure

  • 0085 - Merck Sharp & Dohme Corp.

NDC 0085-1417-02

Package Description: 5 PACKET in 1 CARTON > 1 CAPSULE in 1 PACKET (0085-1417-03)

NDC Product Information

Temodar with NDC 0085-1417 is a a human prescription drug product labeled by Merck Sharp & Dohme Corp.. The generic name of Temodar is temozolomide. The product's dosage form is capsule and is administered via oral form.

Labeler Name: Merck Sharp & Dohme Corp.

Dosage Form: Capsule - A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealed enclosure, or two halves that fit together and which are sometimes sealed with a band. Capsule shells may be made from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and are filled with solid or liquid ingredients that can be poured or squeezed.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Temodar Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TEMOZOLOMIDE 250 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TARTARIC ACID (UNII: W4888I119H)
  • STEARIC ACID (UNII: 4ELV7Z65AP)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • WATER (UNII: 059QF0KO0R)
  • AMMONIA (UNII: 5138Q19F1X)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TARTARIC ACID (UNII: W4888I119H)
  • STEARIC ACID (UNII: 4ELV7Z65AP)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • WATER (UNII: 059QF0KO0R)
  • AMMONIA (UNII: 5138Q19F1X)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TARTARIC ACID (UNII: W4888I119H)
  • STEARIC ACID (UNII: 4ELV7Z65AP)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • WATER (UNII: 059QF0KO0R)
  • AMMONIA (UNII: 5138Q19F1X)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TARTARIC ACID (UNII: W4888I119H)
  • STEARIC ACID (UNII: 4ELV7Z65AP)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • WATER (UNII: 059QF0KO0R)
  • AMMONIA (UNII: 5138Q19F1X)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TARTARIC ACID (UNII: W4888I119H)
  • STEARIC ACID (UNII: 4ELV7Z65AP)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • WATER (UNII: 059QF0KO0R)
  • AMMONIA (UNII: 5138Q19F1X)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TARTARIC ACID (UNII: W4888I119H)
  • STEARIC ACID (UNII: 4ELV7Z65AP)
  • SHELLAC (UNII: 46N107B71O)
  • ALCOHOL (UNII: 3K9958V90M)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • WATER (UNII: 059QF0KO0R)
  • AMMONIA (UNII: 5138Q19F1X)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Alkylating Activity - [MoA] (Mechanism of Action)
  • Alkylating Drug - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Merck Sharp & Dohme Corp.
Labeler Code: 0085
FDA Application Number: NDA021029 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-11-1999 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Temozolomide

Temozolomide is pronounced as (te moe zoe' loe mide)

Why is temozolomide medication prescribed?
Temozolomide is used to treat certain types of brain tumors. Temozolomide is in a class of medications called alkylating agents. It works by slowing or stopping the growt...
[Read More]

* Please review the disclaimer below.

Temodar Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Newly Diagnosed Glioblastoma Multiforme

TEMODAR® (temozolomide) is 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

TEMODAR is 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.

The recommended dose for TEMODAR as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when TEMODAR for Injection was given over 90 minutes [see Clinical Pharmacology (12.3)]. Dosage of TEMODAR 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 TEMODAR dosage calculations based on body surface area (BSA) see Table 5. For suggested capsule combinations on a daily dose see Table 6.

3 Dosage Forms And Strengths

  • TEMODAR (temozolomide) Capsules for oral administration –5-mg capsules have opaque white bodies with green caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "TEMODAR." –20-mg capsules have opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "TEMODAR." –100-mg capsules have opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "TEMODAR."–140-mg capsules have opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "TEMODAR."–180-mg capsules have opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "TEMODAR."–250-mg capsules have opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with "TEMODAR."TEMODAR (temozolomide) is available as 100-mg/vial powder for injection. The lyophilized powder is white to light tan/light pink.

4.1 Hypersensitivity

TEMODAR (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. TEMODAR 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).

5.1 Myelosuppression

Patients treated with TEMODAR 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 × 109/L and a platelet count greater than or equal to 100 × 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 × 109/L and platelet count exceeds 100 × 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 TEMODAR 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 × 109/L and the platelet count falls below 100 × 109/L [see Dosage and Administration (2.1)].

5.5 Hepatotoxicity

Fatal and severe hepatotoxicity have been reported in patients receiving TEMODAR. 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 TEMODAR.

5.6 Use In Pregnancy

TEMODAR can cause fetal harm when administered to a pregnant woman. Administration of TEMODAR 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)].

5.7 Infusion Time

As bioequivalence has been established only when TEMODAR for Injection was given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing. Additionally, the possibility of an increase in infusion-related adverse reactions cannot be ruled out.

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of TEMODAR. 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 syndromeImmune system disorders: Allergic reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMODAR 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

7.1 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)].

Teratogenic Effects

Pregnancy Category D. See Warnings and Precautions section.TEMODAR 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 TEMODAR.

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 TEMODAR to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. TEMODAR Capsules have been studied in 2 open-label studies in pediatric patients (aged 3–18 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 TEMODAR 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 TEMODAR Patients (N=122)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.Body System/Organ ClassAll ReactionsGrade 3/4         Adverse ReactionSubjects Reporting an AE107 (88)69 (57)Body as a WholeCentral and Peripheral Nervous SystemCentral cerebral CNS cortex22 (18)13 (11)Gastrointestinal SystemNausea56 (46)5 (4)Vomiting62 (51)4 (3)Platelet, Bleeding and ClottingThrombocytopenia71 (58)31 (25)Red Blood Cell DisordersDecreased Hemoglobin62 (51)7 (6)White Cell and RES DisordersDecreased WBC71 (58)21 (17)Lymphopenia73 (60)48 (39)Neutropenia62 (51)24 (20)

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 TEMODAR is administered to patients with severe renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

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

10 Overdosage

Doses of 500, 750, 1000, and 1250 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 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 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

TEMODAR contains temozolomide, an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula is: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 TEMODAR can be administered orally and intravenously. 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.

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.

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 (25–125 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.

14.1 Newly Diagnosed Glioblastoma Multiforme

Five hundred and seventy-three patients were randomized to receive either TEMODAR (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the TEMODAR+RT arm received concomitant TEMODAR (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 TEMODAR 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, TEMODAR 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 TEMODAR+RT arm.The addition of concomitant and maintenance TEMODAR 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=0.52-0.75) with a log-rank P<0.0001 in favor of the TEMODAR arm. The median survival was increased by 2.5 months in the TEMODAR arm. FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population)

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 (19–76). 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 (4.2–75.4).TEMODAR 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 × 109/L (1500/µL) and the nadir and Day 29, Day 1 of next cycle platelet count was greater than or equal to 100 × 109/L (100,000/µL), the TEMODAR 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: 16–114 weeks) and the median duration of complete responses was 64 weeks (range: 52–114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31%–58%) and progression-free survival at 12 months was 29% (95% CI: 16%–42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62%–86%) and 12-month overall survival was 65% (95% CI: 52%–78%). Median overall survival was 15.9 months.

15 References

  • OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172–1193.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]Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology.

16.1 Safe Handling And Disposal

Care should be exercised in the handling and preparation of TEMODAR. Vials and capsules should not be opened. If vials or 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 vial or capsules. Procedures for proper handling and disposal of anticancer drugs should be considered {1–4}. Several guidelines on this subject have been published.

16.3 Storage

Store TEMODAR Capsules at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].Store TEMODAR for Injection refrigerated at 2–8°C (36–46°F). After reconstitution, store reconstituted product at room temperature (25°C [77°F]). Reconstituted product must be used within 14 hours, including infusion time.

17 Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Patient Information).Physicians should discuss the following with their patients:Nausea and vomiting are the most frequently occurring adverse reactions. Nausea and vomiting are usually either self-limiting or readily controlled with standard antiemetic therapy. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes. The medication should be kept away from children and pets.

Spl Patient Package Insert

  • Patient InformationTEMODAR® (tĕm-ō-dăr)(temozolomide)CapsulesTEMODAR® (tĕm-ō-dăr)(temozolomide)for InjectionWhat is the most important information I should know about TEMODAR?TEMODAR may cause birth defects. Male and female patients who take TEMODAR should use effective birth control. Female patients and female partners of male patients should avoid becoming pregnant while taking TEMODAR.See the section "What are the possible side effects of TEMODAR?" for more information about side effects.What is TEMODAR?TEMODAR (temozolomide) is a prescription medicine used to treat adults with certain brain cancer tumors. TEMODAR blocks cell growth, especially cells that grow fast, such as cancer cells. TEMODAR may decrease the size of certain brain tumors in some patients.It is not known if TEMODAR is safe and effective in children.Who should not take TEMODAR?Do not take TEMODAR if you:have had an allergic reaction to dacarbazine (DTIC), another cancer medicine.have had a red itchy rash, or a severe allergic reaction, such as trouble breathing, swelling of the face, throat, or tongue, or severe skin reaction to TEMODAR or any of the ingredients in TEMODAR. If you are not sure, ask your doctor. See the end of the leaflet for a list of ingredients in TEMODAR.What should I tell my doctor before taking TEMODAR?Tell your doctor about all your medical conditions, including if you:are allergic to dacarbazine (DTIC) or have had a severe allergic reaction to TEMODAR. See "Who should not take TEMODAR?"have kidney problemshave liver problemsare pregnant. See "What is the most important information I should know about TEMODAR?"are breast-feeding. It is not known whether TEMODAR passes into breast milk. You and your doctor should decide if you will breast-feed or take TEMODAR. You should not do both without talking with your doctor.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 TEMODAR?TEMODAR may be taken by mouth as a capsule at home, or you may receive TEMODAR by injection into a vein (intravenous). Your doctor will decide the best way for you to take TEMODAR.There are two common dosing schedules for taking TEMODAR.Some people take TEMODAR for 42 days in a row (possibly 49 days depending on side effects) with radiation treatment. This is one cycle of treatment. After this, you may have "maintenance" treatment. Your doctor may prescribe 6 more cycles of TEMODAR. For each of these cycles, you take TEMODAR one time each day for 5 days in a row and then you stop taking it for the next 23 days. This is a 28-day maintenance treatment cycle.Another way to take TEMODAR is to take it one time each day for 5 days in a row only, and then you stop taking it for the next 23 days. This is one cycle of treatment (28 days). Your doctor will watch your progress on TEMODAR and decide how long you should take it. You might take TEMODAR until your tumor gets worse or for possibly up to 2 years. Your dose is based on your height and weight, and the number of treatment cycles will depend on how you respond to and tolerate this treatment.Your doctor may modify your schedule based on how you tolerate the treatment.If your doctor prescribes a treatment regimen that is different from the information in this leaflet, make sure you follow the specific instructions given to you by your doctor.TEMODAR Capsules:Take TEMODAR Capsules exactly as prescribed.TEMODAR Capsules come in different strengths. Each strength has a different color cap. Your doctor may prescribe more than one strength of TEMODAR Capsules for you, so it is important that you understand how to take your medicine the right way. Be sure that you understand exactly how many capsules you need to take on each day of your treatment, and what strengths to take. This may be different whenever you start a new cycle.Talk to your doctor before you take your dose if you are not sure how much to take. This will help to prevent taking too much TEMODAR and decrease your chances of getting serious side effects.Take each day's dose of TEMODAR Capsules at one time, with a full glass of water.Swallow TEMODAR Capsules whole. Do not chew, open, or split the capsules.If TEMODAR Capsules are accidentally opened or damaged, be careful not to breathe in (inhale) the powder from the capsules or get the powder on your skin or mucous membranes (for example, in your nose or mouth). If contact with any of these areas happens, flush the area with water.If you vomit TEMODAR Capsules, do not take any more capsules. Wait and take your next planned dose.The medicine is used best by your body if you take it at the same time every day in relation to a meal.To lessen nausea, try to take TEMODAR on an empty stomach or at bedtime. Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to lessen side effects with TEMODAR.See your doctor regularly to check your progress. Your doctor will check you for side effects that you might not notice.If you miss a dose of TEMODAR, talk with your doctor for instructions about when to take your next dose of TEMODAR.Call your doctor right away if you take more than the prescribed amount of TEMODAR. It is important that you do not take more than the amount of TEMODAR prescribed for you.TEMODAR for Injection:You will receive TEMODAR as an infusion directly into your vein. Your treatment will take about 90 minutes.Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to relieve side effects with TEMODAR.What should I avoid while taking TEMODAR?Female patients and female partners of male patients should avoid becoming pregnant while taking TEMODAR. See "What is the most important information I should know about TEMODAR?"What are the possible side effects of TEMODAR?TEMODAR can cause serious side effects.See "What is the most important information I should know about TEMODAR?"Decreased blood cells. TEMODAR affects cells that grow rapidly, including bone marrow cells. This can cause you to have a decrease in blood cells. Your doctor can monitor your blood for these effects. –White blood cells are needed to fight infections. Neutrophils are a type of white blood cell that help prevent bacterial infections. Decreased neutrophils can lead to serious infections that can lead to death. Other white blood cells called lymphocytes may also be decreased.–Platelets are blood cells needed for normal blood clotting. Low platelet counts can lead to bleeding. Tell your doctor about any unusual bruising or bleeding.Your doctor will check your blood regularly while you are taking TEMODAR to see if these side effects are happening. Your doctor may need to change the dose of TEMODAR 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.Pneumocystis pneumonia (PCP). PCP is an infection that people can get when their immune system is weak. TEMODAR decreases white blood cells, which makes your immune system weaker and can increase your risk of getting PCP. All patients taking TEMODAR will be watched carefully by their doctor for this infection, especially patients who take steroids. Tell your doctor if you have any of the following signs and symptoms of PCP infection: shortness of breath and/or fever, chills, dry cough.Secondary cancers. Blood problems such as myelodysplastic syndrome and secondary cancers, such as a certain kind of leukemia, can happen in people who take TEMODAR. Your doctor will watch you for this.Convulsions. Convulsions may be severe or life-threatening in people who take TEMODAR.Liver side effects have been reported, which very rarely included death.Common side effects with TEMODAR include:nausea and vomiting. Your doctor can prescribe medicines that may help reduce these symptoms.headache feeling tired loss of appetitehair lossconstipationbruisingrashparalysis on one side of the bodydiarrheaweaknessfeverdizziness coordination problemsviral infectionsleep problems memory losspain, irritation, itching, warmth, swelling or redness at the site of infusionbruising or small red or purple spots under the skinTell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects with TEMODAR. 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 TEMODAR Capsules?Store TEMODAR Capsules at 77°F (controlled room temperature). Storage at 59°F to 86°F (15°C to 30°C) is permitted occasionally.Keep TEMODAR Capsules out of the reach of children and pets.General information about TEMODAR.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use TEMODAR for a condition for which it was not prescribed. Do not give TEMODAR 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 TEMODAR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about TEMODAR that is written for health professionals.For more information, go to www.TEMODAR.com or call 1-877-888-4231.How are TEMODAR Capsules supplied?TEMODAR 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.TEMODAR Capsule StrengthColor      5 mgGreen Cap     20 mgYellow Cap     100 mgPink Cap     140 mgBlue Cap     180 mgOrange Cap     250 mgWhite CapWhat are the ingredients in TEMODAR?TEMODAR Capsules:Active ingredient: temozolomide.Inactive ingredients: lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, stearic acid.The body of the capsules is made of gelatin and is 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 shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia, potassium hydroxide, and ferric oxide.TEMODAR 5 mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow, sodium lauryl sulfate, and FD&C Blue #2.TEMODAR 20 mg: The yellow cap contains gelatin, sodium lauryl sulfate, and iron oxide yellow.TEMODAR 100 mg: The pink cap contains gelatin, titanium dioxide, sodium lauryl sulfate, and iron oxide red.TEMODAR 140 mg: The blue cap contains gelatin, sodium lauryl sulfate, and FD&C Blue #2.TEMODAR 180 mg: The orange cap contains gelatin, iron oxide red, iron oxide yellow, titanium dioxide, and sodium lauryl sulfate.TEMODAR 250 mg: The white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate.TEMODAR for Injection:Active ingredient: temozolomide.Inactive ingredients: mannitol, L-threonine, polysorbate 80, sodium citrate dihydrate, and hydrochloric acid.

Other

Distributed by: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC., Whitehouse Station, NJ 08889, USAFor patent information: www.merck.com/product/patent/home.htmlThe trademarks depicted herein are owned by their respective companies.Copyright © 1999, 2008 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved.Revised: 12/2015usppi-mk7365-mtl-1512r010

Distributed by: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC., Whitehouse Station, NJ 08889, USAFor patent information: www.merck.com/product/patent/home.htmlCopyright © 2008 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved.Revised: 05/2014usphi-mk7365-pwi-1405r014

TEMODAR® (temozolomide) CapsulesPHARMACIST:Dispense enclosed Patient Package Insert to each patient.PHARMACIST INFORMATION SHEET

Distributed by: Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC., Whitehouse Station, NJ 08889, USAFor patent information: www.merck.com/product/patent/home.htmlCopyright © 2005 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved.Revised: 10/2014usphi-mk7365-cp-1410r011

Boxed Warning

IMPORTANT DISPENSING INFORMATIONFor every patient, TEMODAR must be dispensed in a separate vial or in its original package making sure each container lists the strength per capsule and that patients take the appropriate number of capsules from each package or vial.Please see the dispensing instructions below for more information.

* Please review the disclaimer below.