European Commission and US FDA approve intravenous formulation of temozolomide

Schering-Plough Corporation has announced that the European Commission and the US FDA both approved the intravenous (IV) formulation of temozolomide as an alternative to the already approved oral form of the drug.

Temozolomide is marketed as Temodal in the EU and as Temodar in the US. The EU Commission Decision was based on the positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) in November 2008. On January 22, 2009, the Commission approved a sachet packaging presentation for Temodal Capsules. This new presentation provides greater patient convenience and flexibility. On February 17, 2009, the Commission approved an IV formulation of Temodal. On February 27, 2009, Schering-Plough received approval from the US FDA for the Temodar IV formulation.

Temodal is a chemotherapy agent approved in the EU for treatment of patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and subsequently as monotherapy, and for patients with malignant gliomas, such as GBM or anaplastic astrocytoma (AA), showing recurrence or progression after standard therapy. In the US, Temodar is approved for the treatment of adult patients with newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment, as well as for refractory AA, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

"Temodar is a well recognized, effective treatment for patients with newly diagnosed GBM. The newly approved IV formulation of Temodar provides patients with an important alternative method of administration, and the European Temodal sachet presentation offers flexibility and a convenient alternative form of packaging," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "These two new options recognize Schering-Plough's commitment to providing effective treatments in a variety of presentations for specific patient needs and patient convenience."

About Malignant Gliomas

The worldwide incidence rate of primary malignant brain and central nervous system tumors, using the world standard population, is 3.7 per 100,000 person in males and 2.6 per 100,000 person in females(1). The most common type of primary malignant brain tumors are gliomas, with AA and GBM being the most common and among the most serious types.

About temozolomide

In addition to the new presentations, Temodal (temozolomide), a cytotoxic agent, is currently approved in oral form as 5mg, 20mg, 100mg, 140mg, 180mg and 250mg capsules in Europe. Cytotoxic agents are designed to impact the replication of cells that divide rapidly, such as those in tumors.

Temodal was initially approved in the EU in 1999 for the treatment of patients with malignant glioma, such as GBM or AA, showing recurrence or progression after standard therapy. In June 2005, Temodal received marketing approval in the EU for the treatment of patients with newly diagnosed GBM concomitantly with radiotherapy and subsequently as monotherapy treatment. The Temodal IV formulation approved by the EU Commission was developed for cancer patients who are unable to take Temodal Capsules and has shown bioequivalence to the oral product. The sachet packaging presentation for Temodal Capsules was created to provide greater patient convenience and flexibility.

Temodar capsules (temozolomide) received accelerated approval from the US Food and Drug Administration (FDA) for adult patients with refractory AA in 1999 and full approval in March 2005 for refractory AA, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine, and for the treatment of newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment.

Important Information Regarding US Labeling for Temodar and Temodar Intravenous Formulation

Temodar (temozolomide) is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. 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.

Temodar is contraindicated in patients who have a history of hypersensitivity (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis and Stevens-Johnson syndrome) to any of its components, or to DTIC.

Patients treated with Temodar Capsules 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. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have also been observed.

Prophylaxis against Pneumocystis carinii pneumonia 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.

Temodar can cause fetal harm when administered to a pregnant woman. In nursing women, a decision should be made whether to discontinue nursing or to discontinue Temodar, taking into account the importance of the drug to the mother. The safety and effectiveness of Temodar in children have not been established.

As bioequivalence between Temodar Capsules and Temodar for Injection 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.

Temodar Capsules should not be opened or chewed. 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.

Caution should be exercised when administered to those with severe hepatic or renal impairment.

In newly diagnosed patients with glioblastoma multiforme, the adverse event profile was similar in patients <65 years of age and those greater than or equal to 65 years.

In newly diagnosed glioblastoma multiforme the most common adverse reactions in clinical studies in the Concomitant Phase (Radiotherapy + Temodar) and the Maintenance Phase (Temodar alone), respectively, were alopecia 69%, 55%; fatigue 54%, 61%; nausea 36%, 49%; vomiting 20%, 29%; anorexia 19%, 27%; headache 19%, 23%; rash 19%, 13%; constipation 18%, 22%; with the following important adverse events also reported: convulsions 6%, 11% and thrombocytopenia 4%; 8%. Of these adverse events, those grade greater than or equal to 3 in clinical studies in the Concomitant Phase (Radiotherapy + Temodar) and the Maintenance Phase (Temodar alone), respectively, were fatigue 7%, 9%; nausea 1%, 1%; vomiting <1%, 2%; anorexia 1%, 1%; headache 2%, 4%; constipation 1%, 0%; convulsions 3%, 3%; thrombocytopenia 3%, 4%.

In the newly diagnosed GBM population, when laboratory abnormalities and adverse events were combined, Grade 3 or 4 neutropenia occurred in 8% and Grade 3 or 4 platelet abnormalities including thrombocytopenic events occurred in 14% of patients treated with temozolomide.

Most common adverse reactions in the trial in AA patients overall and Grade 3/4, respectively, were: nausea 53%, 10%; vomiting 42%, 6%; headache 41%, 6%; fatigue 34%, 4%; constipation 33%, 1%; convulsions 23%, 5%; with the following important adverse events also reported: hemiparesis 18%, 6%; asthenia 13%, 6%.

Adverse hematologic effects (Grade 3 to 4) in the AA trial in adults were lymphopenia (55%); platelets (19%); neutrophils (14%); WBC (11%); and hemoglobin (4%).

7% and 9.5% 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% and 5.5% experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively.

Adverse reactions reported from intravenous formulation studies that were not reported in Temodar capsule studies were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma.

Full prescribing information for Temodar can be found at http://www.spfiles.com/piTemodar.pdf