Jane S. Ricciuti, RPh, MS


June 12, 2003


The US Food and Drug Administration (FDA) approved Velcade (bortezomib) Injection, a novel antineoplastic agent. Bortezomib has a unique mechanism of action that targets cancer cell homeostasis mechanisms leading to cell death.

This month's column reviews FDA new product approvals and labeling changes for:

Antineoplastic Agents

  • Gleevec (imatinib mesylate) Tablets

  • Iressa (gefitinib) Tablets

  • Velcade (bortezomib) Injection

(imatinib mesylate) Tablets

Manufacturer: Novartis Pharmaceuticals Corporation

Drug Approval Classification: Supplemental New Drug Application (Approval Date: 05/20/03)

New Indication: Gleevec (imatinib mesylate) is now indicated for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Gleevec is indicated for children whose disease has recurred after stem-cell transplant or who are resistant to interferon-alpha therapy.

Gleevec was previously indicated for:

  • The treatment of patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy

  • For the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) CML

  • For first-line treatment of patients with CML

Dosing: In the treatment of children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon alpha therapy, the recommended daily dose is 260 mg/m2/day. Treatment may be given once daily or as twice-daily dosing.

There is no experience with Gleevec treatment in children younger than 3 years of age.

Clinical Summary: This pediatric indication was approved on the basis of extrapolation of data from adult patients with CML and positive responses in a small number of children.

As a condition of approval, Novartis will conduct pediatric studies to assess the safety and efficacy of Gleevec in pediatric patients.


Gleevec (imatinib mesylate) Tablets Labeling

Medscape DrugInfo

Gleevec (imatinib mesylate) Tablets

(gefitinib) Tablets

Manufacturer: AstraZeneca

Drug Approval Classification: Original New Drug Application (Approval Date: 5/5/03)

Indication: Iressa (gefitinib) is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies.

Results from 2 large, controlled, randomized trials in first-line treatment of NSCLC showed no benefit from adding gefitinib to platinum-based chemotherapy. Therefore, gefitinib is not indicated for use in this setting.

Dosing: Gefitinib is dosed 250 mg daily with or without food.

Clinical Summary: Gefitinib is the first FDA-approved epidermal growth factor receptor (EGFR) inhibitor. EGFR is expressed on the cell surface of many normal cells and cancer cells.

A single multicenter clinical trial in 216 patients with advanced NSCLC evaluated the tumor response rate of gefitinib 250 and 500 mg/day. Patients on study had progressed after at least 2 prior chemotherapy regimens, including a platinum drug and docetaxel.

The efficacy of gefitinib as third-line therapy was determined in the patients with documented disease progression on platinum and docetaxel therapies or who had had unacceptable toxicity on these agents.

The overall response rate for the 250- and 500-mg doses combined was 10.6% (95% CI = 6%, 16.8%).

As a condition of approval, AstraZeneca will conduct postmarketing studies of gefitinib to further demonstrate efficacy in NSCLC.

Adverse Effects: The most frequent adverse events reported were diarrhea, rash, acne, dry skin, nausea, and vomiting.

Interstitial lung disease (ILD) has been observed in patients receiving gefitinib at an overall incidence of about 1%. The incidence of ILD was about 2% in the Japanese postmarketing experience, about 0.3% in approximately 23,000 patients treated with gefitinib in a US expanded access program, and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups).

Pharmacokinetics: Gefitinib has a mean bioavailability of 60% and is metabolized primarily via CYP3A4. The half-life of gefitinib is 48 hours.


Iressa (gefitinib) Tablets Labeling

(bortezomib) Injection

Manufacturer: Millennium Pharmaceuticals, Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 02/03/02)

Indication: Velcade (bortezomib) is indicated for the treatment of multiple myeloma patients who have received at least 2 prior therapies and have demonstrated disease progression on the last therapy.

Dosing: The recommended dose of bortezomib is 1.3 mg/m2/dose administered as a bolus intravenous injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10- day rest period (days 12-21). This 3-week period is considered as 1 treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.

Clinical Summary: Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. Inhibition of the 26S proteasome prevents targeted proteolysis that can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.

The safety and efficacy of bortezomib are based on a study of 202 patients who had received at least 2 prior therapies and demonstrated disease progression on their most recent therapy. Altogether, out of 188 patients evaluated for response, 28% showed a response to bortezomib. The response lasted for a median of 1 year. Another trial in 54 patients with relapsed multiple myeloma showed similar responses.

There are currently no controlled trials of bortezomib demonstrating clinical benefit, such as improvement in survival.

As a condition of approval, Millennium Pharmaceuticals will perform additional studies to demonstrate an effect in patients with multiple myeloma.

Adverse Effects: The following precautions are advised in the product labeling:

  • Since bortezomib may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension, diplopia, or blurred vision, patients should be cautious when operating machinery, including automobiles.

  • Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breast-feeding during treatment.

  • Since patients receiving bortezomib therapy may experience vomiting and/or diarrhea, patients should be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness, or fainting spells.

  • Patients should be cautioned about the use of concomitant medications that may be associated with peripheral neuropathy (such as amiodarone, antivirals, isoniazid, nitrofurantoin, or statins), or with a decrease in blood pressure.

  • Peripheral Neuropathy: Patients should be instructed to contact their physician if they experience new or worsening symptoms of peripheral neuropathy.

The most commonly reported adverse events were:

Asthenic conditions
(including fatigue, malaise, and weakness)
Nausea 64%
Diarrhea 51%
Decreased appetite (including anorexia) 43%
Constipation 43%
Thrombocytopenia 43%
Peripheral neuropathy
(including peripheral sensory neuropathy and peripheral neuropathy aggravated)
Pyrexia 36%
Vomiting 36%
Anemia 32%

Pharmacokinetics: Bortezomib's mean elimination half-life after first dose (1.45-2.0 mg/m2) ranges from 9 to 15 hours. Bortezomib pharmacokinetics has not been fully characterized. It is believed that bortezomib is primarily oxidatively metabolized via the cytochrome P-450 enzymes 3A4, 2D6, 2C19, 2C9, and 1A2.


Velcade (bortezomib) Labeling


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