Pharmaceutical Approval Update

ErlotinibErlotinib (Tarceva)

Manufacturer: Genentech, Inc./OSI Pharmaceuticals, Inc.

Indication: Erlotinib (Tarceva), in combination with gemcitabine (Gemzar, Eli Lilly), is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Drug Class: Erlotinib is a human epidermal growth factor receptor type-1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Its chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazo-linamine.

Uniqueness of Drug: Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Its specificity of inhibition of other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surfaces of normal cells and cancer cells.

Pulmonary Toxicity. There have been infrequent reports of serious interstitial lung disease (ILD)-like events, including fatalities, in patients receiving erlotinib for the treatment of NSCLC, pancreatic cancer, or other advanced solid tumors. In the pancreatic cancer study, the incidence of these events was 2.5% with erlotinib/gemcitabine and 0.4% with placebo/gem-citabine.

Reported diagnoses in patients thought to have ILD-like events included pneumonitis, radiation and hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, and lung infiltration. Symptoms began from five days to more than nine months (median, 39 days) after erlotinib therapy was initiated.

Myocardial Infarction and Ischemia. In the pancreatic carcinoma trial, myocardial infarction (MI)/ischemia developed in six patients receiving erlotinib/gemcitabine (with an incidence of 2.3%). One of these patients died because of an MI. In comparison, three patients receiving placebo/gemcitabine developed MIs (incidence, 1.2%); MI was the cause of death in one of these patients. canada drugs pharmacy

Cerebrovascular Accident. In the same trial, six patients who were given erlotinib/gemcitabine experienced cere-brovascular accidents (CVAs) (incidence, 2.3%). One of the CVAs was hemorrhagic, and this was the only fatal event. In comparison, the placebo/gemcitabine patients had no CVAs.

Microangiopathic Hemolytic Anemia with Thrombo-cytopenia. In the trial, two patients receiving erlotinib and gemcitabine concurrently developed microangiopathic hemolytic anemia with thrombocytopenia (incidence, 0.8%). This event did not occur with any patients in the placebo/gem-citabine arm.

Pregnancy Category D. Erlotinib has been shown to cause maternal toxicity with associated embryo and fetal lethality and abortion in rabbits when it was given at doses that result in plasma drug concentrations of approximately three times those in humans (i.e., an area-under-the-curve [AUC] concentration at a 150-mg daily dose).

Precautions: Co-treatment with the potent cyto-chrome CYP3A4 inhibitor ketoconazole increases the AUC of erlotinib by two thirds. Caution should be used when administering erlotinib with ketocona-zole and other strong CYP3A4 inhibitors. Asymptomatic increases in liver transaminase levels have been observed with erlotinib; therefore, periodic liver function testing of transaminase, bilirubin, and alkaline phosphatase levels should be considered. viagra soft

The erlotinib dose should be reduced or therapy interrupted if changes in liver function are severe. In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. Therefore, erlotinib exposure may be increased in patients with hepatic dysfunction.

Dosage and Administration: The recommended daily dose of erlotinib is 100 mg, taken at least one hour before or two hours after the ingestion of food, in combination with gemcitabine. Treatment should continue until disease progression or unacceptable toxicity occurs.

Commentary: Pancreatic cancer is the fourth leading cause of cancer deaths in the U.S. Erlotinib’s new use focuses on pancreatic cancer patients who have not undergone chemotherapy and whose disease is locally advanced or has spread to other parts of the body.

Erlotinib was originally used to treat non-small cell lung cancer. The Food and Drug Administration (FDA) approved erlotinib for pancreatic cancer based on a phase 3 clinical trial of 569 patients. In a blinded study, 50% of the patients took erlotinib and gemcitabine; the others took gemcitabine and placebo. A year later, 24% of the erlotinib group was still alive, compared with 19% of those who did not take erlotinib.

Pancreatic cancer is a major health problem because there are no effective ways to treat it. It is difficult to diagnose at an early stage, when it is most treatable, and this cancer can be aggressive. Because of the lack of effective systemic therapies, only 1% to 4% of patients are living five years after diagnosis.
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Radiation therapy is commonly used as adjuvant therapy with surgery and may improve survival in some patients. 5-Fluorouracil (5-FU) is the mainstay of chemotherapy for pancreatic cancer, and it is frequently used as a radiation enhancer. When used as a single agent in the treatment of pancreatic cancer, 5-FU can be given in a variety of schedules. Responses last between three and six months.

Gemcitabine represents an important advance in the treatment of pancreatic cancer. It was the first chemotherapy agent approved on the basis of clinical response instead of the traditional increase in survival time. The combination of erlot-inib and gemcitabine represents an advance in treatment, although research is urgently needed to find agents to improve the quality and length of life.

Category: Drugs

Tags: Erlotinib, Nelarabine, Xyrem

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