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Erlotinib

 
AnswerNote: Erlotinib
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Erlotinib is a new drug that is used to treat non-small cell lung cancer and pancreatic cancer. It is also being studied for use in other cancers, including breast cancer.

Approved by the FDA in November 2004, Erlotinib is one of a new group of drugs that target tiny flaws in the cell's communication system. Many cells have receptors on their surfaces for epidermal growth factor (EGF), which is a protein produced by the body that induces growth and multiplication of cells. This protein causes an enzyme called tyrosine kinase to become active within the cells. Erlotinib blocks the cancer cell from getting the message that tells the cell to grow and divide, and the cells stop growing. Doctors have begun to prescribe Erlotinib — in combination with gemcitabine, a standard chemothrapy — for patients with metastatic or locally advanced non-small cell lung cancer who have failed at least one previous round of chemotherapy, and for patients with pancreatic cancer.

A prescription drug, Erlotinib comes in pill form and is taken orally with water at least an hour or two before eating.

Last updated: February 01, 2007.

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Oncology Encyclopedia: Erlotinib
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Key Terms: Cornea.

Definition

Erlotinib is a biological therapy used to interrupt cell division and slow the growth of tumors.

Purpose

Erlotinib is used to treat advanced non-small cell lung cancer (NSCLC), an aggressive type of lung cancer. NSCLC the most common type of lung cancer. It is most often caused by exposure to tobacco smoke. The World Health Organization (WHO) estimates that NSCLC is responsible for about 880,000 deaths each year. Lung cancer is the leading cause of cancer deaths in the United States. The American Cancer Society estimates that lung cancer is responsible for 28% of cancer deaths or the deaths of more than 160,000 individuals annually. Erlotinib is not a first-line treatment for NSCLC, and is used only after the cancer has failed to respond or stopped responding to at least one round of chemotherapy.

Description

Erlotinib is a man-made treatment that combines natural human and animal substances to target specific cells in the body. It sold in the United States under the brand name Tarceva or OSI 744 and is produced jointly by OSI Pharmaceuticals and Genentech. Erlotinib was approved for use by the United States Food and Drug Administration (FDA) in November 2004. Generic substitutes are not available.

Erlotinib works by interrupting the complex chemical pathway that stimulates cells to grow and multiply. Cancer cells grow and divide with abnormal rapidity. One strategy to slow cancer is to interrupt the information pathway that causes this wild growth. Erlotinib works in this way.

The body produces substances called growth factors that tell cells when it is time to divide and spread. Many cells, including cancer cells, have receptors on their surfaces for a growth factor called epidermal growth factor (EGF). Normally when EGF locks on to an epidermal growth factor receptor on the surface of a cell, it stimulates the production of the enzyme tyrosine kinase. Tyrosine kinase is a key chemical in telling the cell to begin growing and dividing. In the healthy body, EGF plays a role in wound healing and tissue maintenance and repair. Cancer cells are especially sensitive to EGF and appear to over-respond and grow excessively when stimulated by this growth factor.

Erlotinib does not block the production of EGF. Instead, it binds to the EGF receptors on the surface of both normal and malignant cells. Because EGF can no longer attach to the receptors, the cells are not stimulated to produce tyrosine kinase and cell growth is slowed or stopped. Erlotinib does not cure cancer, but it has been shown to prolong survival times.

As of 2005, erlotinib was being tested in more than three dozen clinical trials in combination with other drugs to treat many other types of metastic cancer including brain tumors, head and neck tumors, esophageal cancer, inoperable kidney and corectal, and solid tumors in children and adults. Information on current clinical trials that are enrolling patients can be found at .

Recommended Dosage

Erlotinib comes in 25 mg, 100 mg, and 150 mg tablets that are taken once daily for as long as the cancer responds to treatment. Tablets must be taken with a large glass of water at least one hour before or two hours after a meal. The standard dose is 150 mg, although this dose may be adjusted based on the individual's health, other drugs being administered, and the development of side effects.

Precautions

Erlotinib may cause birth defects in a developing fetus. It should not be used by women who are pregnant, breastfeeding, or trying to become pregnant. Both men and women who are sexually active should use contraception while taking erlotinib.

Erlotinib is broken down and deactivated in the liver. Individuals with liver disease should discuss the use of erlotinib with their physician.

Side Effects

The most serious side effect reported from use of erlotinib is the development of potentially fatal interstitial lung disease (ILD). Other rare but serious side effects include inflammation or abscess of the cornea of the eye and bleeding from the digestive system.

More common but less serious side effects include, but are not limited to:

  • rash on the face and upper body
  • loss of appetitive, nausea, vomiting, and diarrhea
  • fatigue
  • headache
  • sore mouth
  • cough and shortness of breath
  • abnormal liver function tests

Interactions

Although formal drug interaction studies have not been completed, a number of drugs are suspected of interacting with erlotinib. Too much erlotinib may cause a toxic reaction. Individuals taking certain drugs may need to take a reduced dose of erlotinib. The following drugs may increase the amount of erlotinib circulating in the body:

Too little erlotinib in the body may result in failure to slow cell growth. The following drugs may decrease the effects of erlotinib. Individuals taking these drugs may need to take an increased dose of erlotinib.

  • carbamazepin (Tegretol)
  • phenobarbitol
  • phenytoin (Dilantin)
  • rifampicin (Rifadin)
  • rifabutin (Mycobutin)
  • rifapentine (Priftin)
  • St John's Wort (herbal remedy)

In addition, grapefruit juice may interact with erlotinib and should be avoided while taking erlotinib.

—Tish Davidson, A. M.

Drug Info: Erlotinib
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Brand names: Tarceva™

Chemical formula:



Erlotinib Oral tablet

What is this medicine?

ERLOTINIB (er LOE ti nib) is a chemotherapy drug. It targets a specific protein within cancer cells and stops the cancer cells from growing. This medicine is used to treat cancers including non-small cell lung cancer and pancreatic cancer.
 
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•liver disease
•lung fibrosis
•previous or ongoing radiation therapy
•an unusual or allergic reaction to erlotinib, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

Take erlotinib tablets by mouth. Follow the directions on the prescription label. Take this medicine on an empty stomach, at least 1 hour before or 2 hours after food. Do not take with food. Taking this drug with food may increase your chance of developing side effects. Do not take your medicine more often than directed.

Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What if I miss a dose?

If you miss a dose, use it as soon as you can. If it is almost time for your next dose, use only that dose. Do not use double or extra doses.

What may interact with this medicine?

Do not take this medicine with any of the following medications:
•cigarette smoking

This medicine may also interact with the following medications:
•amiodarone
•carbamazepine
•ciprofloxacin
•antiviral medicines for HIV or AIDS
•bosentan
•certain medicines for blood pressure
•clarithromycin
•erythromycin
•grapefruit juice
•medicines for depression
•medicines for fungal infections like fluconazole, itraconazole, ketoconazole, or voriconazole
•non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen or naproxen)
•omeprazole
•phenobarbital
•phenytoin
•rifabutin
•rifampin
•rifapentine
•St. John's wort
•warfarin

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

Visit your doctor for regular check ups. Report any side effects. Continue your course of treatment unless your doctor tells you to stop. You will need blood work done while you are taking this medicine.

If you experience any of the following, contact your health care provider: eye irritation; severe or continuing diarrhea, nausea, decreased appetite, or vomiting; or if your breathing gets worse or you develop shortness of breath or cough.

If you smoke cigarettes, you should stop smoking. The effectiveness of this drug is reduced by cigarette smoking. If you stop smoking during treatment, be sure to inform your doctor of this change.

Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information. Do not breast-feed an infant while taking this medicine.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•eye irritation
•eye pain
•fever
•mouth sores
•problems related to breathing including shortness of breath or cough
•severe or persistent diarrhea, nausea, vomiting, or loss of appetite
•unusual bleeding or bruising

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•acne
•diarrhea
•dry skin
•itching
•loss of appetite
•nausea
•weak or tired
•weight loss

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

Keep out of the reach of children.

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medicine after the expiration date.

Last updated: 3/20/2006 2:38:00 PM

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

Wikipedia: Erlotinib
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Erlotinib
Systematic (IUPAC) name
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
quinazolin-4-amine
Identifiers
CAS number 183321-74-6
ATC code L01XE03
PubChem 176870
DrugBank APRD00951
ChemSpider 154044
Chemical data
Formula C22H23N3O4 
Mol. mass 393.436 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Licence data

EU EMEA:link, US FDA:link
Pregnancy cat.

D(US)
Legal status

POM(UK) ℞-only(US)
Routes Oral
 Yes check.svgY(what is this?)  (verify)

Erlotinib hydrochloride (originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche under the tradename Tarceva.

Contents

Overview

Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.[1] For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change in their intracellular structure, exposing a further binding site for binding proteins that cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped.

Erlotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. It has been approved for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen. In November 2005, the U.S. Food and Drug Administration (FDA) approved the use of erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.[2]

A test for the EGFR mutation in cancer patients has been developed by Genzyme. This may predict who will respond to erlotinib and other tyrosine kinase inhibitors. It is reported that responses among patients with lung cancer are seen most often in females who were never smokers, particularly Asian women and those with adenocarcinoma cell type[citation needed].

Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.[3]

The drug's US patent will expire in 2020. [4]. In India, generic pharmaceutical firm Cipla is battling with Roche against the Indian patent for this drug. In April 2009, the Delhi High Court granted a final approval to Cipla to manufacture and sell its generic version of Erlotinib in India. [5] Meanwhile, another generic pharmaceutical firm - Natco is also seeking to manufacture the generic version of Erlotinib in India BUT sell it to patients in Nepal using the TRIPS Agreements' Doha Declaration. [6] [7]

Administration

Oral tablets

Side effects

Common side effects include:

  • Rash occurs in the majority of patients. This resembles acne and primarily involves the face and neck. It is self-limited and resolves in the majority of cases, even with continued use. Interestingly, some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed.[8] The Journal of Clinical Oncology reported in 2004 that "cutaneous [skin] rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies."[9] The newsletter Lung Cancer Frontiers reported in its October 2003 issue, "Patients with moderate to severe cutaneous reactions [rashes] have a far better survival, than those with only mild reactions and much better than those with no cutaneous manifestations of drug effects."[10]
  • Diarrhea
  • Loss of appetite
  • Fatigue
  • Rarely, interstitial pneumonitis, which is characterized by cough and increased dyspnea. This may be severe and must be considered among those patients whose breathing acutely worsens.
  • Rarely, ingrown hairs, such as eyelashes
  • It has also been suggested that erlotinib can cause hearing loss.
  • Partial hair loss (by strands, not typically in clumps)

Rare Side Effects:

In spring 2009, the US Food and Drug Administration issued a warning on erlotinib. The FDA reported serious gastrointestinal tract, skin, and ocular disorders in patients taking the drug. In addition, according to a letter released by Genentech and OSI Pharmaceuticals, some people prescribed erlotinib have developed serious or fatal gastrointestinal tract perforations; "bullous, blistering, and exfoliative skin conditions, some fatal; and serious eye problems such as corneal lesions. Some of the cases, including ones which resulted in death, were suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis.[11]

Resistance to treatment

A key issue with EGFR-directed treatments is that after a period of 8–12 months, the cancer cells become resistant to the treatment, most commonly by recruiting a mutated IGF-1 receptor to act as one of the EGFR partners in the homodimer, so forming a heterodimer.[12] This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538[13] or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541.[14]

Tarceva studies and availability

In November 2008 a study undertaken by Roche Holding of Switzerland claimed that Tarceva given immediately after chemotherapy may prove to stem the progress of lung cancer. Tarceva blocked the spread of advanced non-small cell lung cancer, researchers found.[15]. However, the report of this study, called SATURN, does not indicate the extent of increase in survival-time.

Tarceva is currently (2009) available for free in Scotland but not in England, as the National Institute for Health and Clinical Excellence (NICE) found it was not "an effective use of NHS resources". Tarceva has been shown to extend the lives of some cancer patients and to improve their quality of life. It is used extensively in Europe and the US.[16]

Notes

http://www.cancer.gov/clinicaltrials/results/lung-and-erlotinib0604l http://www.roche.com/med-cor-2007-10-22 http://www.roche.com/med-cor-2009-05-30b http://www.cipla.com/whatsnew/news.htm#27apr09 http://www.cipla.com/whatsnew/news.htm#20mar08

References

  1. ^ Raymond E, Faivre S, Armand J. "Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy". Drugs 60 Suppl 1: 15–23; discussion 41–2. PMID 11129168. 
  2. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  3. ^ Li Z, Xu M, Xing S, Ho W, Ishii T, Li Q, Fu X, Zhao Z (2007). "Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth". J Biol Chem 282 (6): 3428–32. doi:10.1074/jbc.C600277200. PMID 17178722. 
  4. ^ [1][dead link]
  5. ^ http://sify.com/finance/equity/fullstory.php?id=14626687
  6. ^ http://sify.com/finance/equity/fullstory.php?id=14612495
  7. ^ http://www.cipla.com/whatsnew/news.htm#27apr09
  8. ^ Dudek A, Kmak K, Koopmeiners J, Keshtgarpour M (2006). "Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer". Lung Cancer 51 (1): 89–96. doi:10.1016/j.lungcan.2005.09.002. PMID 16290256. 
  9. ^ Román Pérez-Soler, M.D., et al. (2004). "Selected Highlights". Lung Cancer Frontiers 22 (16): 3238–3247. 
  10. ^ Thomas L. Petty, M.D. (2003). "Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer". Journal of Clinical Oncology 1 (17): 3–4. 
  11. ^ http://jama.ama-assn.org/cgi/content/extract/301/24/2542-b
  12. ^ Jones H, Goddard L, Gee J, Hiscox S, Rubini M, Barrow D, Knowlden J, Williams S, Wakeling A, Nicholson R (2004). "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells". Endocr Relat Cancer 11 (4): 793–814. doi:10.1677/erc.1.00799. PMID 15613453.  Free full text
  13. ^ Blum G, Gazit A, Levitzki A (2000). "Substrate competitive inhibitors of IGF-1 receptor kinase". Biochemistry 39 (51): 15705–12. doi:10.1021/bi001516y. PMID 11123895. 
  14. ^ Warshamana-Greene G, Litz J, Buchdunger E, García-Echeverría C, Hofmann F, Krystal G (2005). "The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy". Clin Cancer Res 11 (4): 1563–71. doi:10.1158/1078-0432.CCR-04-1544. PMID 15746061.  Free full text
  15. ^ November 2008 - Tarceva may contain lung cancer, study suggests
  16. ^ Daily Mail - October 2007 - Girl of six raises £4,000 for life-saving drugs the NHS won't provide

External links

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Targeted therapy / extracellular chemotherapeutic agents/antineoplastic agents (L01)
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This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)

 
 
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