What Is Imatinib (Glivec)? FDA Approval, Licensing in Turkey, and Reimbursement Status
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Imatinib (Glivec and Generics): A Turning Point in Targeted Therapy
- FDA Approved: Yes (First approval date: May 10, 2001)
- Brand Name and Manufacturer, Distribution in Turkey: The original brand is Glivec (Novartis). It is also available under various generic names: Gliotin (Abdi İbrahim), Glivon (Nobel İlaç), İmagliv (Saba İlaç), İmatenil (Logus İlaç), İmavec (Koçak Farma), İmatis (Deva Holding), and Maxinib (Centurion Pharma).
- Active Ingredient Name: Imatinib
- Route of Administration: Oral, in tablet form
- Class: Signal Transduction Inhibitor, BCR-ABL Inhibitor
- Category: Targeted Agent
- Approved Cancers:
- Chronic myeloid leukemia (CML),
- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL),
- Gastrointestinal stromal tumors (GIST),
- other related malignancies.
What Is Imatinib?
Imatinib is a small-molecule cancer drug that primarily targets the BCR-ABL tyrosine kinase enzyme and stops cancer cell growth and proliferation by inhibiting intracellular signaling pathways. In addition, its inhibition of other tyrosine kinase receptors, such as PDGFR and c-KIT, makes it effective in conditions such as gastrointestinal stromal tumors, chronic myeloid leukemia (CML), and Philadelphia chromosome-positive leukemia.
One of the Greatest Success Stories in Human History
Approved by the FDA in 2001, imatinib (Glivec) became a turning point in modern cancer treatment. By demonstrating that targeted therapy was possible in diseases such as CML and GIST, it pioneered an era of biologically targeted treatments. Its dramatic improvements in survival and quality of life, particularly in CML, drew widespread attention in the scientific community.
Imatinib's success revolutionized not only oncology but also medical research methods. Traditional chemotherapy targets rapidly dividing cells, whereas imatinib targets specific molecular mechanisms causing disease, increasing effectiveness while reducing adverse effects. This approach became a prototype for developing less toxic, more effective cancer drugs.
This major scientific achievement attracted the attention of the media and the public as well as health authorities. Time magazine featured imatinib on the cover of its May 28, 2001 issue under the title "A Breakthrough in Cancer Treatment." This unusual attention to a drug brought worldwide recognition of its revolutionary impact on oncology. The cover described imatinib's development as "a scientific miracle in cancer treatment."
Image: Time magazine cover (May 28, 2001), a milestone highlighting imatinib's transformative impact on medicine.
Historical Context and Its Impact on Humanity
By the late 20th century, the molecular foundations of cancer biology were becoming better understood. Imatinib was discovered in the late 1990s by biochemist Nicholas Lyndon and tested in clinical trials by a team led by oncologist Dr. Brian Druker to inhibit the BCR-ABL fusion protein found in CML patients. This protein was a continuously active tyrosine kinase causing abnormal cell growth. By selectively targeting it, imatinib became one of the first drugs to attack cancer's molecular foundations.
Within just a few years of FDA approval, CML was transformed from a disease regarded as fatal into a chronic condition. This success gave researchers and doctors hope that similar targeted treatments could be developed for other cancers.
How Does Imatinib Work?
The image above simply illustrates the normal function of BCR-ABL and how imatinib blocks its activity:
Left Panel (A): Normal BCR-ABL Activity
- BCR-ABL is a tyrosine kinase: an enzyme that uses ATP (adenosine triphosphate) to phosphorylate, or add phosphate to, tyrosine-containing substrates.
- ATP binds to the protein, and phosphate groups are added to the substrate. This phosphorylation activates intracellular signaling pathways, triggering cell growth and proliferation.
- Continuously active BCR-ABL causes cancer cells to proliferate uncontrollably.
Right Panel (B): The Effect of Imatinib
- Imatinib binds to the ATP-binding site of BCR-ABL, preventing ATP from reaching it.
- Preventing ATP binding stops phosphorylation. This prevents substrate phosphorylation and subsequent activation of intracellular signaling pathways.
- Cell growth and proliferation are consequently inhibited, and cancer cells die or stop multiplying.
This mechanism is the fundamental principle underlying imatinib's marked effectiveness in cancers such as chronic myeloid leukemia (CML).
Imatinib's other mechanisms of action include:
- Induction of Apoptosis (Cell Death):
- Imatinib kills BCR-ABL-positive cancer cells but does not induce their differentiation.
- Inhibition of PDGFR and c-Kit Receptors:
- Imatinib inhibits platelet-derived growth factor receptors (PDGFR) and c-Kit, which support cancer cell growth, thereby stopping tumor growth.
- Inhibition of Other Tyrosine Kinases:
- It also effectively inhibits other active tyrosine kinases such as P185 in addition to BCR-ABL, broadening its effect on cancer growth.
FDA (US Food and Drug Administration) Approval History
- May 10, 2001: Approved for chronic myeloid leukemia (CML).
- 2002: Approved for gastrointestinal stromal tumors (GIST).
- 2006: Approved for dermatofibrosarcoma protuberans (DFSP).
- January 25, 2013: Approved for pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
- November 22, 2024: Imkeldi, an oral solution formulation of imatinib, was approved for various cancers.
Licensing and Therapeutic Indications in Turkey
- Adult and pediatric patients with newly diagnosed Philadelphia chromosome (BCR-ABL)-positive (Ph+) chronic myeloid leukemia (CML) for whom bone marrow transplantation is not considered first-line treatment.
- Adult or pediatric patients with chronic-phase Ph+ CML after interferon-alpha failure, or adult or pediatric patients with Ph+ CML in accelerated phase or blast crisis.
- In combination with chemotherapy for adult and pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
- As monotherapy in adults with relapsed or resistant Ph+ ALL.
- Adults with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.
- Adults with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with a FIP1L1-PDGFRα rearrangement. The effect of Glivec on bone marrow transplantation outcomes has not been established.
- Treatment of adults with Kit (CD 117)-positive, unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). For adults with resected, C-KIT receptor-positive GIST, adjuvant treatment is used in those at high risk according to AFIP (*) criteria or with tumor perforation, for three years.
- Treatment of adults with unresectable dermatofibrosarcoma protuberans (DFSP), or recurrent and/or metastatic DFSP unsuitable for surgery. Glivec's effectiveness in adults and children is based on overall hematological and cytogenetic response rates and progression-free survival in CML; hematological and cytogenetic response rates in Ph+ ALL and MDS/MPD; hematological responses in HES/CEL; objective responses in adults with unresectable and/or metastatic GIST and DFSP; and recurrence-free survival in adjuvant GIST. Experience with imatinib in PDGFR-rearranged MDS/MPD is very limited. Apart from newly diagnosed chronic-phase CML, no controlled studies demonstrate clinical benefit or improved survival in these diseases.
(*) Definition of high-risk groups according to AFIP criteria:
- Gastric tumors larger than 6 cm with a mitotic index above 5
- Non-gastric tumors measuring 10 cm or more, or with a mitotic index above 5
Is Imatinib Reimbursed?
The treatment situations in which Turkey's Social Security Institution (SGK) reimburses imatinib are:
- Chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST), when used according to the summary of product characteristics.
Price: As of December 2025, the pharmacy retail price of Glivec 100 mg in a pack of 120 tablets is 16613.34 TL and 400 mg in a pack of 30 tablets costs 15028.87 TL.
Imatinib Cost for One "Course" (1 Month)
Because imatinib is taken orally every day , its cost is generally calculated for 1 month of treatment . The following calculations use only December 2025 Glivec pharmacy retail prices.
| Scenario (Daily Dose) | Tablets Required | Packaging/Purchase | Approximate 1-Month Cost | Note |
|---|---|---|---|---|
| 400 mg/day (Chronic-phase CML, standard starting dose, etc.) | 30 days → 30×400 mg | 400 mg, 30 tablets (1 pack) | 15028.87 TL | 1 pack is sufficient. |
| 600 mg/day (Starting doses for accelerated phase/Ph+ ALL, etc.) | 30 days → 30×400 mg + 60×100 mg | 400 mg, 30 tablets (1 pack) + 100 mg, 120 tablets (1 pack) | 31642.21 TL | 60 tablets remain from the 100 mg pack. Because these are not single-use tablets, "leftover tablets" can be used the following month. |
| 800 mg/day (Maximum 2×400 mg/day) | 30 days → 60×400 mg | 400 mg, 30 tablets (2 packs) | 30057.74 TL | The most practical approach is 2 packs of 400 mg. |
Important Note
This calculation covers only the medication cost ; hospital/pharmacy administration expenses, laboratory and follow-up costs, discounts or contractual differences, and reimbursement conditions are excluded.
What Is Imatinib's Status on the List of Off-Label Drugs That May Be Used Without Additional TİTCK Approval in Turkey?
- Advanced Chordoma:
- Appropriate as 1st-line treatment for patients unsuitable for radiotherapy or surgery.
- Advanced Desmoid Tumor (Aggressive Fibromatosis):
- Appropriate for patients unsuitable for local treatment.
- Advanced Tenosynovial Giant Cell Tumor / Pigmented Villonodular Synovitis:
- Appropriate in the second line and beyond.
- Mucosal Malignant Melanoma:
- Appropriate in the 2nd line and beyond for patients with a c-KIT mutation. c-KIT amplification or c-KIT positivity demonstrated by immunohistochemistry must not be regarded as a c-KIT mutation.
Resistance Mechanisms
- Increased BCR-ABL Tyrosine Kinase Expression:
- Amplification of the BCR-ABL gene increases the amount of tyrosine kinase and leads to drug resistance.
- Mutations in BCR-ABL Tyrosine Kinase:
- Mutations in BCR-ABL tyrosine kinase reduce affinity at the drug-binding site, increasing resistance.
- Increased P170 Glycoprotein Expression:
- This protein increases drug transport out of cells, reducing the drug's intracellular effectiveness.
- Increased Drug Breakdown or Metabolism:
- Drug metabolism or intracellular breakdown increases through mechanisms that are not yet fully defined.
- Increased c-Kit Expression:
- Amplification of the c-Kit gene increases tyrosine kinase levels.
- Mutations in c-Kit Tyrosine Kinase:
- Mutations in c-Kit tyrosine kinase reduce the drug's ability to bind to this protein, causing resistance.
Pharmacokinetic Properties
- Absorption
- Imatinib's oral bioavailability is approximately 100%. It is rapidly absorbed after oral administration, generally reaching peak plasma concentration within 2-3 hours.
- Distribution
- Imatinib binds extensively to plasma proteins (95%), primarily albumin and α1-acid glycoprotein. Steady-state concentrations are reached within 2-3 days.
- Metabolism
- Imatinib is metabolized mainly by hepatic microsomal CYP3A4 enzymes. Other cytochrome P450 enzymes play only a minor role.
- Main Metabolite: An N-demethylated piperazine derivative with in vitro activity similar to the parent drug.
- Elimination: Most of the drug is excreted in feces, mainly as metabolites.
- Half-Life: The parent drug's terminal half-life is approximately 18 hours. The main metabolite, the N-desmethyl derivative, has a half-life of approximately 40 hours.
- Imatinib is metabolized mainly by hepatic microsomal CYP3A4 enzymes. Other cytochrome P450 enzymes play only a minor role.
These pharmacokinetic properties allow imatinib to achieve stable plasma concentrations and provide flexibility in dosing.
Dose Range
- Chronic-Phase CML:
- The starting dose is 400 mg daily. In the following situations, escalation from 400 mg to 600 mg or a maximum of 800 mg (400 mg twice daily) may be considered:
- Disease progression at any time,
- Inadequate hematological response despite at least 3 months of treatment,
- No cytogenetic response after 12 months of treatment,
- Loss of a previously achieved hematological and/or cytogenetic response.
- Patients require close monitoring because adverse effects may increase after dose escalation.
- The starting dose is 400 mg daily. In the following situations, escalation from 400 mg to 600 mg or a maximum of 800 mg (400 mg twice daily) may be considered:
- CML in Accelerated Phase or Blast Crisis:
- The starting dose is 600 mg daily. If necessary, it may be increased to 800 mg (400 mg twice daily).
- Gastrointestinal Stromal Tumors (GIST):
- Unresectable/Metastatic GIST: The starting dose is 400 mg daily. It may be increased to 600 mg or 800 mg if disease progresses.
- Early-Stage GIST: The recommended postoperative adjuvant dose is 400 mg daily for 3 years.
- Myelodysplastic/Myeloproliferative Diseases (MDS/MPD):
- The starting dose is 400 mg daily.
- Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL):
- The starting dose is 400 mg daily.
- Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL):
- The starting dose is 600 mg daily.
- Dose Adjustments:
- Need for Higher Doses:
- Doses may be increased provided there is no intolerable toxicity or severe adverse effects.
- Renal or Hepatic Impairment:
- Doses should be reduced in moderate or severe impairment; for example, in mild hepatic impairment the recommended dose may be reduced to 75%.
- Need for Higher Doses:
The physician may adjust these doses throughout treatment according to clinical response and tolerability.
Drug Interactions
- Phenytoin and Other CYP3A4 Enzyme Inducers:
- Drugs that induce hepatic CYP3A4, such as phenytoin, carbamazepine, rifampin, phenobarbital, and St. John's wort, increase imatinib metabolism, leading to drug inactivation and lower effective levels.
- CYP3A4 Enzyme Inhibitors:
- CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and clarithromycin reduce imatinib metabolism. This can increase drug levels and the risk of toxicity.
- Warfarin:
- In patients taking warfarin, imatinib inhibits its metabolism through the hepatic P450 system. This may alter prothrombin time (PT) and the international normalized ratio (INR) or increase bleeding risk. Coagulation parameters (PT and INR) should be closely monitored during imatinib treatment, with careful warfarin dose adjustment if needed.
Precautions
- Patients should be weighed regularly and monitored for signs of fluid retention:
- The risk of fluid retention and edema increases at higher doses and in patients older than 65.
- Hepatic Impairment:
- No dose adjustment is required in mild or moderate hepatic impairment. In severe hepatic impairment, the recommended starting dose should be reduced by 25%.
- Renal Impairment:
- In moderate renal impairment (creatinine clearance 20–39 mL/min), doses above 400 mg are not recommended, and the starting dose should be reduced by 50%. In mild renal impairment (creatinine clearance 40–59 mL/min), doses above 600 mg are not recommended.
- Blood Count Monitoring:
- A complete blood count should be obtained weekly during the first month, every two weeks during the second month, and at regular intervals thereafter.
- The drug should be taken with food and a large glass of water:
- This reduces gastrointestinal irritation. For patients with difficulty swallowing, tablets may be dissolved in water or apple juice.
- Hematological Responses:
- Hematological responses are generally observed within 2 weeks of starting treatment, and a complete hematological response is achieved within 4 weeks. Cytogenetic responses may appear 2 to 10 months after treatment starts. The median time to the best cytogenetic response is approximately 5 months.
- Phenytoin and Other CYP3A4 Inducers:
- Phenytoin and other CYP3A4 enzyme inducers, such as carbamazepine, rifampin, phenobarbital, and St. John's wort, may increase imatinib metabolism and reduce its effectiveness. An imatinib dose increase may be necessary.
- Warfarin Use:
- Imatinib may inhibit warfarin metabolism through the hepatic P450 system, altering PT and INR or increasing bleeding risk. Patients taking warfarin require close monitoring of coagulation parameters. Low-molecular-weight or standard heparin should be used for anticoagulation if necessary.
- Cardiac Monitoring:
- Cardiac function should be monitored before and during treatment using MUGA (radionuclide ventriculography) or echocardiography. Congestive heart failure (CHF) should be considered in patients who develop edema.
- Grapefruit and Similar Foods:
- Grapefruit juice, Seville oranges, star fruit, and pomelo should be avoided. These foods can inhibit CYP3A4 and increase drug levels.
- Patients should be monitored for depressive symptoms and suicidal thoughts:
- Such psychological changes may occur during imatinib treatment.
- Musculoskeletal Pain:
- Musculoskeletal pain may develop in patients who have used imatinib long term and stopped treatment. It is usually felt in the shoulders, hips, limbs, and hands/feet.
- Blood Pressure and Heart Rate Monitoring:
- Blood pressure and heart rate should be monitored monthly during the first year of treatment.
- Hepatitis B Monitoring:
- All patients should be screened for hepatitis B virus (HBV) infection before treatment. Carriers should be monitored for signs of active infection during treatment. If HBV reactivation develops, imatinib should be permanently discontinued.
- Pregnancy:
- Imatinib is classified as pregnancy category D, meaning it may harm the fetus when used during pregnancy. Use during pregnancy is not recommended, nor is breastfeeding. Women of childbearing potential should use effective contraception during treatment.
Adverse Effects
- Nausea and Vomiting (40–50%):
- Occurs in 40-50% of patients. It is generally associated with swallowing capsules and decreases when the drug is taken with food.
- Transient Ankle and Periorbital Edema:
- Usually mild to moderate.
- Occasional Myalgia:
- Some patients may experience muscle pain.
- Fluid Retention:
- Fluid retention may occur with pleural effusion, ascites, pulmonary edema, and weight gain. It is generally dose-related and more common in older patients or those with CML in blast crisis. Congestive heart failure (CHF) is a rare but serious adverse event.
- Diarrhea (25–30%):
- Occurs in approximately a quarter of patients.
- Bone Marrow Suppression:
- Characterized by conditions such as neutropenia and thrombocytopenia.
- Mild, Transient Elevation in Serum Transaminases:
- Clinically asymptomatic in most cases.
- Skin Toxicity:
- Bullous reactions such as erythema multiforme and Stevens-Johnson syndrome may occur.
- Sleep Disturbances, Depression, and Suicidal Thoughts:
- Insomnia, depression, and suicidal thoughts have been reported in some patients.
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