What Is Crizotinib (Xalkori)? FDA Approval, Licensing and Reimbursement in Turkey

Crizotinib (Xalkori)

• FDA Approval: Yes, first approval date: 26 August 2011 (by the FDA for ALK-positive metastatic NSCLC).
• Brand Name: Xalkori
• Active Ingredient: Crizotinib
• Route of Administration: Oral (by mouth, capsule)
• Class: Tyrosine kinase inhibitor (TKI)
• Category: Targeted therapy
• Manufacturer: Pfizer Inc.
• Distribution / Licensing Status in Turkey:It is licensed in Turkey and distributed by Pfizer Turkey.
• Approved Cancers: ALK-positive metastatic NSCLC, ROS1-positive metastatic NSCLC

What Is Crizotinib? What Is Its Mechanism of Action?

The cancer medicine Xalkori, whose active ingredient is crizotinib, is designed to block the function of a protein found in cancer cells called anaplastic lymphoma kinase (ALK) , which is the product of two mutated and fused genes. The protein resulting from ALK fusion causes cancer cells to grow and divide faster, thereby surviving longer. Non-small cell lung cancer (NSCLC) patients have this mutation in approximately 2% to 7% of cases. Crizotinib slows cancer growth and causes some cancer cells to die by blocking the function of the abnormally active ALK protein.

- Related Topic: What Is ALK Fusion? What Does an ALK Mutation Mean in Lung Cancer?

What Is Its Mechanism of Action?

Target Proteins:

Crizotinib selectively inhibits the tyrosine kinases ALK (anaplastic lymphoma kinase), ROS1 and MET (hepatocyte growth factor receptor).

How It Works:

These kinases receive signals from growth factors on the cell surface and transmit them into the cell. When activated, they accelerate cell proliferation, survival and metastasis through the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways.

Crizotinib binds to the ATP-binding site of these receptors, preventing their phosphorylation. As a result:

• Intracellular growth signals are interrupted,
• Tumor cell proliferation stops,
• Apoptosis (programmed cell death) increases.

It is particularly effective in NSCLC cells with ALK or ROS1 gene rearrangements. Because these kinases are not active in normal cells, it produces a targeted, selective effect.

📜 FDA (United States Food and Drug Administration) Approval History

• 14 July 2022: The FDA approved Xalkori (crizotinib) for ALK-positive inflammatory myofibroblastic tumors.
• 14 January 2021: Pfizer’s Xalkori (crizotinib) was approved by the FDA for the treatment of ALK-positive anaplastic large cell lymphoma in children and young adults.
• 11 March 2016 : The FDA expanded approval of Xalkori (crizotinib) to include the treatment of ROS1-positive non-small cell lung cancer (NSCLC).
• 26 August 2011: The FDA approved Xalkori (crizotinib), together with a companion diagnostic test, for a type of advanced non-small cell lung cancer.
• 17 May 2011: Pfizer announced simultaneous New Drug Application (NDA) submissions for crizotinib to the United States Food and Drug Administration and Japan’s Ministry of Health, Labour and Welfare.
• 12 January 2011 : Pfizer announced that it had initiated a rolling New Drug Application submission in the United States for the investigational drug crizotinib (PF-02341066), which had been granted a fast-track review process for patients with ALK-positive advanced non-small cell lung cancer (NSCLC).

🇹🇷 Licensing in Turkey

It is licensed in Turkey and distributed by Pfizer Turkey.

💳 SGK Reimbursement Status

Effective from 06-05-2021, SGK reimburses it in the following situations.

• The Institution covers its cost when used as monotherapy until progression in first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose anaplastic lymphoma kinase (ALK) or receptor tyrosine kinase C-ROS 1 (ROS-1) positivity has been confirmed by a FISH test in an accredited laboratory.
• The Institution covers its cost when used until progression in second-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have anaplastic lymphoma kinase (ALK) positivity confirmed by a FISH test in an accredited laboratory, have previously received chemotherapy and subsequently developed progression.
• The Institution does not reimburse crizotinib when used sequentially or in combination to treat patients whose disease has progressed after alectinib, brigatinib, lorlatinib or ceritinib treatment.
• Without obtaining additional TİTCK approval; it is appropriate for use in patients with Stage 4 NSCLC with an exon 14 skipping mutation. In patients with Met amplification, use is appropriate if the copy number is 10 or higher.

July 2026 Price: Xalkori 200 mg 60 capsules capsules costs 119.092,59 TL, and Xalkori 250 mg 60 capsules costs 127.169,50 TL.

• This information does not replace a doctor/pharmacist and is for general information. Consult your pharmacist for prices.

🧬 Mechanism of Resistance

Target gene mutations (secondary mutations)

• ALK resistance mutations: L1196M (“gatekeeper” mutation); it causes a conformational change at the ATP-binding site, so crizotinib can no longer bind effectively.
• Other mutations, such as G1269A, S1206Y, F1174L and G1202R, also prevent crizotinib binding in the kinase domain.
• ROS1 mutations: the G2032R mutation is the best-known resistance mechanism.

Activation of bypass signaling pathways

• The tumor cell activates proliferative pathways other than ALK/ROS1: EGFR, KIT, KRAS and PI3K/AKT pathways come into play, overcoming crizotinib suppression. As a result, cell growth continues.

MET amplification

• An increase in the MET receptor tyrosine kinase provides an alternative growth signal.
• Although crizotinib has MET-inhibiting properties, it may be ineffective at high amplification levels.

Pharmacological/drug-related factors

• Crizotinib is a P-glycoprotein substrate. P-gp overexpression causes the drug to be expelled from the cell.
• This reduces the intratumoral drug concentration.

📦 Absorption

• It is well absorbed after oral administration.
• Tmax (time to reach peak plasma concentration): approximately 4–6 hours.
• Bioavailability: around 43%.
• Taking it with food does not greatly affect bioavailability.

📦 Distribution

• Plasma protein binding: around 91% (particularly albumin).
• Volume of distribution (Vd): approximately 1772 L; it is widely distributed in tissues.
• It can partially cross the blood–brain barrier, but its effectiveness against central nervous system metastases is limited (which is why later-generation ALK TKIs are preferred).

📦 Metabolism

• It is largely metabolized in the liver.
• CYP3A4/5 are the main enzymes responsible.
• It has active metabolites (for example, O-desalkyl crizotinib), but the main activity belongs to the parent compound.
• Strong CYP3A inhibitors (ketoconazole, clarithromycin) or inducers (rifampicin, carbamazepine) can therefore substantially affect plasma levels of crizotinib.

📦 Elimination

• Half-life (t½): approximately 42 hours; therefore, it is dosed 2 times daily (BID).
• 63% is eliminated in feces (unchanged drug and metabolites)
• 22% is eliminated in urine.
• Significant accumulation is not observed in mild–moderate renal impairment, but liver impairment reduces clearance of the drug.

💉 Dose Range and Administration

• Crizotinib is a 250 mg hard capsule taken by mouth. The medicine is taken regularly every day.
• Take 1 capsule of 250mg in the morning and 1 capsule of 250mg in the evening. There should be 12 hours between the morning and evening doses.
• Crizotinib may cause nausea. To prevent this, you may take the anti-nausea medicine prescribed by your physician 30-60 minutes before taking crizotinib.
• Crizotinib capsules must be swallowed with plenty of water. Do not open, crush or dissolve the capsules in any liquid.
• If not much time has passed since you forgot to take crizotinib, take your medicine immediately. HOWEVER, if more than 8 hours have passed since the dose you forgot, do not make up the dose.
• If you vomit after taking the medicine, do not repeat the dose.
• Some medicines can interact with crizotinib. Tell your physician if you are starting a new medicine.
• Grapefruit and grapefruit juice, St. John’s wort and some sedatives are known to interact with crizotinib.

🔄 Drug Interactions

CYP3A inhibitors

• Strong inhibitors (ketoconazole, itraconazole, clarithromycin, nefazodone, posaconazole, etc.)
• Increase crizotinib levels and the risk of toxicity (QT prolongation, elevated liver enzymes, gastrointestinal toxicity).
• Co-administration should be avoided. If unavoidable, dose adjustment or close monitoring is needed.

CYP3A inducers

• Rifampicin, carbamazepine, phenytoin, St. John’s wort, etc.
• Accelerate crizotinib metabolism and lower plasma levels, causing a loss of effectiveness.
• They should not be used together.

CYP3A substrates

• Because crizotinib is also a CYP3A inhibitor, it may increase levels of other CYP3A substrates.
• Examples: benzodiazepines, calcium channel blockers, immunosuppressants (tacrolimus, cyclosporine).

QT-prolonging medicines

• Crizotinib may prolong the QT interval.
• Risky combinations: amiodarone, sotalol, some antipsychotics (haloperidol, ziprasidone), macrolide antibiotics.
• Recommendation: ECG and electrolyte monitoring should be performed.

Medicines that increase gastric pH

• Proton pump inhibitors (omeprazole, etc.) may reduce crizotinib solubility, but the clinically significant effect has been found to be limited. Caution is nevertheless advised.

Anticoagulants

• When used with warfarin and DOACs (apixaban, rivaroxaban), it may increase bleeding risk (through CYP3A and P-gp).

Other considerations

• Grapefruit juice: inhibits CYP3A and increases crizotinib levels; it should not be used.
• P-gp substrates (for example, digoxin): because crizotinib inhibits P-gp, it may increase levels of these medicines.

🤒 What Are the Side Effects of Crizotinib?

The side effects most frequently reported with crizotinib in clinical studies are listed below. Side effects sometimes have percentage ranges [for example, 48-61% diarrhea]. This is because some results differ between clinical studies:

• Nausea (56%)
• Diarrhea (48 - 61%)
• Vomiting (47%)
• Watery eyes and vision problems (41-71%)
• Sinusitis (26 - 32%)
• Changes in taste (26%)
• Abdominal pain (26%)
• Constipation (24 - 43%)
• Cough (23%)
• Headache (22%)
• Low white blood cells [neutropenia] (21%)
• Pain in the fingertips (20%)
• Fever (19%)
• Swelling in the arms and legs (16 - 49%)
• Arm or leg pain (16%)
• Dizziness (15 - 22%)
• Mouth sores (14%)
• Decreased appetite (13 - 30%)
• Shortness of breath (13 - 18%)
• Weakness (13%)
• Liver damage (12 - 38%)
• Fatigue (10 - 29%)
• Anemia [low red blood cells] (8%)
• Skin rash (9%)
• Hair loss (8%)
• Lung damage (1%)

Approximately 6% - 12% of patients discontinue crizotinib because of unacceptable side effects.

🩺 How Often Is Monitoring Needed?

Blood tests are recommended before starting treatment. After treatment begins, blood tests are checked every two weeks during the first month and then monthly. The required blood tests are a complete blood count (hemogram), a comprehensive metabolic panel (biochemistry) and a blood magnesium level.

🖼️ When Is Radiological Imaging Performed?

Imaging may be performed before treatment and approximately every 6 to 8 weeks during treatment. X-rays, magnetic resonance imaging (MRI), computed tomography (CT) scans or positron emission tomography (PET) scans are imaging procedures performed. Electrocardiograms (ECG) may be performed periodically during treatment to assess your heart rhythm.

⚠️ What Should Be Considered When Taking Crizotinib?

• Taking crizotinib with certain other medicines may increase your risk of a rare but serious heart rhythm problem known as a “prolonged QTc interval.” If you take other medicines, discuss this with your doctor or pharmacist.
• Your oncology pharmacist should always review your medicine list to ensure that drug interactions are appropriately prevented or managed.
• Medicines should not be touched with bare hands. You can take them by putting them into an empty glass or using gloves.
• Unless restricted by your physician, drink plenty of fluids—around two liters daily.
• You may be prone to infection. Therefore, try to stay away from crowds or people with colds, and tell your physician if you develop a fever or any other sign of infection.
• Crizotinib may cause vision changes, dizziness and fatigue. If you have any of these symptoms, be careful when driving, operating machinery or doing anything requiring alertness.
• You may develop sensitivity to sunlight and sunburn while taking these medicines. To prevent this, try not to spend time in the sun at midday. When going out, wear items that protect your body from the sun (sunglasses, an umbrella, etc.). Use factor 15 or higher sunscreens .
• Get plenty of rest.
• Try to eatwell.
• You should not have a child while taking crizotinib. Use a suitable family planning method. Barrier methods such as condoms should continue to be used for up to 90 days after the last dose of crizotinib.
• Do not breastfeed while taking crizotinib. Breastfeeding should be avoided until 45 days after the last dose of crizotinib.
• In general, alcoholic beverages should be kept to a minimum or avoided entirely. Day or night, if you experience any of the following symptoms, contact your healthcare professional and go to the nearest hospital emergency department:
• Fever of 38º C or higher, chills (possible signs of infection)
• Signs of an allergic reaction: rash, hives, itching, skin redness, wheezing, chest or throat tightness, difficulty breathing or speaking, shortness of breath.