Xalkori^® (Capsules) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Manufacturing Deutschland, GmbH (Germany)

Contact Information

Pfizer Innovations LLC (Russia)

ATC Code

L01ED01 (Crizotinib)

Active Substance

Crizotinib (Rec.INN registered by WHO)

Dosage Forms

	Xalkori®	Capsules 200 mg: 10 or 60 pcs.
		Capsules 250 mg: 10 or 60 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size 1, with opaque pink cap and white body, with black print “Pfizer” on the cap and “CRZ 200” on the body; capsule contents – white or slightly yellowish powder.

Excipients: colloidal silicon dioxide, microcrystalline cellulose (PH 102), anhydrous dibasic calcium phosphate, sodium starch glycolate (type A), magnesium stearate.

Composition of the gelatin capsule body gelatin, titanium dioxide (E171).
Composition of the gelatin capsule cap gelatin, titanium dioxide (E171), iron oxide red dye (E172).
Composition of the printing ink shellac, propylene glycol, concentrated ammonia solution, potassium hydroxide, iron oxide black dye (E172).

10 pcs. – PVC/Aluminum blisters (1) – cardboard packs.
10 pcs. – PVC/Aluminum blisters (6) – cardboard packs.

Capsules hard gelatin, size 0, with opaque pink cap and pink body, with black print “Pfizer” on the cap and “CRZ 250” on the body; capsule contents – white or slightly yellowish powder.

Excipients: colloidal silicon dioxide, microcrystalline cellulose (PH 102), anhydrous dibasic calcium phosphate, sodium starch glycolate (type A), magnesium stearate.

Composition of the gelatin capsule body gelatin, titanium dioxide, iron oxide red dye (E172).
Composition of the gelatin capsule cap gelatin, titanium dioxide, iron oxide red dye (E172).
Composition of the printing ink shellac, propylene glycol, concentrated ammonia solution, potassium hydroxide, iron oxide black dye (E172).

10 pcs. – PVC/Aluminum blisters (1) – cardboard packs.
10 pcs. – PVC/Aluminum blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents, protein kinase inhibitors, anaplastic lymphoma kinase (ALK) inhibitors

Pharmacological Action

Antitumor drug. Crizotinib is a selective low molecular weight inhibitor of receptor tyrosine kinases (RTK), including anaplastic lymphoma kinase (ALK) and its oncogenic variants (i.e., ALK fusion products and specific mutations). Crizotinib is also an inhibitor of hepatocyte growth factor receptor (HGFR, c-Met), a member of the RTK family. Crizotinib inhibits ALK and c-Met activity in biochemical assays in a concentration-dependent manner and inhibits phosphorylation and modulates kinase-dependent phenotypes in cell-based assays. Crizotinib has potent and selective inhibitory activity and induces apoptosis in tumor cell lines expressing ALK fusion products (including EML4-ALK and NPM-ALK) or demonstrating amplification of ALK or MET. The antitumor effect of crizotinib is dose-dependent and correlates with the extent of pharmacodynamic inhibition of phosphorylation of ALK fusion products (including EML4-ALK and NPM-ALK) in tumors in vivo.

Pharmacokinetics

Absorption and Distribution

After a single oral dose of crizotinib under fasting conditions, the time to reach maximum plasma concentration (T_max) is from 4 to 6 hours. With crizotinib administered at a dose of 250 mg twice daily, steady-state concentration of crizotinib is achieved within 15 days and remains unchanged, with a mean accumulation ratio of 4.8. Systemic exposure parameters (maximum plasma concentration (C_max) and area under the concentration-time curve (AUC)) increase more than proportionally relative to the administered dose in the range of 200 mg-300 mg twice daily.

When crizotinib is administered twice daily, steady-state concentration is achieved within 15 days.

The absolute bioavailability of crizotinib after a single oral 250 mg dose is 43%.

In healthy volunteers, a single oral dose of crizotinib 250 mg administered with a high-fat meal reduced AUC_inf and C_max by approximately 14%. Therefore, Crizotinib can be taken with or without food.

In vitro, crizotinib plasma protein binding is 91%, independent of concentration. In vitro studies suggest that Crizotinib is a substrate of P-glycoprotein. The plasma-to-blood concentration ratio is approximately 1.

Metabolism and Excretion

In vitro studies have shown that the metabolic clearance of crizotinib is primarily mediated by CYP3A4/5 isoenzymes. The main metabolic pathways in humans are oxidation of the piperidine ring to crizotinib lactam and O-dealkylation followed by phase 2 conjugation of the O-dealkylated metabolites.

After a single dose of crizotinib, the terminal plasma T_1/2 was 42 hours.

After a single 250 mg dose of radiolabeled crizotinib administered to healthy volunteers, 63% and 22% of the administered dose was excreted in feces and urine, respectively. Unchanged crizotinib accounted for approximately 53% and 2.3% of the administered dose in feces and urine, respectively. The mean apparent clearance of crizotinib at steady state was lower (60 L/h) after administration of crizotinib 250 mg twice daily compared to administration of 250 mg once daily (100 L/h). This is likely due to increased inhibition of the CYP3A isoenzyme after multiple doses.

Pharmacokinetics in Special Patient Groups

Patients with Renal Impairment

No dose adjustment of crizotinib is required in patients with mild renal impairment (creatinine clearance (CrCl) from 60 ml/min to 90 ml/min) and moderate renal impairment (CrCl from 30 ml/min to 60 ml/min), as steady-state concentrations in these cases are not significantly different from the steady-state concentration of crizotinib in patients with normal renal function. Furthermore, it was found that CrCl does not affect the pharmacokinetics of crizotinib.

After a single 250 mg dose of crizotinib in patients with severe renal impairment (CrCl <30 ml/min) not requiring peritoneal dialysis or hemodialysis, the AUC and C_max of crizotinib increased by 79% and 34%, respectively. In such patients, the dose of crizotinib should be adjusted (see section “Dosage and Administration”). Precise dosing recommendations cannot be given for patients with end-stage renal disease (not studied).

The use of crizotinib in patients with severe renal impairment or on hemodialysis has not been studied. Patients with serum creatinine more than 2 times the upper limit of normal (ULN) were excluded from clinical studies.

Patients with Hepatic Impairment

The use of crizotinib in patients with hepatic impairment has not been studied. Patients with AST or ALT elevations more than 2.5 times ULN (more than 5 times ULN due to malignancy) or total bilirubin concentration more than 1.5 times ULN were excluded from clinical studies. Based on a population pharmacokinetic analysis, baseline total bilirubin concentration or AST activity were found not to affect the pharmacokinetics of crizotinib. Since Crizotinib is extensively metabolized by the liver, increased plasma concentrations of crizotinib can be expected in hepatic impairment.

Age

The pharmacokinetics of crizotinib do not change with age.

Body Weight and Sex

Patient sex and body weight do not affect the pharmacokinetics of crizotinib.

Ethnicity

The estimated steady-state AUC in Asian subjects was found to be 23-37% higher than in other ethnic groups.

Use in Children

The safety and efficacy of crizotinib in children have not been established.

Effect on Cardiac Function

Signs of QT interval prolongation were assessed in all patients receiving Crizotinib 250 mg twice daily. An analysis of the pharmacokinetic-pharmacodynamic relationship suggested an association between crizotinib plasma concentration and QT_c interval duration. In addition, a decrease in heart rate was found to be associated with an increase in crizotinib plasma concentration.

Indications

• Advanced non-small cell lung cancer (NSCLC) expressing anaplastic lymphoma kinase (ALK).

ICD codes

Dosage Regimen

Xalkori^® is taken orally, regardless of meals. Capsules should be swallowed whole.

Before using Xalkori^® in patients with NSCLC, assessment of ALK expression by the tumor is necessary, as a treatment response has been shown to be achieved only in these patients.

This testing should be performed in a laboratory with appropriate experience. Improper methodology for this assay may lead to false results.

The recommended dose of crizotinib is 250 mg twice daily.

Treatment with the drug is long-term, as long as there is a positive effect from therapy.

If a dose of crizotinib is missed, it should be taken as soon as the patient remembers (if there are 6 hours or more until the next dose), or not taken at all (if there are less than 6 hours until the next dose). The next dose should not be doubled to compensate for a missed dose.

Depending on individual tolerance and safety, temporary discontinuation of the drug and/or dose reduction of crizotinib may be required. If a dose reduction is necessary, it should be reduced to 200 mg twice daily. If a further dose reduction is necessary, it is reduced to 250 mg once daily.

Recommendations for dose reduction in case of hematological and non-hematological toxicity are provided in Tables 1 and 2.

Table 1. Dose adjustment of crizotinib for hematological toxicity^a

^a except lymphopenia (unless associated with clinical manifestations, e.g., opportunistic infections).

^b National Cancer Institute Common Terminology Criteria for Adverse Events.

^c if the adverse event recurs, temporarily discontinue the drug until symptoms resolve to ≤ Grade 2, then resume therapy with the drug at a dose of 250 mg once daily. Recurrent Grade 4 adverse events require permanent discontinuation of therapy.

Table 2. Dose adjustment of crizotinib for non-hematological toxicity.

^a National Cancer Institute Common Terminology Criteria for Adverse Events.

^b if the adverse event recurs, temporarily discontinue the drug until symptoms resolve to ≤ Grade 1, then resume therapy with the drug at a dose of 250 mg once daily. Recurrent adverse events of Grade 3 or higher require permanent discontinuation of therapy.

^c not associated with NSCLC progression, other lung diseases, infections, or prior radiation therapy.

^d Grade 2 – associated symptoms present, medical intervention indicated; Grade 3 – severe, medical intervention indicated; Grade 4 – life-threatening, urgent medical intervention indicated.

^e permanent discontinuation of the drug for recovery.

Hepatic Impairment

The use of crizotinib has not been studied in patients with AST or ALT elevations more than 2.5 times ULN (more than 5 times ULN due to malignancy) or with total bilirubin concentration more than 1.5 times ULN. Crizotinib should be used with caution in patients with hepatic impairment.

Renal Impairment

No dose adjustment of the drug is required in patients with mild (CrCl 60-90 ml/min) and moderate (CrCl 30-60 ml/min) renal impairment.

In patients with severe renal impairment (CrCl <30 ml/min), the plasma concentration of crizotinib may increase. In patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis, the dose of Xalkori^® should be adjusted to 250 mg once daily. After taking the drug for at least 4 weeks, the dose can be increased based on individual tolerance and safety to 200 mg twice daily (see section “Pharmacological Properties”). The use of crizotinib in patients with end-stage renal disease has not been studied.

Elderly Patients

No initial dose adjustment is required in elderly patients.

Adverse Reactions

The most serious adverse reactions were hepatotoxicity, ILD or pneumonitis, and QT interval prolongation.

The most frequent adverse reactions (reported in ≥25% of patients) were nausea, visual impairment, vomiting, diarrhea, constipation, edema, elevated transaminases, decreased appetite, fatigue, dizziness, and neuropathy.

The frequency of adverse reactions is presented according to the following classification

Cardiovascular system very common – bradycardia (including sinus); common – decreased heart rate, QT interval prolongation on electrocardiogram, syncope.

Special senses very common – visual impairment (diplopia, photopsia, blurred vision, vitreous floaters, photophobia, visual field defects, halos around lights, impaired light brightness perception).

Digestive system very common – nausea, diarrhea, vomiting, constipation, esophageal disorders (gastroesophageal reflux disease, dysphagia, painful swallowing, esophageal pain, esophageal spasm, esophageal ulcer, esophagitis, reflux esophagitis), abdominal pain, stomatitis (glossodynia, glossitis, cheilitis, mucosal inflammation and ulcers of the oral cavity, oropharyngeal pain); common – dyspepsia; uncommon – hepatic failure, gastrointestinal perforation.

Laboratory parameters Very often – increased activity of hepatic transaminases* (ALT, AST, GGT), impaired liver function; often – increased activity of alkaline phosphatase.

Hematologic disorders Very often – neutropenia (febrile neutropenia, decreased neutrophil count), leukopenia, decreased white blood cell concentration; often – lymphopenia, anemia, decreased hemoglobin; infrequently – thrombocytopenia.

Metabolism and nutrition disorders Very often – decreased appetite; often – hypophosphatemia.

Nervous system disorders Very often – neuropathy (burning sensation, neuralgia, peripheral neuropathy (including motor, sensory neuropathy and motor-sensory neuropathy), neurotoxicity, dysesthesia, paresthesia, gait disturbance, hypotension, neuritis, paresthesia, hypesthesia, hyperesthesia, sensory disorder, motor disorder, peroneal nerve palsy, polyneuropathy), dizziness, balance disorders, postural dizziness, presyncope, dysgeusia, headache, insomnia.

Respiratory, thoracic and mediastinal disorders Often – ILD (acute respiratory distress syndrome, pneumonitis, alveolitis), upper respiratory tract infections (nasopharyngitis, rhinitis, pharyngitis), dyspnea, cough.

Skin and subcutaneous tissue disorders: Very often – rash.

Renal and urinary disorders Often – multiple renal cysts, renal cyst hemorrhage, renal cyst infection, renal abscess.

Musculoskeletal and connective tissue disorders Very often – arthralgia, back pain, musculoskeletal chest pain, muscle weakness, muscle atrophy.

General disorders and administration site conditions Very often – edema (peripheral edema, facial edema, generalized edema, localized edema, periorbital edema), increased fatigue, asthenia, chest pain, chest discomfort, pyrexia.

* Increased transaminase activity was typically observed within the first two months of therapy. Episodes of increased transaminase activity were mostly asymptomatic and resolved after temporary therapy interruption. After resuming the drug, usually at a lower dose, recurrence of changes was not observed.

Contraindications

• Impaired liver function – increase in AST or ALT activity more than 2.5 times the ULN (more than 5 times the ULN due to malignancy) or increase in total bilirubin concentration more than 1.5 times the ULN;
• Severe renal impairment or patients on hemodialysis;
• Concomitant use with potent inducers or inhibitors of the CYP3A isoenzyme, as well as with substrates of the CYP3A isoenzyme characterized by a narrow therapeutic range (see section “Drug Interactions”);
• Pregnancy;
• Breastfeeding period;
• Children and adolescents under 18 years of age (insufficient data on safety and efficacy);
• Hypersensitivity to crizotinib or to any excipient of the drug.

With caution

Xalkori^® should be used with caution in patients with a history of QT_c interval prolongation, predisposed to this condition (patients with congestive heart failure, bradycardia, electrolyte imbalances) or receiving medications that prolong the QT interval (see section “Special Precautions”), as well as in patients with impaired liver function. Caution should be exercised when using Xalkori^® in combination with drugs primarily metabolized by the CYP3A isoenzyme (see section “Drug Interactions”).

Use in Pregnancy and Lactation

Adequate and well-controlled studies of crizotinib use during pregnancy have not been conducted. Crizotinib may cause fetal harm when administered during pregnancy.

Women of childbearing potential should be advised to avoid becoming pregnant during crizotinib therapy. For this purpose, during the therapy period and for at least 90 days after its completion, women of childbearing potential or their partners taking Xalkori^® should use adequate contraceptive methods.

If Xalkori^® is used during pregnancy or if pregnancy occurs during treatment with this drug in the patient or her sexual partner, they should be informed about the potential risks of adverse effects of the drug on the fetus.

It is unknown whether Crizotinib is excreted in breast milk. During breastfeeding, either Crizotinib should be discontinued or breastfeeding should be stopped, taking into account the importance of the drug to the mother.

Based on preclinical studies, Crizotinib is presumed to affect fertility in men and women.

Use in Hepatic Impairment

The use of crizotinib has not been studied in patients with an increase in AST or ALT activity more than 2.5 times the ULN (more than 5 times the ULN due to malignancy) or with an increase in total bilirubin concentration more than 1.5 times the ULN. Crizotinib should be used with caution in patients with impaired liver function.

Use in Renal Impairment

No dose adjustment of the drug is required in patients with mild (CrCl 60-90 ml/min) and moderate (CrCl 30-60 ml/min) renal impairment.

In patients with severe renal impairment (CrCl <30 ml/min), the plasma concentration of crizotinib may increase. In patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis, the dose of Xalkori^® should be adjusted to 250 mg once daily. After taking the drug for at least 4 weeks, the dose can be increased based on individual tolerance and safety to 200 mg twice daily (see section “Pharmacological properties”). The use of crizotinib in patients with end-stage renal disease has not been studied.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (insufficient data on safety and efficacy).

Geriatric Use

No initial dose adjustment is required in elderly patients.

Special Precautions

There have been reports of drug-induced hepatotoxicity with fatal outcome in patients taking Crizotinib. According to clinical studies, the frequency of this complication is less than 0.5%. The following symptoms are characteristic: weakness, increased fatigue, anorexia, nausea, vomiting, abdominal pain, jaundice, dark urine, generalized pruritus, hemorrhagic diathesis, especially in combination with fever and rash).

Cases of severe, life-threatening or fatal ILD or pneumonitis have been observed during crizotinib therapy. This condition generally developed within 3 months of starting therapy. Patients should be continuously monitored for the development of clinical manifestations from the lungs. If abnormalities occur that may indicate the development of ILD or pneumonitis, patients should be examined to rule out alternative causes of this condition. After diagnosis of ILD or pneumonitis associated with the therapy, Crizotinib should be discontinued.

If visual disturbances appear or worsen, including diplopia, photopsia, decreased visual acuity, vitreous floaters, the need for an ophthalmological examination should be assessed. These disturbances usually appear within the first 2 weeks of taking the drug. It should be considered that the development of severe vitreous floaters and/or photopsia or worsening of these disturbances may be a sign of retinal tear or threatened retinal detachment. No cases requiring temporary or permanent discontinuation of crizotinib or dose reduction due to visual disturbances have been recorded.

The most common adverse reactions from the digestive system are nausea, diarrhea, vomiting and constipation. Nausea and vomiting typically develop within 2-3 days. Most reactions were mild or moderate in severity, and their frequency decreased after 3-4 weeks of therapy. If adverse effects from the digestive system occur, standard supportive therapy with antiemetics, antidiarrheals and/or laxatives may be administered.

During crizotinib therapy, monitoring of liver function tests, including ALT, AST activity and total bilirubin concentration, is necessary. Monitoring should be performed every 2 weeks for the first 2 months of therapy, then at least once a month or more frequently if clinically indicated, for an increase in the listed parameters to grade 2, 3 or 4 toxicity according to CTCAE classification. The dose should be adjusted according to the recommendations in the “Dosage and Administration” section.

During crizotinib therapy, complete blood count monitoring (with differential white blood cell count) should be performed, and the frequency should be increased if grade 3 or 4 abnormalities according to CTCAE classification, fever or infection develop. Monitoring should be performed as clinically indicated. The dose should be adjusted according to the recommendations in the “Dosage and Administration” section.

When using crizotinib in patients with a history of QT_c interval prolongation, predisposed to this condition or receiving medications that prolong the QT interval, periodic monitoring of ECG parameters and blood electrolyte concentrations should be considered. The dose should be adjusted according to the recommendations in the “Dosage and Administration” section.

It is recommended to avoid the use of crizotinib in patients with congenital long QT syndrome.

There have been reports of bradycardia cases noted during clinical studies. Usually, this bradycardia is asymptomatic. The full effect of crizotinib on heart rate may not manifest until several weeks after starting therapy. Due to the potential risk of clinical manifestations of bradycardia (syncope, dizziness, decreased blood pressure), the concomitant use of crizotinib and other medications that lower heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) should be avoided if possible. Monthly monitoring of heart rate and blood pressure is recommended. In case of asymptomatic bradycardia, no dose adjustment of the drug is required. If bradycardia develops with associated symptoms, crizotinib therapy should be interrupted and the appropriateness of concomitant therapy should be assessed (see sections “Dosage and Administration” and “Adverse Reactions”).

Cases of cystic kidney disease have been observed during crizotinib administration. These patients did not show clinically significant abnormalities in urinalysis or impaired renal function, however, in some patients, cyst extension beyond the renal capsule was noted. If cystic kidney disease develops, monitoring including laboratory and functional examination methods is recommended.

Effect on ability to drive and operate machinery

Studies on the effect of Xalkori^® on the ability to drive a car and operate machinery have not been conducted. Nevertheless, adverse effects such as visual disturbances, dizziness or increased fatigue may occur during crizotinib administration, therefore patients experiencing the described adverse events should refrain from performing potentially hazardous activities requiring increased concentration and speed of psychomotor reactions (driving a car, working with moving machinery, etc.).

Overdose

In case of overdose, standard supportive therapy should be administered. A specific antidote for crizotinib is unknown.

Drug Interactions

In vitro studies on human hepatocytes have shown that clinically significant drug interaction resulting from crizotinib-mediated inhibition of the metabolism of other drugs that are substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 isoenzymes is unlikely.

In vitro, Crizotinib is an inhibitor of the CYP2B6 isoenzyme, so it may potentially increase the plasma concentration of drugs primarily metabolized by the CYP2B6 isoenzyme.

In vitro studies on human liver microsomes have shown that Crizotinib inhibits the activity of CYP2B6 and CYP3A isoenzymes in a time-dependent manner.

Crizotinib is a substrate of the CYP3A4/5 isoenzyme and a moderate inhibitor of the CYP3A isoenzyme. In vitro and in vivo studies have shown that Crizotinib is an inhibitor of the CYP3A isoenzyme.

Concomitant use with drugs that are substrates of uridine-5-diphosphate-glucuronosyltransferase (UDP-GT)

In vitro studies have shown that drug interaction due to Crizotinib-mediated inhibition of the metabolism of UDP-GT substrates is unlikely.

Drugs that may increase the plasma concentration of crizotinib

Combining crizotinib with potent inhibitors of the CYP3A isoenzyme may lead to an increase in its plasma concentration. Therefore, combining crizotinib with potent inhibitors of the CYP3A isoenzyme, including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin and voriconazole, should be avoided.

Combined single oral administration of crizotinib 150 mg and ketoconazole 200 mg twice daily leads to an increase in the systemic exposure of crizotinib. The AUC_inf and C_max values increase approximately 3.2-fold and 1.4-fold, respectively, compared to crizotinib monotherapy. However, the extent of the effect of CYP3A isoenzyme inhibitors on crizotinib exposure at steady state is undetermined.

Grapefruit or grapefruit juice may also increase the plasma concentration of crizotinib, so its consumption should be avoided during therapy with this drug. Caution should be exercised when crizotinib is used concomitantly with moderate inhibitors of the CYP3A isoenzyme.

Drugs that may decrease the plasma concentration of crizotinib

Combining crizotinib with potent inducers of the CYP3A isoenzyme may lead to a decrease in its plasma concentration. Therefore, concomitant use of crizotinib with potent inducers of the CYP3A isoenzyme, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s wort preparations, should be avoided.

Single administration of crizotinib 250 mg concomitantly with rifampicin (600 mg once daily) led to a decrease in crizotinib AUC_inf and C_max values by 82% and 69%, respectively, compared to its monotherapy. However, the extent of the effect of CYP3A isoenzyme inducers on crizotinib exposure at steady state is undetermined.

Drugs whose plasma concentrations may change when combined with crizotinib

Caution should be exercised when using crizotinib in combination with drugs primarily metabolized by the CYP3A isoenzyme; a dose reduction of these drugs may be necessary. Combining crizotinib with substrates of the CYP3A isoenzyme characterized by a narrow therapeutic range (such as alfentanil, cyclosporine, fentanyl, quinidine, sirolimus, tacrolimus), as well as with drugs whose use may be associated with the development of life-threatening arrhythmias (pimozide, dihydroergotamine, ergotamine, as well as astemizole, cisapride and terfenadine), should be avoided.

After administration of crizotinib 250 mg twice daily for 28 days to patients with malignancies, the AUC of midazolam (upon its oral administration) was 3.65 times (90% CI: 2.63-5.07) higher than that during midazolam monotherapy.

Combination of crizotinib with drugs that increase gastric pH

The solubility of crizotinib in water is pH-dependent: at low (acidic) pH values its solubility increases. Single administration of 250 mg crizotinib after using 40 mg omeprazole once daily for 5 days leads to an approximate 10% decrease in the total AUC_inf of crizotinib and no change in C_max of crizotinib in plasma; the extent of increase in drug exposure is clinically insignificant. Thus, no initial dose adjustment of crizotinib is required when used concomitantly with drugs that cause an increase in gastric pH (such as proton pump inhibitors, H₂-receptor blockers or antacids).

Combination with transporter substrates

Crizotinib is an in vitro inhibitor of P-glycoprotein. Therefore, it may increase the plasma concentrations of concomitantly administered drugs that are substrates of P-glycoprotein.

In vitro, Crizotinib is an inhibitor of the OCT1 and OCT2 transport proteins. Therefore, Crizotinib may potentially increase the plasma concentration of drugs that are substrates of these proteins.

In vitro studies, Crizotinib at therapeutic concentrations did not inhibit the hepatic transport proteins OATP1B1 or OATP1B3. Therefore, clinically significant drug interaction resulting from crizotinib-mediated inhibition of hepatic or renal uptake of drugs that are substrates of these transporters is unlikely.

In vitro, at clinically significant concentrations, Crizotinib is not an inhibitor of bile salt transport proteins.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.