Crizotinib oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Crizotinib oral formulations
Drugs List
Therapeutic Indications
Uses
Anaplastic lymphoma kinase (ALK)+ve advanced non-small cell lung cancer
ROS1-positive advanced non-small cell lung cancer (NSCLC)
First line treatment of adults with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
Treatment of adults with previously treated anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
Treatment of adults with ROS1-positive advanced non-small cell lung cancer (NSCLC).
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
250 mg twice daily.
Patients with Renal Impairment
Severe renal impairment (creatinine clearance less than 30 ml/minute) not requiring dialysis: Initially 250 mg once daily. If dose is well tolerated for 4 weeks it may be increased to 200 mg twice daily.
Patients with Hepatic Impairment
Moderate hepatic impairment (AST or total bilirubin greater than 1.5 times the upper limit of normal (ULN), and less than or equal to 3 times ULN): 200mg twice daily.
Severe hepatic impairment (AST or total bilirubin greater than 3 times ULN): 250mg once daily.
Additional Dosage Information
Missed doses
A missed dose may be taken if it is more than 6 hours before next scheduled dose. Patients may not take two doses at the same time to make up for missed dose.
Dose modifications for haematological toxicities
Grade 3: Withhold treatment until recovery to Grade 2 or below then resume treatment as normal.
Grade 4, first occurrence: Withhold treatment until recovery to Grade 2 or below then resume treatment at reduced level of 200 mg twice daily.
Grade 4, second occurrence: Withhold treatment until recovery to Grade 2 or below then resume treatment at reduced level of 250 mg once daily.
Grade 4, further occurrence: Permanently discontinue.
Dose modifications for Non-haematological toxicities
First occurrence of Grade 3 or 4 ALT/AST elevation with Grade 1 total bilirubin: Withhold treatment until recovery to Grade 1 or baseline, then resume at reduced level of 250mg once daily then escalate to 200 mg twice daily if tolerated.
Second occurrence of grade 3 or 4 ALT/AST elevation with Grade 1 total bilirubin: Permanently discontinue.
Grade 2, 3 or 4 ALT/AST elevation with concurrent Grade 2, 3 or 4 total bilirubin elevation (in the absence of cholestasis or haemolysis): Permanently discontinue.
First occurrence of Grade 3 QTc prolongation: Withhold treatment until recovery to Grade 1 or baseline, then resume at reduced level of 200 mg twice daily.
Second occurrence of Grade 3 QTc prolongation: Permanently discontinue.
Grade 4 QTc prolongation: Permanently discontinue.
Grade 2 or 3 bradycardia: Withhold treatment until recovery to Grade 1 or heart rate 60 bpm or above. If contributing concomitant medication is identified and adjusted, resume treatment at 250mg twice daily. If no contributing concomitant medication is identified resume treatment at 200mg twice daily.
Grade 4 bradycardia: Withhold treatment until recovery to Grade 1 or heart rate 60 bpm or above. If contributing concomitant medication is identified and adjusted resume treatment at 250mg once daily. If no contributing concomitant medication is identified permanently discontinue.
Contraindications
Children under 18 years
Breastfeeding
Long QT syndrome
Pregnancy
Torsade de pointes
Precautions and Warnings
Family history of long QT syndrome
Predisposition to gastrointestinal perforation
Bradycardia
Cardiovascular disorder
Electrolyte imbalance
History of torsade de pointes
Moderate hepatic impairment
Severe renal impairment
Correct electrolyte disorders before treatment
Reduce dose in patients with severe renal impairment
Advise ability to drive/operate machinery may be affected by side effects
Confirm ALK-positive status prior to treatment
Confirm ROS1-positive status prior to treatment
Give pre-treatment counselling and consideration of oocyte cryopreservation
Give pre-treatment counselling and consideration of sperm cryopreservation
Treatment to be initiated and supervised by a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Advise patient to report signs of gastrointestinal perforation immediately
Monitor full blood count and differential WBC before and during therapy
Monitor renal function before treatment and regularly during treatment
Consider imaging and urinalysis if renal cysts develop
If visual disturbances occur, perform ophthalmic evaluation
Monitor ECG in patients at risk of QT prolongation
Monitor for signs and symptoms of interstitial lung disease
Monitor for signs and symptoms of pneumonitis
Monitor heart rate and blood pressure regularly
Monitor liver function every week for 2 months then monthly & as required
Monitor patients for signs and symptoms of cardiac failure
Monitor serum electrolytes
Perform blood counts if unexplained infection or fever develops
Advise patient to report any symptoms of interstitial lung disease
Advise patient to report new or worsening signs of cardiac failure
Advise patient to report new visual problems and symptoms
Discontinue treatment if interstitial lung disease develops
Reduce dose or discontinue if symptoms of severe bradycardia occur
Suspend treatment if pneumonitis is suspected
Discontinue if first occurrence or worsening of visual disturbances
Discontinue if treatment related pneumonitis is diagnosed
Discontinue or review if symptoms of congestive heart failure occur
Discontinue treatment if gastrointestinal perforation occurs
Interrupt treatment if heart rate less than 60 bpm
Suspend treatment if grade 3 or greater haematological toxicity
Suspend treatment if interstitial lung disease is suspected
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
May cause impaired fertility
Male & female: Contraception required during & for 3 months after treatment
Patients should be monitored for signs and symptoms of cardiac failure. Treatment should be interrupted, reduced or discontinued permanently if cardiac failure is suspected as fatal reactions have occurred.
Pregnancy and Lactation
Pregnancy
Crizotinib is contraindicated during pregnancy.
The manufacturer states that crizotinib should not be used during pregnancy unless the clinical condition of the mother requires it.
Crizotinib may cause foetal harm when administered to a pregnant woman. At the time of writing there is limited information on pregnant women using crizotinib. However, animal studies have shown reproductive toxicity.
The effect of concurrent therapies must also be considered.
Lactation
Crizotinib is contraindicated during breastfeeding.
The manufacturer advises avoiding breastfeeding when receiving crizotinib as it is not known whether crizotinib and its metabolites are excreted in human milk.
The effect of concurrent therapies must also be considered.
Side Effects
Abdominal pain
Acute respiratory distress
Alanine aminotransferase increased
Alveolitis
Anaemia
Aspartate aminotransferase increased
Blurred vision
Bradycardia
Cardiac failure
Constipation
Decrease in creatinine clearance
Decrease in plasma testosterone (transient)
Decreased appetite
Diarrhoea
Diplopia
Dizziness
Dysaesthesia
Dysgeusia
Dyspepsia
Electrolyte disturbances
Fatigue
Febrile neutropenia
Floaters
Gait abnormality
Gamma glutamyl transferase (GGT) increased
Gastro-intestinal perforation
Haemoglobin decrease
Hepatic failure
Hypoaesthesia
Hypogonadism
Hypophosphataemia
Hypotension
Impaired vision
Increase in alkaline phosphatase
Interstitial lung disease
Leukopenia
Loss of balance
Loss of vision
Muscle weakness
Nausea
Neuralgia
Neuropathy
Neutropenia
Oedema
Oesophagitis
Optic atrophy
Optic neuritis
Paraesthesia
Peripheral motor neuropathy
Peripheral neuropathy
Photophobia
Photopsia
Pneumonitis
Polyneuropathy
Presyncope
Prolongation of QT interval
Rash
Renal cysts
Renal failure
Sensory disturbances
Serum creatinine increased
Syncope
Visual disturbances
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: May 2019
Reference Sources
Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press Accessed on October 22, 2015.
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Summary of Product Characteristics: Xalkori 200mg and 250mg hard capsules. Pfizer Ltd. Revised February 2019.
Health Products Regulatory Authority
Available at: https://www.hpra.ie
Safety Notices: Xalkori (crizotinib) Important Safety Information from Pfizer Healthcare. 15 October 2015
Last accessed: 28 May 2019
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