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entrectinib

Trade Name:

Rozlytrek®

Appearance:

capsule

in various strengths and colours

Monograph Name:

entrectinib

Monograph Body:

Drug Monograph

A - Drug Name

entrectinib

COMMON TRADE NAME(S): Rozlytrek®

B - Mechanism of Action and Pharmacokinetics

Entrectinib is a tyrosine kinase inhibitor targeting TRKA, TRKB, TRKC (encoded by NTRK genes), proto-oncogene tyrosine-protein kinase ROS1, and anaplastic lymphoma kinase (ALK). Fusion proteins that include TRK, ROS1, or ALK kinase domains act as oncogenic drivers to promote hyperactivation of downstream signaling pathways, resulting in unchecked cell proliferation. By potently inhibiting the TRK kinases, ROS1, and ALK, entrectinib inhibits downstream signalling pathways, cell proliferation and induces tumour cell apoptosis.

Absorption

Bioavailability

55%

Peak plasma levels

4 - 6 hours

Time to reach steady state

5 days

Effects with food

Co-administration of a high-fat , high-calorie meal delayed T_max by ~ 2 hours without significant impact to C_max or AUC.

Distribution

Entrectinib has extensive tissue distribution.

PPB

>99% to plasma proteins.

Cross blood brain barrier?

Yes

Metabolism

Entrectinib is metabolized by CYP3A4 (~76%), other CYPs and UGT1A1.

Active metabolites

Yes (major metabolite: M5)

Inactive metabolites

Yes

Elimination

Feces

83%; 36% as unchanged drug, and 22% as M5

Urine

Half-life

Entrectinib: 20 hours; M5: 40 hours

C - Indications and Status

Health Canada Approvals:

Solid tumors with NTRK fusion-positive status
Non-Small Cell Lung Cancer (NSCLC)

(Includes conditional approvals)

Refer to the product monograph for a full list and details of approved indications.

D - Adverse Effects

Emetogenic Potential:

Low – No routine prophylaxis; PRN recommended

The following table lists pooled adverse effects that occurred in ≥ 10% of patients who received entrectinib in 4 clinical trials including patients with NTRK gene fusion positive tumors and patients with ROS1 Positive NSCLC. Severe or life-threatening adverse effects from other sources or post-marketing are also included.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Cardiotoxicity (3%)	E D L
	Hypotension (18%)	E
	QT interval prolonged (2%)	E
Dermatological	Rash (11%)	E
Gastrointestinal	Abdominal pain (13%)	E
	Anorexia (13%)	E
	Constipation (46%) (1% severe)	E
	Dehydration (10%)	E
	Diarrhea (35%)	E
	Nausea, vomiting (34%)	E
	Weight gain (25%)	E
General	Edema (40%) (1% severe)	E
	Fatigue (48%)	E
	Fever (21%)	E
Hematological	Myelosuppression ± infection (28%) (including anemia) (11% severe)	E
Hepatobiliary	↑ LFTs (16%)	E D
Metabolic / Endocrine	Hyperuricemia (9%) (2% severe)	E
Musculoskeletal	Fracture (5%)	E D
	Musculoskeletal pain (21%)	E
Nervous System	Ataxia (17%)	E
	Cognitive disturbance (26%) (5% severe)	E D
	Dizziness (38%)	E
	Dysesthesia (29%) (including peripheral neuropathy)	E
	Dysgeusia (44%) (<1% severe)	E
	Headache (18%)	E
	Mood changes (10%)	E D
	Sleep disorder (14%)	E
	Syncope (4%)	E
Ophthalmic	Eye disorders (21%) (<1% severe)	E
Renal	Creatinine increased (23%)	E
Respiratory	Cough, dyspnea (30%)	E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The most common side effects for entrectinib include fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, vomiting, cough, dyspnea, dysesthesia and myelosuppression.

Congestive heart failure (CHF) has been reported. Reactions were observed in patients with or without a history of cardiac disease and resolved in some patients upon treatment with diuretics and/or dose reduction/interruption of entrectinib. The median time to onset of heart failure was 2 months (range: 11 days to 12 months). In addition, myocarditis in the absence of CHF was documented in <1% of patients.

Entrectinib increases the risk of fractures. In adult patients, some fractures occurred secondary to a fall or other trauma to the affected area. Most fractures occurred in the hip or other lower extremity fractures (e.g., femoral or tibial shaft) within 3.8 months (median time). There are no data on the effects of entrectinib on healing fractures or on the risk of future fractures.

Cognitive disorders, including confusion, memory impairment, and hallucinations, have been reported. Symptoms occurred within 3 months of entrectinib initiation in the majority of patients. Patients who had brain metastases at baseline had a higher frequency of cognitive disorders (39%) compared to those without brain metastases (24.9%). Mood disorders including anxiety, depression, agitation and one case of suicide have also been reported. They generally occurred within 1 month of treatment (ranging from 1 day to 9 months).

Increases in liver function tests (AST and ALT) have been reported in clinical trials. The time to onset of elevated AST and ALT was 2 weeks (median) but ranged from 1 day to 29.5 months for AST and 1 day to 9.2 months for ALT.

Hyperuricemia has been reported, including 1 death due to tumor lysis syndrome. Hyperuricemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of entrectinib.

E - Dosing

Refer to protocol by which patient is being treated.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Solid tumours: NTRK fusion-positive status should be established using a validated test prior to initiation of entrectinib.

NSCLC: ROS1-positive status should be established using a validated test prior to initiation of entrectinib.

In patients with symptoms or known risk factors of CHF, LVEF should be assessed prior to initiation of entrectinib.

Adults:

Oral: 600 mg Daily

Dosage with Toxicity:

Dose Level	Entrectinib Dose (mg/day)
0	600
-1	400
-2	200
-3	Discontinue

Refer to interactions section for dosing recommendations when co-administered with CYP3A inhibitors.

Toxicity	Grade	Action
Anemia or Neutropenia	≥ Grade 3	Hold*; resume at same dose level or 1 dose level ↓.
CNS Effects	≥ Grade 2	Hold; resume at 1 dose level ↓. If recurs, hold; further ↓ 1 dose level. Discontinue if prolonged, severe, or intolerable events occur.
Hepatotoxicity	Grade 3	Hold*. If recovery in: ≤ 4 weeks; resume at same dose level > 4 weeks; discontinue If recurs, and recovery in: ≤ 4 weeks; resume at 1 dose level ↓ > 4 weeks; discontinue
	Grade 4	Hold*. If recovery in: ≤ 4 weeks; resume at 1 dose level ↓ > 4 weeks; discontinue If recurs; discontinue.
	ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN (in the absence of cholestasis or hemolysis)	Discontinue.
Hyperuricemia	Symptomatic or Grade 4	Hold until improvement of signs and/or symptoms . Initiate urate-lowering medication. Resume at same dose level or 1 dose level ↓.
Syncope	Any	Hold until recovered; resume at 1 dose level ↓. If recurs, hold until recovered; further ↓ 1 dose level or discontinue.
Congestive Heart Failure	Grade 2 or 3	Hold until recovery to ≤ grade 1; resume at 1 dose level ↓.
Congestive Heart Failure	Grade 4	Discontinue.
QT Interval Prolongation	QTc 481 to 500 msec	Hold until recovery to baseline; resume at same dose level.
	QTc >500 msec	Hold until recovery to baseline; If QT prolongation risk factors are: Identified and corrected; resume at same dose level NOT identified; resume at 1 dose level ↓
	Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia	Discontinue.
Vision Disorders	≥ Grade 2	Hold until improvement or stabilization; resume at same dose level or 1 dose level ↓.
All other toxicities	≥ Grade 3	Hold*. If recovery in: ≤ 4 weeks; resume at same dose level or 1 dose level ↓ > 4 weeks; discontinue
All other toxicities	Recurrent Grade 4	Discontinue.

*Resume when hematologic toxicities recovered to ≤ grade 2 or baseline and other specified toxicities recovered to ≤ grade 1 or baseline.

Dosage with Hepatic Impairment:

Hepatic impairment may increase the plasma concentration of entrectinib and/or its major active metabolite as entrectinib is primarily eliminated through metabolism in the liver.

Hepatic Impairment	Entrectinib Dose
Child-Pugh A	No dose adjustment required
Child-Pugh B	No dose adjustment required
Child-Pugh C	No dose adjustment required; closely monitor hepatic function and toxicities

Dosage with Renal Impairment:

The pharmacokinetics of entrectinib are not significantly affected by renal impairment.

Creatinine Clearance (mL/min)	Entrectinib Dose
≥ 30	No dose adjustment required
< 30	Has not been studied

Dosage in the elderly:

No dose adjustment required. No differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients.

Dosage based on ethnicity:

No dose adjustment required.

Children:

Safety and efficacy in children have not been established. Entrectinib was associated with a higher risk of skeletal fractures in the pediatric population compared to adults.

F - Administration Guidelines

Administer with or without food.
Capsules should be swallowed whole and not opened, crushed, chewed, or dissolved.
Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
If a dose is missed, a make-up dose can be administered unless the next dose is within 12 hours.
If vomiting occurs immediately after the dose, the dose may be repeated.

Store at room temperature (15-30°C).

G - Special Precautions

Contraindications:

Patients who have a hypersensitivity to this drug or any components of the formulation.

Other Warnings/Precautions:

Entrectinib contains lactose; consider use in patients with lactose intolerance, hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Patients with symptomatic CHF, myocardial infarction, unstable angina, or coronary artery bypass graft within three to six months of study entry were excluded from clinical trials.
Entrectinib should be avoided in patients with congenital long QT syndrome.
Caution with driving or using machinery as visual disturbances, dizziness, and syncope may occur with treatment.

Other Drug Properties:

Carcinogenicity: Unknown

Pregnancy and Lactation:

Clastogenicity: No
Mutagenicity: No
Genotoxicity: Probable
Teratogenicity: Probable
Fetotoxicity: Yes

Entrectinib is not recommended for use in pregnancy.
- Adequate contraception should be used by patients who can become pregnant and their partners during treatment, and for at least 5 weeks after the last dose.
- Adequate contraception should be used by patients who produce sperm and their partners during treatment, and for at least 3 months after the last dose.
Breastfeeding:
Breastfeeding is not recommended during treatment and for at least 2 weeks after the final dose.
Fertility effects:
Documented in male animals

H - Interactions

CYP3A4 is the predominant enzyme mediating the metabolism of entrectinib and formation of its major active metabolite M5.

Entrectinib is a weak inhibitor of BCRP, OATP 1B1 and MATE1 and a weak P-gp substrate. Entrectinib is not a BCRP substrate, but M5 is a P-gp and BCRP substrate.

Entrectinib and M5 do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.

No dose adjustment is required when entrectinib is co-administered with proton pump inhibitors or other drugs that raise gastric pH.

AGENT	EFFECT	MECHANISM	MANAGEMENT
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit)	↑ entrectinib concentration and/or toxicity. (exposure of entrectinib was increased by 500% when given with itraconazole)	↓ metabolism of entrectinib	Avoid co-administration or limit concomitant use with strong or moderate CYP3A4 inhibitors to ≤14 days. If concomitant use of strong inhibitors cannot be avoided, reduce entrectinib dose to 100mg daily. If concomitant use of moderate inhibitors cannot be avoided, reduce entrectinib dose to 200mg daily. After discontinuation of strong or moderate CYP3A4 inhibitor for 3 to 5 t1/2, resume entrectinib dose from prior to initiating the inhibitor.
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc)	↓ entrectinib concentration and/or efficacy (exposure of entrectinib was reduced by 77% when given with rifampin)	↑ metabolism of entrectinib	Avoid concomitant use with CYP3A4 inducers.
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc)	Enhance the QTc-prolonging effect	Additive	Avoid concomitant use with drugs that may prolong QT interval.
CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors)	↑ substrate concentration and/or toxicity. (exposure of midazolam increased by ~50%).	↓ metabolism of substrate	Caution and monitor with drugs with narrow therapeutic index.
P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron)	↑ substrate concentration and/or toxicity. (digoxin Cmax increased by 28% and AUC by 18%%, with minimal effect on digoxin clearance)	Entrectinib is a weak P-gp inhibitor	No dose adjustment required. Caution and monitor with drugs with narrow therapeutic index.

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
CBC	Baseline, at each visit and as clinically indicated
ECG	Baseline and as clinically indicated; more frequently in patients with risk factors such as CHF, electrolyte abnormalities, or concomitant medications known to prolong QT interval
LVEF	Baseline in patients with symptoms or known risk factors for CHF, and as clinically indicated
Liver function tests	Every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated
Electrolytes, uric acid levels	Baseline and as clinically indicated
Renal function tests	Baseline and as clinically indicated
Clinical toxicity assessment for signs/symptoms of edema, fatigue, fractures, cardiotoxicity, tumor lysis syndrome, visual changes, GI and CNS effects	As clinically indicated

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

entrectinib - For the treatment of locally advanced (not amenable to curative therapy) or metastatic NSCLC, according to clinical criteria
entrectinib - Treatment of patients with unresectable locally advanced, or metastatic solid extracranial tumours documented to have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, according to specific criteria

K - References

Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6.

Dziadziuszko R, Krebs MG, De Braud F, et al. Updated integrated analysis of the efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small-cell lung cancer. J Clin Oncol. 2021 Apr 10;39(11):1253-1263. doi: 10.1200/JCO.20.03025.

Prescribing Information: Rozlytrek® (entrectinib). Genentech USA, Inc. South San Francisco, CA. November 2021.

Product Monograph: Rozlytrek® (entrectinib). Hoffmann-La Roche Limited. November 9, 2023.

March 2024 Modified Dosage with toxicity and Dosage with hepatic toxicity sections

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.

Info Sheet Name:

entrectinib (patient)

Info Sheet Introduction:

• For treating certain types of lung cancer called non-small cell lung cancer (NSCLC) and other cancers.

Info Sheet Date: Vendredi, mars 1, 2024 Info Sheet body:

Medication Information Sheet

entrectinib (en-TREK-ti-nib)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Rozlytrek®

Appearance:

capsule

in various strengths and colours

What is this medication for?

For treating certain types of lung cancer called non-small cell lung cancer (NSCLC) and other cancers.

What should I do before I have this medication?

Tell your health care team if you have or had significant medical condition(s), especially if you have / had:

Heart problems including irregular heartbeats, or problems like fainting
Liver or kidney problems,
Bone fractures, or
Any allergies.

This drug contains a small amount of lactose. If you cannot tolerate lactose, talk to your health care team.

Remember to:

Tell your health care team about all of the other medications you are taking.
Keep taking other medications that have been prescribed for you, unless you have been told not to by your health care team.

You will have a blood test to check for hepatitis B before starting treatment. See the Hepatitis B and Cancer Medications pamphlet for more information.

How will this medication affect sex, pregnancy and breastfeeding?

Talk to your health care team about:

How this medication may affect your sexual health.
How this medication may affect your ability to have a baby, if this applies to you.

This medication may harm an unborn baby. Tell your health care team if you or your partner are pregnant, become pregnant during treatment, or are breastfeeding.

If there is any chance you may become pregnant, you and your partner together must use 2 effective forms of birth control at the same time until at least 5 weeks after your last dose. Talk to your health care team about which birth control options are best for you.
If you are a patient that can get somebody pregnant, you and your partner together must use 2 effective forms of birth control at the same time until at least 3 months after your last dose. Talk to your health care team about which birth control options are best for you.
Do not breastfeed while on this medication and for at least 2 weeks after your last dose.

How is this medication given?

This medication is usually taken once a day by mouth with or without food. Talk to your health care team about how and when to take your medication.
You may need a mix of capsules of different strengths to get the right dose. Make sure you look at your capsules closely so that you take the right dose.
Swallow whole. Do not open or dissolve the capsules.
Do not eat or drink grapefruit, starfruit, Seville oranges or their juices (or products that contain these) while taking this drug. They may increase the amount of drug in your blood and increase side effects.
If you forget to take a dose of your entrectinib:
- If it has been less than 12 hours from the missed dose, take the dose as usual. Then take your next dose at the normal scheduled time.
- If it has been longer than 12 hours, do not take the dose. Take your next dose at the normal scheduled time. Do not take extra (double up) to make up for the missed dose.
If you vomit right after taking a dose, you may take the dose again.
If you take too much of your medication by accident, or if you think a child or a pet may have swallowed your medication, you must call the Ontario Poison Control Center right away at: 1-800-268-9017.

What else do I need to know while on this medication?

Will this medication interact with other medications or natural health products?
- This medication can interact with other medications, vitamins, foods and natural health products. Interactions can make the treatment not work as well or cause severe side effects.
- Tell your health care team about all of your:
  - prescription and over-the-counter (non-prescription) medications and all other drugs, such as cannabis/marijuana (medical or recreational)
  - natural health products such as vitamins, herbal teas, homeopathic medicines, and other supplements
- Check with your health care team before starting or stopping any of them.
What should I do if I feel unwell, have pain, a headache or a fever?
- Always check your temperature to see if you have a fever before taking any medications for fever or pain (such as acetaminophen (Tylenol®) or ibuprofen (Advil®)).
  - Fever can be a sign of infection that may need treatment right away.
  - If you take these medications before you check for fever, they may lower your temperature and you may not know you have an infection.
How to check for fever:

Keep a digital (electronic) thermometer at home and take your temperature if you feel hot or unwell (for example, chills, headache, mild pain).
- You have a fever if your temperature taken in your mouth (oral temperature) is:
  - 38.3°C (100.9°F) or higher at any time
    
    OR
  - 38.0°C (100.4°F) or higher for at least one hour.
If you do have a fever:
- Try to contact your health care team. If you are not able to talk to them for advice, you MUST get emergency medical help right away.
- Ask your health care team for the Fever pamphlet for more information.
If you do not have a fever but have mild symptoms such as headache or mild pain:
- Ask your health care team about the right medication for you. Acetaminophen (Tylenol®) is a safe choice for most people.
- Talk to your health care team before you start taking Ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or ASA (Aspirin®), as they may increase your chance of bleeding or interact with your cancer treatment.
- Talk to your health care team if you already take low dose aspirin for a medical condition (such as a heart problem). It may still be safe to take.

What to DO while on this medication:

DO check with your health care team before getting any vaccinations, surgery, dental work or other medical procedures.
DO talk to your health care team about your risk of getting heart problems after this treatment.

What NOT to DO while on this medication:

DO NOT smoke or drink alcohol while on treatment without talking to your health care team first. Smoking and drinking can make side effects worse and make your treatment not work as well.
DO NOT eat or drink grapefruit, starfruit, Seville oranges or their juices (or products that contain these) while taking this drug. They may increase the amount of drug in your blood and increase side effects.
DO NOT drive, operate machinery or do any tasks that need you to be alert if you feel dizzy or have blurred vision.

How should I safely store this medication?

Do not throw out any unused medications at home. Bring them to your pharmacy to be thrown away safely.
Keep this medication in the original packaging at room temperature in a dry place, away from heat and light. Keep out of sight and reach of children and pets.
How to safely touch oral anti-cancer medications

If you are a patient:
- Wash your hands before and after touching your oral anti-cancer medication.
- Swallow each pill whole. Do not crush or chew your pills.
If you are a caregiver:
- Wear nitrile or latex gloves when touching tablets, capsules or liquids.
- Wash your hands before putting on your gloves and after taking them off, even if your skin did not touch the oral anti-cancer medication.
- Throw out your gloves after each use. Do not re-use gloves.
- Do not touch oral anti-cancer medications if you are pregnant or breastfeeding.
What to do if oral anti-cancer medication gets on your skin or in your eyes

If medication gets on your skin:
- Wash your skin with a lot of soap and water.
- If your skin gets red or irritated, talk to your health care team.
If medication gets in your eyes:
- Rinse your eyes with running water right away. Keep water flowing over your open eyes for at least 15 minutes.

What are the side effects of this medication?

The following table lists side effects that you may have when getting entrectinib. The table is set up to list the most common side effects first and the least common last. It is unlikely that you will have all of the side effects listed and you may have some that are not listed.

Read over the side effect table so that you know what to look for and when to get help. Refer to this table if you experience any side effects while on entrectinib.

Common Side Effects (25 to 49 out of 100 people)
Side effects and what to do	When to contact health care team
Fatigue What to look for? Feeling of tiredness or low energy that lasts a long time and does not go away with rest or sleep. What to do? Be active. Aim to get 30 minutes of moderate exercise (you are able to talk comfortably while exercising) on most days. Check with your health care team before starting any new exercise. Pace yourself, do not rush. Put off less important activities. Rest when you need to. Ask family or friends to help you with things like housework, shopping, and child or pet care. Eat well and drink at least 6 to 8 glasses of water or other liquids every day (unless your health care team has told you to drink more or less). Avoid driving or using machinery if you are feeling tired. Ask your health care team for the Fatigue pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe
Constipation What to look for? Having bowel movements (going poo) less often than normal. Small hard stools (poo) that look like pellets. The need to push hard and strain to have any stool (poo) come out. Stomach ache or cramps. A bloated belly, feeling of fullness, or discomfort. Leaking of watery stools (poo). Lots of gas or burping. Nausea or vomiting. What to do? To help prevent constipation: Try to eat more fiber rich foods like fruits with skin, leafy greens and whole grains. Drink at least 6 to 8 cups of liquids each day unless your health care team has told you to drink more or less. Be Active. Exercise can help to keep you regular. If you take opioid pain medication, ask your health care team if eating more fibre is right for you. To help treat constipation: If you have not had a bowel movement in 2 to 3 days you may need to take a laxative (medication to help you poo) to help you have regular bowel movements. Ask your health care team what to do. Ask your health care team for the Constipation Pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe
Taste changes What to look for? Food and drinks may taste different than usual. What to do? Eat foods that are easy to chew, such as scrambled eggs, pasta, soups, cooked vegetables. Taste foods at different temperatures, since the flavour may change. Try different forms of foods, like fresh, frozen or canned. Experiment with non-spicy foods, spices and seasonings.	Talk to your health care team if it does not improve or if it is severe
Mild swelling What to look for? You may have mild swelling or puffiness in your arms and/or legs. Rarely, this may be severe. What to do? To help prevent swelling: Eat a low-salt diet. If you have swelling: Wear loose-fitting clothing. For swollen legs or feet, keep your feet up when sitting.	Talk to your health care team if it does not improve or if it is severe
Dizziness What to look for? You may feel light-headed and like you might faint (pass out). What to do? Lay down right away so you do not fall. Slowly get up and start moving once you feel better. Do not drive a motor vehicle or use machinery if you feel dizzy.	Talk to your health care team if it does not improve or if it is severe
Diarrhea What to look for? Loose, watery, unformed stool (poo) that may happen days to weeks after you get your treatment. What to do? If you have diarrhea: Take anti-diarrhea medication if your health care team prescribed it or told you to take it. Do not eat foods or drinks with artificial sweetener (like chewing gum or ‘diet’ drinks), coffee and alcohol, until your diarrhea has stopped. Eat many small meals and snacks instead of 2 or 3 large meals. Drink at least 6 to 8 cups of liquids each day, unless your health care team has told you to drink more or less. Talk to your health care team if you can’t drink 6 to 8 cups of liquids each day when you have diarrhea. You may need to drink special liquids with salt and sugar, called Oral Rehydration Therapy. Talk to your health care team if your diarrhea does not improve after 24 hours of taking diarrhea medication or if you have diarrhea more than 7 times in one day. Ask your health care team for the Diarrhea pamphlet for more information.	Talk to your health care team if no improvement after 24 hours of taking diarrhea medication or if severe (more than 7 times in one day)
Nausea and vomiting (Generally mild) What to look for? Nausea is feeling like you need to throw up. You may also feel light-headed. You may feel nausea within hours to days after your treatment. What to do? To help prevent nausea: It is easier to prevent nausea than to treat it once it happens. If you were given anti-nausea medication(s), take them as prescribed, even if you do not feel like throwing up. Drink clear liquids and have small meals. Get fresh air and rest. Do not eat spicy, fried foods or foods with a strong smell. Limit caffeine (like coffee, tea) and avoid alcohol. If you have nausea or vomiting: Take your rescue (as-needed) anti-nausea medication(s) as prescribed. Ask your health care team for the Nausea & Vomiting pamphlet for more information. Talk to your health care team if: nausea lasts more than 48 hours vomiting lasts more than 24 hours or if it is severe	Talk to your healthcare team if nausea lasts more than 48 hours or vomiting lasts more than 24 hours or if it is severe
Cough and feeling short of breath What to look for? You may have a cough and feel short of breath. Symptoms that commonly occur with a cough are: wheezing or a whistling breathing runny nose sore throat heartburn weight loss fever and chills Rarely this may be severe with chest pain, trouble breathing or coughing up blood. What to do? Check your temperature to see if you have a fever. Read the above section "What should I do if I feel unwell, have pain, a headache or a fever?". If you have a fever, try to talk to your health care team. If you are not able to talk to them for advice, you MUST get emergency medical help right away. If you have a severe cough with chest pain, trouble breathing or you are coughing up blood, get medical help right away.	Talk to your health care team. If you are not able to talk to your health care team for advice, and you have a fever or severe symptoms, you MUST get emergency medical help right away
Neuropathy (Tingling, numb toes or fingers) What to look for? Numbness or tingling of your fingers and toes may happen after starting your treatment. It can also happen to other parts of your body. Sometimes it can be painful and feel like a burning sensation, which may be severe. What to do? Talk to your health care team if you have symptoms of neuropathy. Numbness and tingling may slowly get better after your treatment ends. In rare cases, it may continue long after treatment ends. If you continue to have bothersome symptoms, talk to your health care team for advice.	Talk to your health care team, especially if you have trouble doing tasks like doing up buttons, writing, moving, or if you have severe pain or numbness
Low neutrophils (white blood cells) in the blood (neutropenia) When neutrophils are low, you are at risk of getting an infection more easily. Ask your health care team for the Neutropenia (Low white blood cell count) pamphlet for more information. What to look for? If you feel hot or unwell (for example if you have chills or a new cough), you must check your temperature to see if you have a fever. Do not take medications that treat a fever before you take your temperature (for example, Tylenol® (acetaminophen), or Advil® (ibuprofen)). Do not eat or drink anything hot or cold right before taking your temperature. You have a fever if your temperature taken in your mouth (oral temperature) is: 38.3°C (100.9°F) or higher at any time OR 38.0°C (100.4°F) or higher for at least one hour. What to do? If your health care team has told you that you have low neutrophils: Wash your hands often to prevent infection. Check with your health care team before getting any vaccines, surgeries, medical procedures or visiting your dentist. Keep a digital thermometer at home so you can easily check for a fever. If you have a fever: If you have a fever, try to contact your health care team. If you are unable to talk to the team for advice, you must get emergency medical help right away.	If you have a fever, try to contact your health care team. If you are unable to talk to the team for advice, you MUST get emergency medical help right away.
Low platelets in the blood When your platelets are low, you are at risk for bleeding and bruising. Ask your health care team for the Low Platelet Count pamphlet for more information. What to look for? Watch for signs of bleeding: bleeding from your gums unusual or heavy nosebleeds bruising easily or more than normal black coloured stools (poo) or blood in your stools (poo) coughing up red or brown coloured mucus dizziness, constant headache or changes in your vision heavy vaginal bleeding red or pink coloured urine (pee) What to do? If your health care team has told you that you have low platelets: Tell your pharmacist that your platelet count may be low before taking any prescriptions or over-the-counter medication. Check with your healthcare team before you go to the dentist. Take care of your mouth and use a soft toothbrush. Try to prevent cuts and bruises. Ask your health care team what activities are safe for you. Your treatment may have to be delayed if you have low platelets. Your health care team may recommend a blood transfusion. If you have signs of bleeding: If you have a small bleed, clean the area with soap and water or a saline (saltwater) rinse. Apply pressure for at least 10 minutes. If you have bleeding that does not stop or is severe (very heavy), you must get emergency medical help right away.	Talk to your health care team if you have any signs of bleeding. If you have bleeding that doesn’t stop or is severe (very heavy), you MUST get emergency help right away.
Effects on your brain or nerves (how you think and move) What to look for? You may have: A severe headache, pass out (faint), or have seizures Confusion Hallucinations (seeing or hearing things that aren’t there) Delusions (a strong belief that isn't real) Trouble thinking and talking or swallowing Trouble with moving, balance or coordination. This may lead to falls What to do? If you have any of these symptoms, get emergency medical help right away.	Get emergency medical help right away

Less Common Side Effects (10 to 24 out of 100 people)
Side effects and what to do	When to contact health care team
Eye problems What to look for? Your eyes may feel dry, irritated, or painful. They may look red and have a lot of tears. They may feel sensitive to light and your vision may be blurry. What to do? Avoid wearing contact lenses. Wear sunglasses with UV protection. Use protective eyewear (goggles or helmet with face mask) when playing sports, mowing the lawn or doing anything that may get particles or fumes in your eyes. You may try artificial tears (eye drops) or ointment.	Contact your health care team as soon as possible (office hours)
Headache; mild joint, muscle pain or cramps What to look for? Mild headache New pain in your muscles or joints, muscle cramps, or feeling achy. What to do? Take pain medication (acetaminophen or opioids such as codeine, morphine, hydromorphone, oxycodone) as prescribed. Read the above section: "What should I do if I feel unwell, have pain, a headache or a fever?" before taking acetaminophen (Tylenol®), ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or Aspirin. These medications may hide an infection that needs treatment or they may increase your risk of bleeding. Rest often and try light exercise (such as walking) as it may help. Ask your health care team for the Pain pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe
Low blood pressure What to look for? You may feel tired, dizzy or light-headed. You may have nausea (feeling like you need to throw up), vomiting or blurred vision. You may faint (pass out). What to do? Check your blood pressure often. Talk to your health care team to find out what a safe blood pressure is for you. If you feel dizzy or unwell lay down right away so that you do not fall. Try to get up and move slowly only once you feel better. Do not drive a motor vehicle or operate machinery if you feel dizzy. Your blood pressure may drop when the medication is being given to you. Let your health care team know right away if you start to feel dizzy or lightheaded.	Talk to your health care team if it does not improve or if it is severe
Liver problems Your health care team may check your liver function with a blood test. Liver changes do not usually cause any symptoms. What to look for? Rarely, you may develop yellowish skin or eyes, unusually dark pee or pain on the right side of your belly. This may be severe. What to do? If you have any symptoms of liver problems, get emergency medical help right away.	Get emergency medical help right away
Drowsiness (sleepiness) or trouble sleeping Your medication(s) may cause you to feel sleepy at times when you are usually awake, or cause trouble sleeping. It may get better once your body gets used to the medication or when your treatment ends. What to look for? You may find it hard to fall asleep or stay asleep. How well you sleep may change over your treatment. For example, you may have several nights of poor sleep followed by a night of better sleep. You may wake up too early or not feel well-rested after a night's sleep. You may feel tired or sleepy during the day. What to do? Try to keep a regular bedtime routine. Go to bed and get up at the same time every day. Talk to your health care team if it does not improve or if it is severe.	Talk to your health care team if it does not improve or if it is severe
Low appetite What to look for? Loss of interest in food or not feeling hungry. Weight loss. What to do? Try to eat your favourite foods. Eat small meals throughout the day. You may need to take meal supplements to help keep your weight up. Talk to your health care team if you have no appetite. Ask your health care team for the Loss of Appetite pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe
Rash; dry, itchy skin What to look for? You may have cracked, rough, flaking or peeling areas of the skin. Your skin may look red and feel warm, like a sunburn. Your skin may itch, burn, sting or feel very tender when touched. What to do? To prevent and treat dry skin: Use fragrance-free skin moisturizer. Protect your skin from the sun and the cold. Use sunscreen with UVA and UVB protection and a SPF of at least 30. Avoid perfumed products and lotions that contain alcohol. Drink 6 to 8 cups of non-alcoholic, non-caffeinated liquids each day, unless your health care team has told you to drink more or less. Rash may be severe in some rare cases and cause your skin to blister or peel. If this happens, get emergency medical help right away.	Talk to your health care team if it does not improve or if it is severe
Mood changes What to look for? You may feel hopeless or sad most of the day. You may feel anxious, nervous, restless, agitated or stressed. You may feel like you have less energy or have little or no interest in activities that you usually enjoy. You may have changes in your personality. What to do? Eating well and exercising may give you more energy and help you feel better. Always check with your health care team before starting a new exercise program to make sure it is safe for you. Try to keep a regular bedtime routine. Go to bed and get up at the same time every day. Get support from your family, friends, community and your health care team. Talk to your health care team if your mood changes do not improve or if they are severe.	Talk to your health care team if it does not improve or if it is severe

Other rare, but serious side effects are possible.
If you experience ANY of the following, speak to your cancer health care provider or get emergency medical help right away:

An irregular heartbeat, shortness of breath, chest pain or fainting spells.
Severe muscle cramping, or twitching, swelling in your joints or pain in your lower back
Changes in urination (peeing) such as less urine than usual and weight gain that is not normal for you
Severe or unusual bone pain especially in your back, hips and wrist. This may be a symptom of a bone fracture (broken bone).

Who do I contact if I have questions or need help?

My cancer health care provider is: ______________________________________________

During the day I should contact:________________________________________________

Evenings, weekends and holidays:______________________________________________

Other Notes:

____________________________________________________________________________

March 2024 Updated “How will this medication affect sex, pregnancy and breastfeeding?“ section

For more links on how to manage your symptoms go to www.cancercareontario.ca/symptoms.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

entrectinib patient.pdf Info Sheet (French):

entrectinib pour le patient.pdf Monograph:

entrectinib.pdf Funding Program: Exceptional Access Program Funding Instance:

entrectinib - For the treatment of locally advanced (not amenable to curative therapy) or metastatic NSCLC, according to clinical criteria
entrectinib - Treatment of patients with unresectable locally advanced, or metastatic solid extracranial tumours documented to have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, according to specific criteria

Phonetic Spelling:

en-TREK-ti-nib

Cancer Type: Breast Endocrine Adrenal Neuroendocrine Pancreatic Neuroendocrine Parathyroid Thymoma Thyroid Gastrointestinal Anus Colorectal Esophagus Gastric / Stomach Gastrointestinal Stromal Tumours Hepatobiliary / Liver / Bile Duct Mesothelioma (Peritoneal) Neuroendocrine (GI) Pancreas Rectal Small bowel and appendix Genitourinary Bladder / Urothelial Penile Prostate Renal cell / Kidney Testis Gynecologic Cervix Endometrial Germ Cell Gestational Trophoblastic Disease Ovary Uterine Sarcoma Vagina Vulva Head and Neck Larynx Nasopharynx Oral Paranasal Sinus Pharynx Salivary Gland Squamous Cell Lung Neuroendocrine (Lung) Non-Small Cell Small Cell Mesothelioma Ocular / Eye Sarcoma Desmoid Tumour Ewing's Ewing's and Soft Tissue GIST Giant Cell Tumour Kaposi's Sarcoma Osteogenic / Bone Soft Tissue Uterine Wilm's Tumour Skin Basal Cell Melanoma Merkel Cell Squamous Cell Unknown Primary Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Vendredi, mars 1, 2024 Universal Date: 2024-03-01 00:00:00 AddThis: Title URL: entrectinib Drug Display Status: Active Revision Summary:
Drug Monograph: Modified Dosage with toxicity and Dosage with hepatic toxicity sections
Patient Info Sheet EN: Updated “How will this medication affect sex, pregnancy and breastfeeding?“ section
Patient Info Sheet FR: Updated “How will this medication affect sex, pregnancy and breastfeeding?“ section (Mise à jour de la section « Comment ce médicament affecte-il les relations sexuelles, la grossesse et l’allaitement?»)