Consumer medicine information

Retevmo

Selpercatinib

BRAND INFORMATION

Brand name

Retevmo

Active ingredient

Selpercatinib

Schedule

SUMMARY CMI

RETEVMO^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I taking RETEVMO?

RETEVMO contains the active ingredient selpercatinib. RETEVMO is used to treat a type of lung cancer (non-small cell lung cancer (NSCLC)) in adults, caused by an abnormal RET gene.

For more information, see Section 1. Why am I taking RETEVMO? in the full CMI.

2. What should I know before I take RETEVMO?

Do not take if you have ever had an allergic reaction to RETEVMO or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take RETEVMO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with RETEVMO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take RETEVMO?

Your doctor will prescribe the right dose for you. The maximum doses are: 1) for patients with less than 50 kg body weight: 120 mg twice a day; 2) for patients with 50 kg body weight or greater: 160 mg twice a day.

More instructions can be found in Section 4. How do I take RETEVMO? in the full CMI.

5. What should I know while taking RETEVMO?

Things you should do	You and your partner should use an effective method of birth control (contraception) to avoid becoming pregnant while taking RETEVMO and for at least one week after your final dose. Tell your doctor straight away if you experience any signs of bleeding or liver problems. You will need to have regular blood tests, blood pressure checks and ECG testing. Remind any doctor, dentist or pharmacist you visit that you are using RETEVMO.
Things you should not do	Do not take RETEVMO to treat any other complaints unless your doctor tells you to. Do not give your medicine to anyone else, even if they have the same condition as you. Do not stop taking your medicine, or change the dosage, without checking with your doctor.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how RETEVMO affects you. RETEVMO may make you feel tired or dizzy.
Looking after your medicine	Keep your capsules in the original pack until it is time to take them. This medicine does not require any special storage conditions.

For more information, see Section 5. What should I know while taking RETEVMO? in the full CMI.

6. Are there any side effects?

Potential side effects include swelling, diarrhoea, tiredness, dry mouth, abdominal pain, constipation, rash, nausea, headache, vomiting, dizziness, decreased appetite, fever. Serious potential side effects include severe or life threatening inflammation of the lungs, raised liver enzymes, high blood pressure, bleeding, heart rhythm changes (which prolong the QT interval), low thyroid hormone levels (characterised by weight gain, feeling cold, tiredness that worsens or does not go away, constipation), allergic reactions (characterised by fever, rash, and muscle and joint pain), accumulation of fluid in the lung and in the abdominal area.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

RETEVMO^®

Active ingredient: selpercatinib

This medicine has provisional approval for the treatment of adults with a type of lung cancer called non-small cell lung cancer (NSCLC). The decision to approve this medicine has been made on the basis of promising results from a preliminary study. More evidence is required to be submitted when available to fully confirm the benefit and safety of the medicine for this use.

Consumer Medicine Information (CMI)

This leaflet provides important information about using RETEVMO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking RETEVMO.

Where to find information in this leaflet:

1. Why am I taking RETEVMO?
2. What should I know before I take RETEVMO?
3. What if I am taking other medicines?
4. How do I take RETEVMO?
5. What should I know while taking RETEVMO?
6. Are there any side effects?
7. Product details

1. Why am I taking RETEVMO?

RETEVMO contains the active ingredient selpercatinib. RETEVMO is an anti-cancer prescription medicine.

RETEVMO is used to treat a lung cancer, called non-small cell lung cancer (NSCLC), in adults, caused by abnormal changes in the RET gene.

Your doctor will perform a test to check if your cancer has a change in the RET gene to make sure that RETEVMO is right for you.

In patients whose cancer has an altered RET gene, the change in the gene causes the body to make an abnormal RET protein, which can lead to uncontrolled cell growth and cancer. RETEVMO blocks the action of the abnormal RET protein and so may slow or stop the growth of the cancer. It may also help to shrink the cancer.

2. What should I know before I take RETEVMO?

Warnings

Do not take RETEVMO if:

you are allergic to selpercatinib, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have liver problems.
have lung or breathing problems other than lung cancer.
have high blood pressure.
have heart problems including a condition called QT prolongation.
have bleeding problems.
have a history of kidney problems or low blood pressure as this may increase your risks associated with tumour lysis syndrome (TLS).
take any medicines for any other condition, including prescription, over the counter medicines, vitamins, minerals and herbal supplements.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you or your partner are pregnant or intend to become pregnant.

RETEVMO can harm your unborn baby.
Females who are able to become pregnant should use an effective method of birth control (contraception) to avoid becoming pregnant while taking RETEVMO and for at least one week after your final dose. Your doctor can discuss the risks and benefits involved.
Males with female partners, who are able to become pregnant, should use effective method of contraception during treatment with RETEVMO and for at least 1 week after the final dose of RETEVMO.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if RETEVMO passes into your breastmilk.
Do not breastfeed if you are taking RETEVMO and for at least 1 week after the last dose.

Use in children

RETEVMO is not intended for use by children under the age of 18 years.

Use in elderly

RETEVMO may be used in elderly patients aged 65 years and over.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with RETEVMO and affect how it works.

Medicines that may increase the effect of RETEVMO include:

itraconazole, ketoconazole, posaconazole, voriconazole (used to treat fungal infections)
ritonavir, saquinavir (used to treat HIV infections/AIDS)

Medicines that may reduce the effect of RETEVMO include:

carbamazepine (used to treat epilepsy, nerve pain, bipolar disorder)
phenytoin, phenobarbital (used to treat epilepsy)
rifampicin, rifabutin (used to treat tuberculosis (TB) and some other infections)
St. John's wort (a herbal product used to treat mild depression and anxiety)

RETEVMO may affect the way some medicines work, including the following:

medicines that are a substrate of the liver enzyme CYP3A4, for example:
- midazolam (used for sedation prior surgery)
- alfentanil (used in anaesthetic procedures)
- avanafil, vardenafil (used to treat erectile dysfunction)
- darunavir (used to treat HIV infections)
- naloxegol (used to treat constipation)
- simvastatin (used to treat high blood cholesterol)
medicines that are a substrate of the liver enzyme CYP2C8, for example:
- enzalutamide, paclitaxel, sorafenib (used to treat different cancers)
- buprenorphine (used to treat pain or, when combined with another medicine, opiate dependence)
- selexipag (used to treat hypertension)
- montelukast (used to treat asthma)
ranitidine or other H2 blockers (used to treat ulcers and acid reflux).
omeprazole or other proton pump inhibitors (used to treat heartburn, ulcers, and acid reflux).
dabigatran (used to treat deep vein thrombosis and clots in lung, and used to prevent stroke)
digoxin (used to treat heart disorders).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect RETEVMO.

4. How do I take RETEVMO?

How much to take

Your doctor will prescribe the right dose for you.

The maximum recommended dose is:

for patients with less than 50 kg body weight: 120 mg twice a day
for patients with 50 kg body weight or greater: 160 mg twice a day.

Follow the instructions provided and use RETEVMO until your doctor tells you to stop.

If you get certain side effects while you are taking RETEVMO your doctor may lower your dose or stop treatment temporarily or permanently.

When to take RETEVMO

RETEVMO is taken twice a day at about the same time every day, preferably in the morning and evening.
Swallow the capsule whole with a glass of water. Do not chew, crush or split the capsule before swallowing.
You can take the capsules either with or without food. Please note, if you are also taking omeprazole or other proton pump inhibitors (used to treat heartburn, ulcers, and acid reflux), then take RETEVMO with a full meal.
If you are also taking ranitidine or other H2 blockers (used to treat ulcers and acid reflux), then take RETEVMO 2 hours before or 10 hours after taking them.
If you are taking omeprazole or other proton pump inhibitors (used to treat heartburn, ulcers, and acid reflux), then take RETEVMO with a full meal.
If you are taking antacid containing aluminium, magnesium, calcium, simethicone, or buffered medicines, then take RETEVMO 2 hours before or 2 hours after.

If you forget to take RETEVMO

If you vomit after taking the dose or forget a dose, take your next dose at your usual time. Do not take a double dose to make up for the forgotten or vomited dose.

If you take too much RETEVMO

If you think that you have taken too much RETEVMO, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking RETEVMO?

Things you should do

RETEVMO may cause inflammation of the lungs. Your doctor will monitor you before and during treatment with Retevmo for symptoms. Tell your doctor right away if you notice any symptoms of lung problems including breathlessness, cough and raised temperature as your dose may need to be lowered, or treatment paused.

You will have regular blood tests before and during treatment with RETEVMO, to check your liver function and electrolytes (such as sodium, potassium, magnesium and calcium) in your blood.

RETEVMO may result in abnormal ECGs. You will have an ECG taken before and during your treatment with RETEVMO. Tell your doctor if you experience fainting as it may be a symptom of abnormal ECG.

RETEVMO may affect your blood pressure. Your blood pressure will be measured before and during your treatment.

RETEVMO can affect the way your wounds heal. Tell your doctor if you plan to have surgery. You may need to stop taking RETEVMO at least 7 days before your planned surgery and at least 2 weeks after the surgery.

Your doctor will do blood tests to check your thyroid function before and during treatment with RETEVMO. Tell your doctor if you develop signs or symptoms of low thyroid hormone levels such as weight gain, feeling cold, tiredness that worsens or that does not go away and constipation. Your doctor may prescribe you thyroid hormone replacement and/or your treatment with RETEVMO may be paused until your thyroid hormone levels normalise.

Your doctor may do blood tests to check you for tumour lysis syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. It can cause kidney failure, the need for dialysis treatment, and an abnormal heartbeat. Staying well hydrated may help prevent TLS from occurring.

Call your doctor or go to emergency if you develop nausea, vomiting, weakness, swelling, shortness of breath, muscle cramps and seizures during treatment of RETEVMO.

Call your doctor straight away if you:

experience signs of bleeding (see additional information under Section 6. Are there any side effects?)
develop symptoms of liver problems (see additional information under Section 6. Are there any side effects?)
become pregnant while taking this medicine.
You and your partner should use an effective method of contraception to avoid becoming pregnant while taking RETEVMO and for at least one week after your final dose.

Remind any doctor, dentist or pharmacist you visit that you are using RETEVMO.

Things you should not do

Do not take RETEVMO to treat any other complaints unless your doctor tells you to.
Do not give your medicine to anyone else, even if they have the same condition as you.
Do not stop taking your medicine, or change the dosage, without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how RETEVMO affects you.

RETEVMO may make you feel tired or dizzy.

Looking after your medicine

Keep your capsules in the original pack until it is time to take them.
Store below 30°C.

Keep it where young children cannot reach it.

When to discard your medicine

Do not take this medicine if the inner seal is broken or the packaging is torn or shows signs of tampering.

If it is damaged, return it to your pharmacist for safe disposal.

Getting rid of any unwanted medicine

If you no longer need to use medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Gastrointestinal related:

diarrhoea
dry mouth
abdominal pain
constipation
nausea
vomiting

Metabolism related:

decreased appetite

Nervous system related:

headache
dizziness

Skin disorder:

rash

General disorders:

swelling
tiredness
fever

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Liver related:

increase in liver enzymes (ALT or AST)

Symptoms may include:

yellowing of your skin or the white part of your eyes (jaundice)
loss of appetite
nausea or vomiting
dark urine
pain on the upper right side of your stomach area
sleepiness
bleeding or bruising

Thyroid related:

low thyroid levels

Symptoms may include:

weight gain
feeling cold
tiredness that worsens or that does not go away
constipation

Blood pressure related:

high blood pressure

Symptoms may include:

confusion
dizziness
headaches
chest pain
shortness of breath

Heart related:

heart rhythm changes (which prolong the QT interval)

Symptoms may include:

loss of consciousness
fainting
dizziness
a change in the way your heart beats (heart palpitations)

Allergy related:

allergic reactions, characterised by fever, rash, and muscle and joint pain, typically in the first month of treatment.

Tell your doctor if you have any of these serious side effects as you may require medical attention.

Blood related:

bleeding

Signs may include:

vomiting blood or if your vomit looks like coffee-grounds
coughing up blood or blood clots
unusual vaginal bleeding or menstrual bleeding that is heavier than normal
nose bleeds that happen often
pink or brown urine
red or black (looks like tar) stools
unusual bleeding or bruising of your skin

Lung related:

infection, inflammation or scarring of the lungs

Symptoms may include:

breathlessness
cough
fever
accumulation of fluid in the lung

Symptoms may include:

breathlessness
pressure in the chest

Gastrointestinal related:

accumulation of fluid in the abdominal area.

Symptoms may include:

Weight gain
abdominal pain
shortness of breath

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Elderly patients aged 65 years and older may experience a higher number of side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Some side effects (for example, changes in liver or other enzymes, kidney markers, electrolyte levels and blood cells levels) can only be found when your doctor does tests from time to time.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects that you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What RETEVMO contains

Active ingredient (main ingredient)	selpercatinib
Other ingredients (inactive ingredients)	Capsule content: microcrystalline cellulose colloidal anhydrous silica 40 mg capsule shell: gelatin titanium dioxide iron oxide black 80 mg capsule shell: gelatin titanium dioxide Brilliant Blue FCF Capsule shell black ink: TekPrint SW-9049 Black Ink

Do not take this medicine if you are allergic to any of these ingredients.

What RETEVMO looks like

RETEVMO 40 mg is a grey, opaque capsule imprinted with "Lilly 3977" and "40 mg" in black ink (Aust R 391331).

RETEVMO 80 mg is a blue, opaque capsule imprinted with "Lilly 2980" and "80 mg" in black ink (Aust R 391330).

Who distributes RETEVMO

Eli Lilly Australia Pty Ltd
Level 9, 60 Margaret Street, Sydney, NSW 2000
AUSTRALIA

®= Registered Trademark

If you have any questions about RETEVMO, contact Eli Lilly at 1800 454 559 (Australia) or your healthcare professional for assistance.

This leaflet was prepared in October 2024.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Retevmo

Active ingredient

Selpercatinib

Schedule

1 Name of Medicine

Selpercatinib.

2 Qualitative and Quantitative Composition

Retevmo 40 mg immediate release hard capsule.

Each immediate release capsule contains 40 mg selpercatinib.

Retevmo 80 mg immediate release hard capsule.

Each immediate release capsule contains 80 mg selpercatinib.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Retevmo 40 mg immediate release hard capsule.

Grey, opaque capsule imprinted with "Lilly 3977" and "40 mg" in black ink.

Retevmo 80 mg immediate release hard capsule.

Blue, opaque capsule imprinted with "Lilly 2980" and "80 mg" in black ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Retevmo has provisional approval for the treatment of adult patients with locally advanced or metastatic RET fusion positive non-small cell lung cancer (NSCLC).
The decision to approve this indication has been made on the basis of objective response rate (ORR) and duration of response (DOR) from a single arm study. Continued approval of this indication depends on verification and description of benefit in a confirmatory trial.

4.2 Dose and Method of Administration

Retevmo therapy should be initiated and supervised by physicians experienced in the use of anti-cancer therapies.

Dose.

The recommended dose of Retevmo based on body weight is:
Less than 50 kg: 120 mg twice daily.
50 kg or greater: 160 mg twice daily.
If a patient vomits or misses a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.
Treatment should be continued until disease progression or unacceptable toxicity.
Avoid concomitant use of strong CYP inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If coadministration with strong CYP3A inhibitor cannot be avoided, reduce the current selpercatinib dose by 50%. If the CYP3A inhibitor is discontinued, increase the selpercatinib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.

Dose adjustments.

Management of some adverse reactions may require dose interruption and/or dose reduction. Generally, dose reductions should be in 40 mg decrements. Retevmo dose modifications are summarised in Table 1 and Table 2.

Special populations.

Elderly.

No dose adjustment is required based on age (see Section 5.2 Pharmacokinetic Properties).
No overall differences were observed in the treatment emergent adverse events or effectiveness of selpercatinib between patients who were ≥ 65 years of age and younger patients. Limited data are available in patients ≥ 75 years.

Renal impairment.

Dose adjustment is not necessary in patients with mild, moderate or severe renal impairment. There are no data in patients with end stage renal disease, or in patients on dialysis (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

Close monitoring of patients with impaired hepatic function is important. No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Patients with severe (Child-Pugh class C) hepatic impairment should be dosed with 80 mg selpercatinib twice daily (see Section 5.2 Pharmacokinetic Properties).

Paediatric population.

There is no data in children or adolescents with RET fusion-positive NSCLC.

Method of administration.

Retevmo is for oral administration.
The capsules should be swallowed whole (patients should not open, crush, or chew the capsule before swallowing) and can be taken with or without food.
Patients should take the doses at approximately the same time every day.
Retevmo concomitant use with strong CYP inducers should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Retevmo must be accompanied by a meal if used concomitantly with a proton pump inhibitor (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Retevmo should be administered 2 hours before or 10 hours after concomitant H₂ receptor antagonists (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Locally acting antacids should be administered 2 hours before or 2 hours after Retevmo.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Interstitial lung disease/pneumonitis.

Interstitial lung disease (ILD) and/or pneumonitis, including severe and life-threatening disease, was reported in patients receiving selpercatinib (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and treat as medically appropriate. Based on the severity of ILD/pneumonitis, selpercatinib may require dose interruption or discontinuation (see Section 4.2 Dose and Method of Administration).

Increased alanine aminotransferase (ALT)/ aspartate aminotransferase (AST).

Grade ≥ 3 increased ALT and Grade ≥ 3 increased AST were reported in patients receiving selpercatinib (see Section 4.8 Adverse Effects (Undesirable Effects)). ALT and AST should be monitored prior to the start of selpercatinib therapy, every 2 weeks during the first 3 months of treatment, monthly for the next 3 months of treatment, and otherwise as clinically indicated. Based on the level of ALT or AST elevations, selpercatinib may require dose modification (see Section 4.2 Dose and Method of Administration).

Hypertension.

Hypertension was reported in patients receiving selpercatinib (see Section 4.8 Adverse Effects (Undesirable Effects)). Patient blood pressure should be controlled before starting selpercatinib treatment, monitored during selpercatinib treatment and treated as needed with standard anti-hypertensive therapy. Based on the level of increased blood pressure, selpercatinib may require dose modification (see Section 4.2 Dose and Method of Administration). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy.

QT interval prolongation.

QT interval prolongation was reported in patients receiving selpercatinib (see Section 5.1 Pharmacodynamic Properties). Selpercatinib should be used with caution in patients with such conditions as congenital long QT syndrome or acquired long QT syndrome or other clinical conditions that predispose to arrhythmias (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients should have a QTcF interval of ≤ 470 ms and serum electrolytes within normal range before starting selpercatinib treatment. Electrocardiograms and serum electrolytes should be monitored in all patients after 1 week of selpercatinib treatment, at least monthly for the first 6 months and otherwise, as clinically indicated, adjusting frequency based upon risk factors including diarrhoea, vomiting, and/or nausea. Hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiating selpercatinib and during treatment. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.
Selpercatinib may require dose interruption or modification (see Section 4.2 Dose and Method of Administration).

Strong CYP3A4 inducers.

Concomitant use of strong CYP3A4 inducers should be avoided due to the risk of decreased efficacy of selpercatinib (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Women of childbearing potential/contraception in females and males.

Women of childbearing potential must use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib (see Section 4.6 Fertility, Pregnancy and Lactation).

Fertility.

Based on nonclinical safety findings, male and female fertility may be compromised by treatment with Retevmo (see Section 4.6 Fertility, Pregnancy and Lactation; Section 5.3 Preclinical Safety Data). Both men and women should seek advice on fertility preservation before treatment.

Hypersensitivity.

Hypersensitivity was reported in patients receiving selpercatinib with a majority of events observed in patients with NSCLC previously treated with anti-PD-1/PD-L1 immunotherapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or elevated aminotransferases.
Suspend selpercatinib if hypersensitivity occurs and begin steroid treatment. Based on the grade of hypersensitivity reactions, selpercatinib may require dose modification (see Section 4.2 Dose and Method of Administration). Steroids should be continued until patient reaches target dose and then tapered. Permanently discontinue selpercatinib for recurrent hypersensitivity.

Haemorrhages.

Serious including fatal haemorrhagic events were reported in patients receiving selpercatinib (see Section 4.8 Adverse Effects (Undesirable Effects)).
Permanently discontinue selpercatinib in patients with severe or life-threatening haemorrhage (see Section 4.2 Dose and Method of Administration).

Hypothyroidism.

Selpercatinib can cause hypothyroidism. Hypothyroidism occurred in 16.1% (135/837) of patients with other solid tumours including NSCLC; all reactions were Grade 1 or 2.
Monitor thyroid function before treatment with Retevmo and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold Retevmo until clinically stable or permanently discontinue Retevmo based on severity (see Section 4.2 Dose and Method of Administration).

Risk of impaired wound healing.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Retevmo has the potential to adversely affect wound healing.
Withhold Retevmo for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Retevmo after resolution of wound healing complications has not been established.

Tumour lysis syndrome (TLS).

Cases of TLS have been observed in patients treated with selpercatinib. Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely and treated as clinically indicated, and appropriate prophylaxis including hydration should be considered.

Use in the elderly.

No dose adjustment is required based on age (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
No overall differences were observed in the treatment emergent adverse events or effectiveness of selpercatinib between patients who were ≥ 65 years of age and younger patients. Limited data are available in patients ≥ 75 years.

Paediatric use.

The safety of selpercatinib in children aged less than 18 years has not been established.

Effects on laboratory tests.

Hepatic transaminase should be monitored prior to the start of selpercatinib therapy, at every 2 weeks interval during the first 3 months, monthly for the next 3 months and as clinically indicated.
Serum electrolytes should be monitored in all patients after 1 week of selpercatinib treatment, at least monthly for the first 6 months and as clinically indicated (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro studies indicate that selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

Effects of other medicinal products on the pharmacokinetics of selpercatinib.

Selpercatinib metabolism is through CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of selpercatinib.
Selpercatinib is a substrate for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) in vitro, however these transporters do not appear to limit the oral absorption of selpercatinib, as its oral bioavailability is 73% and its exposure was increased minimally by co-administration of the P-gp inhibitor rifampicin (increase of approximately 6.5% and 19% in selpercatinib AUC_0-24 and C_max, respectively).

Agents that may increase selpercatinib plasma concentrations.

Co-administration of a single 160 mg selpercatinib dose with itraconazole, a strong CYP3A4 inhibitor, increased the C_max and AUC of selpercatinib by 30% and 130%, respectively, compared to selpercatinib given alone, which may increase the risk of an ADR, including QTc prolongation. If strong CYP3A and/or P-gp inhibitors, including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, saquinavir, telithromycin, posaconazole and nefazodone, have to be co-administered, the dose of selpercatinib should be reduced (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, QT interval prolongation).

Agents that may decrease selpercatinib plasma concentrations.

Co-administration of rifampicin, a strong CYP3A4 inducer resulted in a decrease of approximately 87% and 70% in selpercatinib AUC and C_max, respectively, compared to selpercatinib alone, therefore the concomitant use of strong CYP3A4 inducers including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's wort (Hypericum perforatum), should be avoided.

Effects of selpercatinib on the pharmacokinetics of other medicinal products (increase in plasma concentration).

Sensitive CYP2C8 substrates.

Selpercatinib increased the C_max and AUC of repaglinide (a substrate of CYP2C8) by approximately 91% and 188%, respectively. Therefore, co-administration with sensitive CYP2C8 substrates (e.g. odiaquine, cerivastatin, enzalutamide, paclitaxel, repaglinide, torasemide, sorafenib, rosiglitazone, buprenorphine, selexipag, dasabuvir and montelukast), should be avoided.

Sensitive CYP3A4 substrates.

Selpercatinib increased C_max and AUC of midazolam (a CYP3A4 substrate) by approximately 39% and 54%, respectively. Therefore, concomitant use with sensitive CYP3A4 substrates, (e.g. alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, ebastine, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, tipranavir, triazolam, vardenafil), should be avoided.

Coadministration with medicinal products that affect gastric pH.

Selpercatinib has pH-dependent solubility, with decreased solubility at higher pH. No clinically significant differences in selpercatinib pharmacokinetics were observed when co-administered with multiple daily doses of ranitidine (H₂ receptor antagonist) given 2 hours after the selpercatinib dose.

Coadministration with medicinal products that are proton pump inhibitors.

Co-administration with multiple daily doses of omeprazole (a proton pump inhibitor) decreased selpercatinib AUC_0-inf and C_max when selpercatinib was administered fasting. Co-administration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC_0-inf and C_max when Retevmo was administered with food.

Co-administration with medicinal products that are substrates of transporters.

In vitro studies indicate that selpercatinib inhibits MATE1, P-gp, and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. In vivo interactions of selpercatinib with clinically relevant substrates of MATE1, such as creatinine, may occur.
In vivo, selpercatinib increased C_max and AUC of dabigatran, a P-gp substrate, by 43% and 38%, respectively. Therefore, caution should be used when taking a sensitive P-gp substrate (e.g. fexofenadine, dabigatran etexilate, colchicine, saxagliptin) and particularly those with a narrow therapeutic index (e.g. digoxin).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of selpercatinib on fertility are available. Based on findings from animal studies, male and female fertility may be compromised by treatment with Retevmo (see Section 4.6 Fertility, Pregnancy and Lactation, Reproduction toxicity). Both men and women should seek advice on fertility preservation before treatment.
Women of childbearing potential have to use highly effective contraception during treatment and for at least one week after the last dose of selpercatinib. Men with female partners of childbearing potential should use effective contraception during treatment and for at least one week after the last dose of selpercatinib.

Reproduction toxicity.

Results of studies conducted in rats and minipigs suggest that selpercatinib could impair fertility in males and females.
In a fertility study in male rats, dose-dependent germ cell depletion and spermatid retention were observed at subclinical AUC-based exposure levels. These effects were associated with reduced organ weights, reduced sperm motility, and an increase in the number of abnormal sperm exposures 2-fold the human exposure based on AUC at the maximum recommended human dose. Microscopic findings in the fertility study in male rats were consistent with effects in repeat dose studies in rats and minipigs, in which dose-dependent, non-reversible testicular degeneration was associated with reduced luminal sperm in the epididymis at subclinical AUC-based exposure levels.
In a fertility and early embryonic study in female rats, a reduction in the number of oestrus cycles as well as embryolethality were observed at AUC-based exposure levels approximately equal to clinical exposure at the maximum recommended human dose. In repeat-dose studies in rats, reversible vaginal mucification with individual cell cornification and altered oestrus cycles were noted at clinically relevant AUC-based exposure levels. In minipigs, decreased corpora lutea and/or corpora luteal cysts were observed at subclinical AUC-based clinical exposure levels.
(Category D)
There are no available data from the use of selpercatinib in pregnant women. Studies in animals have shown reproductive toxicity. Retevmo is not recommended during pregnancy and in women of childbearing potential not using contraception. It should only be used during pregnancy if the potential benefit justifies the potential risk to the foetus.

Embryotoxicity/teratogenicity.

Based on data from animal reproduction studies and its mechanism of action, selpercatinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal development study, once daily oral administration of selpercatinib at a dose level of 50 mg/kg (approximately 1.4 times the human exposure based on AUC at the clinical dose of 160 mg twice daily) to pregnant rats during the period of organogenesis resulted in mean 96.4% post-implantation loss per litter and an increase in external malformations.
It is unknown whether selpercatinib is excreted in human milk. A risk to breastfed newborns/infants cannot be excluded. Breastfeeding should be discontinued during treatment with Retevmo and for at least one week after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies have been conducted to determine the effects of selpercatinib on the ability to drive or use machines.
Retevmo may have minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with Retevmo (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety data from study LIBRETTO-001 is based mainly on an adult population who were treated with selpercatinib for solid tumours, which includes participants with non-small cell lung cancer, thyroid cancer, and medullary thyroid cancer.
The most common serious adverse events (SAE) occurring in ≥ 2% of the overall LIBRETTO-001 safety population were pneumonia (6.6%), dyspnoea (3.1%), pleural effusion (3.0%), hyponatraemia (2.7 %), abdominal pain (2.6%), sepsis (2.3%) and diarrhoea (2.0%). Hypersensitivity occurred in 3.9% of patients with RET fusion positive NSCLC but was below 2% incidence for the overall safety population. Permanent discontinuation of Retevmo for treatment emergent adverse events, regardless of attribution occurred in 9.6% of patients.
Treatment emergent adverse events (TEAE) occurring in > 10% in patients receiving single agent selpercatinib (LIBRETTO-001) are shown in Table 3.

Tabulated list of adverse drug reactions.

The ADRs reported in the 837 patients treated with selpercatinib are shown in Table 4, of these 362 patients had RET fusion positive NSCLC.
The most common ADRs resulting in permanent discontinuation (3 or more patients) were increased ALT (0.7%), fatigue (0.6%), increased AST (0.5%), blood bilirubin increased (0.4%), pneumonia (0.4%), thrombocytopenia (0.4%), and haemorrhage (0.4%).
The ADRs are classified according to MedDRA the system organ class. Frequency groups are defined by the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), and not known (cannot be estimated from available data).
Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Median time on treatment with selpercatinib was 30.1 months with mean (standard deviation) for relative dose intensity 83.4% (19.6).

Description of selected adverse reactions.

Aminotransferase elevations (AST/ALT increased).

Based on laboratory assessment, ALT and AST elevations were reported in 56.7% and 61.3% patients, respectively. Grade 3 or 4 ALT or AST elevations were reported in 12.2% and 10.4% patients respectively.
The median time to first onset was: AST increase 4.7 weeks (range: 0.7, 227.9), ALT increase 4.4 weeks (range: 0.9, 186.1).
Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see Section 4.2 Dose and Method of Administration).

QT interval prolongation.

In the 837 patients who had ECGs, review of data showed 8.1% of patients had > 500 msec maximum post-baseline QTcF value, and 21.6% of patients had a > 60 msec maximum increase from baseline in QTcF intervals. At the time of the last post-baseline measurement, increase in QTc value > 60 msec was reported in 2.0% of patients.
There were no reports of Torsades de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, or ventricular flutter related to selpercatinib. One patient (0.1%) discontinued treatment due to QT prolongation.
Retevmo may require dose interruption or modification (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hypertension.

In the 837 patients who had blood pressure measurements, the median maximum increase from baseline systolic pressure was 32 mm Hg (range: -15, +100). Only 10.3% of patients retained their baseline grade during treatment, 40.7% had an increasing shift of 1 grade, 38.5% of 2 grades, and 9.8% of 3 grades. A treatment emergent adverse event of hypertension was reported in 44.8% patients with history of hypertension (28.2% with grade 3, 4) and 41.7% of patients without history of hypertension (14.1% with grade 3, 4).
Overall, a total of 19.8% displayed treatment-emergent grade 3 hypertension (defined as maximum systolic blood pressure greater than 160 mm Hg). Grade 4 treatment emergent hypertension was reported in 0.1% patients. Diastolic blood pressure results were similar, but the increases were of lesser magnitude.
Two patients (0.2%) permanently discontinued treatment due to hypertension. Dose modification is recommended in patients who develop hypertension (see Section 4.2 Dose and Method of Administration). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy (see Section 4.4 Special Warnings and Precautions for Use).

Hypersensitivity.

Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or increased aminotransferase.
In study LIBRETTO-001, 24.0% (201/837) of patients treated with selpercatinib had previously received anti-PD-1/PD-L1 immunotherapy. Hypersensitivity occurred in a total of 5.7% (48/837) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.9% (16/837) of patients.
Of the 48 patients with hypersensitivity, 54.2% (26/48) had NSCLC and had received prior anti-PD-1/PD-L1 immunotherapy.
Grade 3 hypersensitivity occurred in 3.5% (7/201) of the patients previously treated with anti-PD-1/PD-L1 immunotherapy.
The median time to onset was 1.9 weeks (range: 0.7 to 203.9 weeks): 1.7 weeks in patients with previous anti-PD-1/PD-L1 immunotherapy and 4.4 weeks in patients who were anti-PD-1/PD-L1 immunotherapy naïve.
Retevmo may require dose interruption or modification (see Section 4.2 Dose and Method of Administration).

Haemorrhages.

Grade ≥ 3 haemorrhagic events occurred in 3.5% (29/837) of patients treated with selpercatinib, including 4 (0.5%) patients with fatal haemorrhagic events, two cases of cerebral haemorrhage, and one case each of tracheostomy site haemorrhage, and haemoptysis. The median time to onset was 34.1 weeks (range: 0.1 week to 234.6 weeks).
Selpercatinib should be discontinued permanently in patients with severe or life-threatening haemorrhage (see Section 4.2 Dose and Method of Administration).

Additional information on special populations.

Paediatric patients.

The safety of selpercatinib in children aged less than 18 years has not been established.

Elderly.

In patients receiving selpercatinib for solid tumours including NSCLC, thyroid cancer and medullary thyroid cancer, 24.7% were ≥ 65-74 years of age, 8.6% were ≥ 75-84 years of age, and 1.0% ≥ 85 years of age. The frequency of serious adverse events reported was higher in patients ≥ 65-74 years (58.0%), 75-84 years (62.5%), and ≥ 85 years (100.0%), than in patients < 65 years (46.7%) of age.
The frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥ 65-74 years (10.1%), 75-84 years (19.4%), and ≥ 85 years (37.5%), than in patients < 65 years of age (7.6%).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms of overdose have not been established. In the event of suspected overdose, supportive care should be provided.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, antineoplastic agents, protein kinase inhibitors.
ATC code: L01EX22.

Cardiac electrophysiology.

In a thorough QT study with positive control in 32 healthy subjects, no large change (that is, > 20 ms) in the QTcF interval was detected at selpercatinib concentrations similar to those observed with a therapeutic dosing schedule. An exposure-response analysis indicated that supra therapeutic concentrations could lead to an increase in QTc > 20 ms.
In patients receiving selpercatinib, QT interval prolongation was reported. Therefore, dose interruption or modification may be required in patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Mechanism of action.

Selpercatinib is an orally available, small molecule inhibitor of the rearranged during transfection (RET) receptor tyrosine kinase. Chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers, promoting cell proliferation and survival in tumor cell lines. Point mutations in RET can also result in constitutively activated RET proteins that can promote cell growth and survival in tumor cell lines.
In RET enzyme assays, selpercatinib inhibits the kinase activity of RET, RET-V804L, RET-V804M, RET-A883F, RET-S904F, RET-A764T, RET-S891A and RET-M918T with IC50 values of 0.20 nanoM to 2.21 nanoM. In kinase screening assays, selpercatinib at a concentration of 100 nanoM inhibits only six of 329 non-RET kinases by more than 50% of the control. Among these, selpercatinib inhibits two kinases with IC50 values within 35-fold of RET: FLT4 (0.7-fold in an enzyme-based assay and 8-fold in a cell-based assay); and FLT1 (1.6-fold). Selpercatinib inhibits PDGFRB with an IC50 value of 2100 nanoM, and JAK1, JAK2, JAK3, TRKA, and TRKC with IC50 values greater than 5000 nanoM in enzyme assays.
Selpercatinib demonstrates in vitro inhibition of human cancer cell lines derived from multiple tumour types harbouring RET fusion genes and RET mutations with EC50 values equal to 10 nanoM or less. In in vivo mouse studies, selpercatinib demonstrates inhibition of tumor growth in RET fusion and RET mutant cancer cell lines, patient-derived RET fusion xenograft models, and a patient-derived RET fusion xenograft model harbouring a RET V804M mutation. Selpercatinib also exhibits intracranial anti-tumour activity of patient-derived RET fusion xenograft tumours implanted directly into the brain of mice.
In additional radioligand binding assays, selpercatinib inhibits two out of 54 non-kinase targets at a concentration of 1 microM: 5-HT transporter (70.2%) and α2c receptor (51.7%).

Clinical trials.

Clinical efficacy and safety.

The efficacy of Retevmo was evaluated in adult patients with advanced RET fusion-positive NSCLC in a phase 1/2, multi-centre, open-label, single-arm clinical study: Study LIBRETTO-001. This study included two parts: phase 1 (dose escalation) and phase 2 (dose expansion). The primary objective of the phase 1 portion was to determine the recommended phase 2 dose of selpercatinib. The primary objective of the phase 2 part was to evaluate the anti-tumour activity of selpercatinib by determining ORR, as assessed by independent review committee. Patients with measurable or non-measurable disease as determined by RECIST 1.1, with evidence of a RET gene alteration in tumour and who had failed or were intolerant to standard of care were enrolled. Patients with CNS metastases were eligible if stable, while patients with symptomatic primary CNS tumour, metastases, leptomeningeal carcinomatosis or spinal cord compression were excluded. Patients with known primary driver alteration other than RET, clinically significant active cardiovascular disease or history of myocardial infarction, QTcF interval > 470 msec were excluded.
Patients in the phase 2 portion of the study received Retevmo 160 mg orally twice daily until unacceptable toxicity or disease progression. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), or fluorescence in situ hybridization (FISH) and Nanostring technology. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (IRC) according to RECIST v1.1.

Treatment-naïve RET fusion-positive NSCLC.

Of the 362 RET fusion-positive NSCLC patients enrolled in LIBRETTO-001, 69 were treatment naïve. Most patients (98.6%) had metastatic disease at enrolment. The median age was 63 years (range 23 years to 92 years), 62.3% of patients were female, 69.6% of patients were White, 18.8% were Asian, 5.8% were Black and 69.6% were never smokers. ECOG performance status was reported as 0-1 (94.2%) or 2 (5.8%). The most common fusion partner was KIF5B (69.6%), followed by CCDC6 (14.5%) and then NCOA4 (1.4%).
Efficacy results for treatment-naïve RET fusion-positive NSCLC patients are summarised in Table 5.

Treatment-experienced RET fusion-positive NSCLC.

A total of 247 patients had received prior platinum-based chemotherapy. Most patients (97.2%) had metastatic disease at enrolment. The median age was 61 years (range 23 years to 81 years). 56.7% of patients were female, 43.7% of patients were White, 47.8% were Asian, 4.9% were Black, and 66.8% were never smokers. ECOG performance status was reported as 0-1 (97.1%) or 2 (2.8%). The most common fusion partner was KIF5B (61.9%), followed by CCDC6 (21.5%) and then NCOA4 (2.0%). The median number of prior systemic therapies was 2 (range 1-15) and 43.3% (n = 107/247) received 3 or more prior systemic regimens; prior treatments included anti PD1/PD-L1 therapy (58.3%), multi-kinase inhibitor (MKI) (31.6%) and taxanes (34.8%); 41.3% had other systemic therapy.
Efficacy results for previously treated RET fusion-positive NSCLC patients are summarised in Table 6.

CNS response in RET fusion-positive NSCLC.

A total of 106 RET fusion-positive NSCLC patients had CNS metastasis at baseline, including 26 patients with measurable CNS lesions according to IRC assessment. The CNS ORR in patients with measurable disease was 84.6% (22/26; 95% CI: 65.1, 95.6). CR was observed in 7 (26.9%) patients and PR in 15 (57.5%) patients. The median CNS DOR was 9.36 months (range: 7.4, 15.3).

5.2 Pharmacokinetic Properties

The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumours administered 160 mg twice daily unless otherwise specified. Steady-state selpercatinib AUC and C_max increased in a linear to supra-dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily.
Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] C_max was 2,980 (53%) nanogram/mL and AUC_0-24h was 51,600 (58%) nanogram*h/mL.
Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1.

Absorption.

After an oral dose of 160 mg, Retevmo was rapidly absorbed, with T_max of approximately 2 hours. Geometric mean absolute oral bioavailability was 73.2% (range: 60.2-81.5%).

Effect of food.

Compared to selpercatinib AUC and C_max in the fasted state, selpercatinib AUC was increased by 9% and C_max was reduced by 14% after oral administration of a single 160 mg dose to healthy subjects taken with a high-fat meal. These changes were not considered to be clinically relevant. Therefore, selpercatinib can be taken with or without food.

Distribution.

Selpercatinib mean (CV%) volume of distribution (Vss/F), estimated by Population PK analysis, is 191 L (69%) following oral administration of selpercatinib in adult patients. Selpercatinib is 96% bound to human plasma proteins in vitro and binding is independent of concentration. The blood-to-plasma concentration ratio is 0.7.

Metabolism.

Selpercatinib is metabolised predominantly by CYP3A4. Following oral administration of a single [¹⁴C] radiolabelled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the measured radioactive components in plasma.

Excretion.

The mean (CV%) clearance (CL/F) of selpercatinib is 6.0 L/h (49%) and the half-life is 22 hours following oral administration of selpercatinib in adult patients. Following oral administration of a single [¹⁴C] radiolabelled 160 mg dose of selpercatinib to healthy subjects, 69% (14% unchanged) of the administered radioactivity was recovered in faeces and 24% (11.5% unchanged) was recovered in urine.