Consumer medicine information

Qinlock

Ripretinib

BRAND INFORMATION

Brand name

Qinlock

Active ingredient

Ripretinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Qinlock.

SUMMARY CMI

QINLOCK®

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 using QINLOCK?

QINLOCK contains the active ingredient ripretinib. QINLOCK is used to treat people with advanced gastrointestinal stromal tumours (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib.

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

2. What should I know before I use QINLOCK?

Do not use if you have ever had an allergic reaction to ripretinib 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, are pregnant or plan to become pregnant, or are breastfeeding.

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

3. What if I am taking other medicines?

Some medicines may interfere with QINLOCK 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 use QINLOCK?

  • The usual dose of QINLOCK is 150 mg (three 50 mg tablets) taken orally once daily.

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

5. What should I know while using QINLOCK?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using QINLOCK.
  • Use sunscreen with high sun protection factor and wear protective clothing (long sleeves and hat) that covers your skin when exposed to strong sunlight.
Things you should not do
  • Do not go out in strong sunlight or use sunlamps or other sources of ultraviolet (UV) light, such as tanning beds.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how QINLOCK affects you.
Looking after your medicine
  • Store below 25°C.

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

6. Are there any side effects?

Common side effects include hair loss and hair thinning, tiredness, nausea, abdominal pain, constipation, muscle pain (myalgia), diarrhoea, decreased appetite, redness or thickening skin of the hands and/or feet, and vomiting.

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

QINLOCK® (kin-lok)

Active ingredient(s): ripretinib

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using QINLOCK?

QINLOCK contains the active ingredient ripretinib. QINLOCK is a kinase inhibitor which slows down the growth or spread of tumour cells.

QINLOCK is used to treat people with advanced gastrointestinal stromal tumours (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib. GIST is a cancer of the stomach and bowels.

2. What should I know before I use QINLOCK?

Warnings

Do not use QINLOCK if:

  • you are allergic to ripretinib, 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 any other medical conditions
  • take any medicines for any other condition. See additional information under Section 3. What if I am taking other medicines?
  • have high blood pressure
  • have or had a history of skin problems
    - new skin cancers (cutaneous squamous cell carcinoma (SCC) or melanoma)
    - palmar-plantar erythrodysaesthesia syndrome (PPES)
  • have any heart conditions
  • have skin or eyes that become more sensitive to sunlight or other forms of light
  • plan to have any surgical procedures or have had recent surgery
  • have wounds from any recent surgery that aren't healing as expected
  • have a history of liver or kidney problems

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

Check with your doctor if you are pregnant or intend to become pregnant.

Tell your doctor immediately if you become pregnant.

QINLOCK may harm your unborn baby.

If you are a woman who is able to become pregnant:

  • Your healthcare provider may perform a pregnancy test before you start treatment with QINLOCK.
  • Use effective birth control (contraception) during treatment with QINLOCK and for at least 1 week after the last dose of QINLOCK if you are:
    - a woman who is able to become pregnant.
    - a man with a female partner who is able to become pregnant.
  • Talk to your healthcare provider about birth control methods that may be right for you. If hormonal contraception is used, a barrier method (such as condoms) should be added

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

It is not known if QINLOCK passes into breast milk. Do not breastfeed during treatment with QINLOCK and for at least 1 week after your last dose of QINLOCK.

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 QINLOCK and affect how it works.

Medicines that may increase the effect of QINLOCK include:

  • ketoconazole, a medicine to treat fungal infections
  • itraconazole, a medicine to treat fungal infections
  • ritonavir, a medicine to treat HIV infection
  • indinavir, a medicine to treat HIV infection
  • clarithromycin, a medicine to treat infections

Medicines that may decrease the effect of QINLOCK include:

  • rifampin, a medicine to treat bacterial infections such as tuberculosis (TB)
  • efavirenz, a medicine to treat HIV infection

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

4. How do I use QINLOCK?

How much to take

  • The usual dose of QINLOCK is 150 mg (three 50 mg tablets) taken orally once daily.
  • QINLOCK tablets should be swallowed whole. Do not chew, split, or crush tablets.
  • Do not ingest if tablets are broken, cracked, or otherwise not intact.
  • If you vomit after taking a dose of QINLOCK, do not take an extra dose. Take your next dose at your scheduled time.
  • Follow the instructions provided and use QINLOCK until your doctor tells you to stop.

When to take QINLOCK

  • Take QINLOCK regularly at the same time each day, with or without food.

If you forget to use QINLOCK

QINLOCK should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, if it is within 8 hours of the scheduled dose.

If more than 8 hours have passed, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much QINLOCK

If you think that you have used too much QINLOCK, 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.

If you have kidney or severe liver problems

While you are being treated with QINLOCK, your doctor will monitor your kidney or liver function more closely.

5. What should I know while using QINLOCK?

Things you should do

QINLOCK may affect the way wounds heal. Talk to your doctor if you have wounds from any surgery that are not healing as expected. Your doctor may decide to temporarily stop your treatment with QINLOCK until your wound has healed after surgery. Your doctor will decide when to start QINLOCK again. It is also important that you inform your doctor if you have any planned surgery in future.

  • Use sunscreen with high sun protection factor and wear protective clothing that covers your skin when exposed to strong sunlight.
    Your skin or eyes may be more sensitive to sunlight while taking QINLOCK and for at least 1 week after stopping treatment with QINLOCK.
  • Follow your doctor's instructions and keep all appointments.
    You will need regular follow-up to make sure the treatment is working.
    Your doctor will measure your blood pressure. You will also have blood tests to check for side effects.

Call your doctor straight away if you:

  • Become pregnant
  • Are told your blood pressure is high

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

Things you should not do

  • Do not go out in strong sunlight or use sunlamps, or other sources of ultraviolet (UV) light, such as tanning beds. Your skin or eyes may be more sensitive to sunlight and UV light while taking QINLOCK and for at least 1 week after stopping treatment with QINLOCK.
  • Do not drink grapefruit juice or eat grapefruit whilst taking QINLOCK.
  • Do not take QINLOCK to treat any other complaints unless your doctor tells you to.
  • Do not give QINLOCK to anyone else, even if their condition seems similar to yours.

Driving or using machines

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

Looking after your medicine

  • Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this 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 effectsWhat to do
Broad or affecting different parts of the body:
  • Tiredness
  • Swelling in arms and/or legs
  • Increased levels of blood bilirubin, which is a pigment produced by the liver. Increased levels can cause possible yellowing of the skin and/or eyes and may indicate liver injury
Muscle or pain related:
  • Muscle pain, spasms
  • Joint pain
Stomach and digestive system related:
  • Nausea
  • Abdominal pain
  • Constipation
  • Diarrhoea
  • Loss of appetite, weight loss
  • Vomiting
Skin related:
  • Hair thinning or hair loss
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Broad or affecting different parts of the body:
  • Anaemia (decreased red blood cells in the blood, which may make you feel tried or short of breath)
  • High blood pressure (headache, feeling of lightheadedness, dizziness)
  • Blood tests showing high blood levels of lipase, an enzyme that breaks down fat
  • Blood tests showing decreased levels of phosphate (a chemical in the blood)
  • Heart problems (heart failure including symptoms of feeling very tired, have swollen feet and/or ankles, chest pain, difficulty breathing, and/or dizziness, heart pounding or racing)
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.
Skin related:
  • PPES includes symptoms of redness, pain, blisters/peeling, swelling, or callouses on the palms of your hands or soles of your feet
  • An increased risk of certain types of skin cancer such as ‘cutaneous squamous cell carcinoma of skin’ and ‘melanoma’. It is important to check your skin regularly
Tell your doctor if you notice any skin changes during treatment including a new wart, open sore or reddish bump that bleeds or does not heal, or a change in size or colour of a mole. Your doctor will check your skin when starting treatment with QINLOCK and routinely during treatment

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

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

Reporting side effects

After you have received medical advice for any side effects 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 QINLOCK contains

Active ingredient
(main ingredient)		Ripretinib
Other ingredients
(inactive ingredients)		Crospovidone
Hypromellose acetate succinate
Lactose monohydrate
Magnesium stearate
Microcrystalline cellulose
Silicon dioxide

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

What QINLOCK looks like

QINLOCK tablets are white to off-white oval shaped tablets debossed with 'DC1' on one side.
Aust R 327899

Who distributes QINLOCK

Specialised Therapeutics PM Pty Ltd
Level 2, 17 Cotham Road
Kew, VIC 3101
Australia
Phone: +61 3 9859 1493
Website: www.stbiopharma.com

This leaflet was prepared in February 2024.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Qinlock

Active ingredient

Ripretinib

Schedule

S4

 

1 Name of Medicine

Ripretinib.

2 Qualitative and Quantitative Composition

Each Qinlock tablet contains 50 mg of ripretinib.
Ripretinib is a white to off-white crystalline solid. Ripretinib is a lipophilic, weak base compound, practically insoluble in aqueous media.

Excipients with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Qinlock tablets are white to off-white oval shaped tablets debossed with 'DC1' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Qinlock is a kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumours (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

4.2 Dose and Method of Administration

Dosage.

The recommended dosage of Qinlock is 150 mg (three 50 mg tablets) orally once daily with or without food until disease progression or unacceptable toxicity.
Instruct patients to swallow tablets whole.
Advise patients to take Qinlock at the same time each day.
Advise patients to take a missed dose if less than 8 hours have passed since the missed scheduled dose. If a patient misses a dose by more than 8 hours of the time it is usually taken, the patient should be instructed not to take the missed dose and simply resume the usual dosing schedule on the following day.
Advise patients not to take an additional dose if vomiting occurs after taking Qinlock and to continue with their next scheduled dose.

Dose modification guidelines.

The recommended dose reduction for adverse reactions is Qinlock 100 mg orally once daily.
Permanently discontinue Qinlock in patients who are unable to tolerate 100 mg orally once daily.
The recommended dosage modifications of Qinlock for adverse reactions are provided in Table 1.

Paediatrics.

The safety and effectiveness of Qinlock in paediatric patients have not been established.

Patients with renal impairment.

No dose adjustment is recommended for patients with mild and moderate renal impairment [creatinine clearance (CrCl 30 to 89 mL/min estimated by Cockcroft-Gault)]. The pharmacokinetics and safety of Qinlock in patients with severe renal impairment (CrCl 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied. No dosing recommendation can be made in patients with severe renal impairment.

Patients with hepatic impairment.

No dose adjustment is recommended in patients with mild (Child-Pugh A), moderate (Child-Pugh B), or severe hepatic impairment (Child-Pugh C). Data in patients with severe hepatic impairment is limited, thus close monitoring of overall safety is recommended in these patients.

Dose modifications for CYP3A inducers.

Avoid concomitant strong or moderate CYP3A inducers during Qinlock treatment.
If co-administration of a moderate CYP3A inducer can't be avoided, increase the Qinlock dosing frequency to twice daily during the co-administration period (e.g. from the recommended dose of 150 mg once daily to 150 mg twice daily). Monitor for clinical response and tolerability. If the concomitant moderate CYP3A inducer is discontinued, reduce the dose back to once daily, 14 days after the discontinuation of the moderate CYP3A inducer [see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions].
If co-administration of a strong CYP3A inducer absolutely can't be avoided, the above approach could be considered, but must be balanced against a risk of reduced efficacy due to reduced exposure [see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions]. Warn patients of this risk, and monitor for clinical response and tolerability. For patients who need to take Qinlock twice daily: advise patients to take a missed dose if less than 4 hours have passed since they were meant to take it. Otherwise, leave it as a missed dose and just take the next dose as scheduled.

4.3 Contraindications

Use of Qinlock is contraindicated in patients with hypersensitivity to ripretinib or to any other component of Qinlock tablets.

4.4 Special Warnings and Precautions for Use

Palmar-plantar erythrodysaesthesia syndrome.

In the double-blind period of a randomised, placebo-controlled phase 3 trial (INVICTUS), Grade 1-2 palmar-plantar erythrodysaesthesia syndrome (PPES) occurred in 21% of the 85 patients who received Qinlock [see Section 4.8 Adverse Effects (Undesirable Effects)]. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 2.4% of patients, and dose reduction in 1.2% of patients.
Based on severity, withhold Qinlock and then resume at same or reduced dose [see Section 4.2 Dose and Method of Administration].

New primary cutaneous malignancies.

In INVICTUS, cutaneous squamous cell carcinoma (cuSCC) occurred in 4.7% of the 85 patients who received Qinlock, with a median time to event of 4.6 months (range: 3.8 to 6 months). In the pooled safety population, cuSCC and keratoacanthoma occurred in 7% and 1.9% of 351 patients, respectively.
In INVICTUS, melanoma occurred in 2.4% of the 85 patients who received Qinlock. In the pooled safety population, melanoma occurred in 0.9% of 351 patients.
Perform dermatologic evaluations when initiating Qinlock and routinely during treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Continue Qinlock at the same dose.

Hypertension.

In INVICTUS, Grade 1-3 hypertension occurred in 14% of the 85 patients who received Qinlock, including Grade 3 hypertension in 7% [see Section 4.8 Adverse Effects (Undesirable Effects)].
Do not initiate Qinlock in patients with uncontrolled hypertension. Adequately control blood pressure prior to initiating Qinlock. Monitor blood pressure as clinically indicated during treatment with Qinlock and initiate or adjust antihypertensive therapy as appropriate.
Based on severity, withhold Qinlock and then resume at same or reduced dose or permanently discontinue [see Section 4.2 Dose and Method of Administration].

Cardiac failure.

In INVICTUS, cardiac failure occurred in 1.2% of the 85 patients who received Qinlock. In the pooled safety population, cardiac failure (cardiac failure, cardiac failure acute, acute left ventricular failure, and diastolic dysfunction) occurred in 1.7% of 351 patients, including Grade 3 adverse reactions in 1.1%.
In INVICTUS, Grade 3 decreased ejection fraction occurred in 2.6% of the 77 patients who received Qinlock and who had a baseline and at least one post-baseline echocardiogram. In the pooled safety population, Grade 3 decreased ejection fraction occurred in 3.4% of the 263 patients who received Qinlock and who had a baseline and at least one post-baseline echocardiogram.
In INVICTUS, cardiac dysfunction led to dose discontinuation in 1.2% of the 85 patients who received Qinlock. The safety of Qinlock has not been assessed in patients with a baseline ejection fraction below 50%.
Assess ejection fraction by echocardiogram or MUGA scan prior to initiating Qinlock and during treatment, as clinically indicated. Permanently discontinue Qinlock for Grade 3 or 4 left ventricular systolic dysfunction [see Section 4.2 Dose and Method of Administration].
See Section 4.6 Fertility, Pregnancy and Lactation for potential embryo-fetal toxicity.

Risk of impaired wound healing.

Impaired wound healing complications can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Qinlock has the potential to adversely affect wound healing.
Withhold Qinlock for at least 1 week 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 Qinlock after resolution of wound healing complications has not been established.

Phototoxicity.

Due to the risk of phototoxicity associated with the use of Qinlock, it is recommended to advise patients to avoid or minimise exposure to direct sunlight, sunlamps, and other sources of ultraviolet radiation during treatment with Qinlock and for at least one week after discontinuation of treatment. Patients should be instructed to use measures such as protective clothing (long sleeves and hat) and sunscreen with high sun protection factor (SPF).

Use in the elderly.

Of the 85 patients in INVICTUS who received Qinlock 150 mg orally once daily, 24% were between 65 to 74 years of age and 9% were 75 years of age or older. Clinical studies of Qinlock did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

Paediatric use.

The safety and effectiveness of Qinlock in paediatric patients have not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medications on Qinlock.

Since both ripretinib and its active metabolite are mainly cleared by CYP3A, plasma concentrations of ripretinib and the active metabolite DP-5439 are increased by CYP3A inhibitors and decreased by CYP3A inducers.

Effect of strong CYP3A inhibitors.

Coadministration of Qinlock with itraconazole (a strong CYP3A inhibitor) increased ripretinib Cmax by 36% and AUC0-∞ by 99%. Use strong CYP3A inhibitors with caution and monitor for increased toxicity.

Effect of strong CYP3A inducers.

Coadministration of Qinlock with rifampin (a strong CYP3A inducer) decreased ripretinib Cmax by 18% and AUC0-∞ by 61% and also decreased DP-5439 AUC0-∞ by 57% with increased Cmax by 37% [see Section 4.2 Dose and Method of Administration].
In the presence of a strong CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 40% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.
Avoid concomitant strong CYP3A inducers during Qinlock treatment [see Section 4.2 Dose and Method of Administration].

Effect of moderate CYP3A inducers.

Coadministration of Qinlock with efavirenz (a moderate CYP3A inducer) was predicted to decrease ripretinib Cmax by 24% and decrease AUC0-∞ by 56% [see Section 4.2 Dose and Method of Administration].
In the presence of a moderate CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 17% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.
Avoid concomitant moderate CYP3A inducers during Qinlock treatment [see Section 4.2 Dose and Method of Administration].

Effect of P-gp inhibitors.

Ripretinib and its active metabolite DP-5439 are substrates of P-gp (MDR1) and BCRP, as indicated by in vitro studies. P-gp and BCRP inhibitors may increase plasma concentrations of ripretinib and its active metabolite DP-5439.

Effect of acid-reducing agents.

Coadministration of Qinlock with pantoprazole (a proton pump inhibitor) did not affect exposure to ripretinib.

Effect of Qinlock on other medications.

CYP substrates.

Ripretinib and DP-5439 are inhibitors of CYP2C8 in vitro. Ripretinib is expected to increase clinical exposures of drugs that are predominantly cleared by CYP2C8.
Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4 in vitro.

Drug transporter systems.

Ripretinib is an inhibitor of P-gp and BCRP in vitro. DP-5439 is an inhibitor of BCRP and MATE1 (Multidrug And Toxin Extrusion Protein 1) in vitro. Ripretinib may increase clinical exposures of drugs that are substrates of P-gp, BCRP, or MATE1.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on findings from animal studies, Qinlock may impair fertility in males of reproductive potential. Decreased testis and epididymis weights, as well as atrophy of the testes and degeneration of the seminiferous epithelium were observed in male rats at exposure levels (AUC) similar to the human exposure at 150 mg once daily.
(Category D)
There are no clinical data on the use of Qinlock in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.
Based on findings from animal studies, Qinlock can cause embryo-fetal harm when administered to a pregnant woman. Qinlock should not be used during pregnancy.
Qinlock should not be used during pregnancy. In an embryo-fetal development study in which pregnant rats were administered daily doses of ripretinib during organogenesis, ripretinib was given from gestational days 6 through 18 at doses 1, 5, or 20 mg/kg/day. Dose-related malformations primarily associated with the cardiovascular and skeletal systems were observed at a dose of 20 mg/kg/day (approximately 0.4 times the human exposure at 150 mg once daily).
An increased incidence of anatomic variations, indicative of developmental toxicity, also occurred at 20 mg/kg/day. Variations included malpositioned carotid and subclavian artery origins, malpositioned subclavian artery, absent or elongated innominate artery, misshapen and nodulated ribs, bipartite, incompletely ossified, or unossified vertebral centra, small or misshapen vertebral arches, and reductions in ossified forelimb and hindlimb phalanges, hindlimb metatarsals, and caudal vertebrae were also observed at 20 mg/kg/day.
Verify the pregnancy status of females of reproductive potential prior to initiating Qinlock. Advise female patients of reproductive potential to use effective contraception during treatment and for at least 1 week after the final dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for at least 1 week after the final dose. Effects of Qinlock on contraceptive steroids have not been studied. A barrier method contraception should be added if systemic contraceptive steroids are used.
 There are no data regarding the presence of ripretinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with ripretinib and for at least 1 week after the final dose.

4.7 Effects on Ability to Drive and Use Machines

No data available.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

In the Phase 3 double-blind, randomised (2:1), placebo-controlled trial (INVICTUS), 129 study participants with a diagnosis of advanced GIST were randomised to Qinlock (N=85) or placebo (N=44) [see Section 5.1 Pharmacodynamic Properties]. The data described in this section reflect the safety population (N=128) who had received at least one dose of Qinlock (N=85) or placebo (N=43). One study participant who was randomised to the placebo arm did not receive placebo. The safety results from the double-blind treatment period of INVICTUS are described below.
The most common adverse events (≥ 20%) observed in patients treated with Qinlock (all grades) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhoea, decreased appetite, palmar-plantar erythrodysaesthesia syndrome (PPES), and vomiting (Table 2). The most common Grade 3 or 4 laboratory abnormalities were increased lipase and decreased phosphate (Table 3).
For additional information on palmar-plantar erythrodysaesthesia syndrome, new primary cutaneous malignancies such as squamous cell carcinoma of the skin keratoacanthoma and melanoma, hypertension and cardiac failure (cardiac failure, cardiac failure acute, acute left ventricular failure, and diastolic dysfunction) (see Section 4.4 Special Warnings and Precautions for Use).

Tabulated list of adverse events.

Table 2 summarises the most frequently reported treatment-emergent adverse events (TEAEs) in ≥ 10% of patients with advanced GIST who received Qinlock in the double-blind treatment period of INVICTUS.
Table 3 summarises the most frequently reported treatment-emergent laboratory abnormalities in ≥ 10% of patients with advanced GIST who received Qinlock in the double-blind treatment period of INVICTUS. Also see Table 4.

Other adverse reactions.

The following additional adverse reactions have occurred in < 10% of Qinlock-treated patients in INVICTUS:
Peripheral sensory neuropathy (7.1% vs 2.3% placebo), dermatitis acneiform (5.9% vs 0% placebo), rash (4.7% vs 4.7% placebo), seborrheic keratosis (4.7% vs 0% placebo), skin papilloma (3.5% vs 0% placebo) and melanocytic naevus (2.4% vs 0% placebo).
Clinically relevant adverse reactions that occurred in <10% of patients in the pooled safety population included cardiac ischemic events (1.1%) (including acute coronary syndrome and fatal cardiac arrest or myocardial infarction). Photosensitivity occurred in 0.6% (see Section 4.4 Special Warnings and Precautions for Use).

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 and [email protected].

4.9 Overdose

There is no known specific antidote for Qinlock overdose. In the event of suspected overdose, interrupt Qinlock, undertake general supportive measures, and observe until clinical stabilisation.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ripretinib is a switch-control tyrosine kinase inhibitor with a dual mechanism of action. Ripretinib binds to both the switch pocket and the activation loop to lock the kinase in the inactive state, preventing downstream signalling and cell proliferation. This dual mechanism of action provides broad inhibition of KIT and PDGFRA kinase activity, including wild type and multiple primary and secondary mutations. Ripretinib also inhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF.

Cardiac electrophysiology.

Following treatment with Qinlock 150 mg once daily, no clinically meaningful QT interval prolongation was observed.

Clinical trials.

The efficacy of Qinlock was evaluated in INVICTUS, an international, multi-centre, randomised (2:1), double-blind, placebo-controlled trial. Eligible patients had unresectable, locally advanced or metastatic gastrointestinal stromal tumour (GIST) and had received prior treatment with imatinib, sunitinib, and regorafenib. Randomisation was stratified by prior lines of therapy (3 versus ≥ 4) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1 or 2). Patients received Qinlock 150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Tumour response assessments were performed every 28 days through for the first 4 months and then every 56 days thereafter.
The major efficacy outcome measure was progression-free survival (PFS) based on disease assessment by blinded independent central review (BICR) using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumour nodule within a pre-existing tumour mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included objective response rate (ORR) by BICR and overall survival (OS). Patients randomised to receive placebo could be treated with Qinlock at the time of disease progression.
A total of 129 patients were randomised, 85 to Qinlock and 44 to placebo.
Patient characteristics of the intent-to-treat (ITT) population in INVICTUS were median age of 60 years (range: 29 to 83 years), with 39% aged ≥ 65 years; 57% were male; 75% were White; and 92% had an ECOG performance status of 0 or 1. Sixty-three percent (63%) of patients received 3 prior therapies and 37% received 4 or more prior therapies. Sixty-six percent (66%) of patients randomised to placebo switched to Qinlock after disease progression.
Efficacy results from INVICTUS are summarised in Table 5. Also see Figures 1 and 2.

5.2 Pharmacokinetic Properties

Absorption.

Ripretinib reaches peak plasma concentrations at 4 hours after a single oral dose of 150 mg ripretinib (given as three tablets each containing 50 mg). The steady state AUC0-12h observed in patients at 150 mg is 5678 nanogram.h/mL. Steady state is achieved by approximately Day 15.
Administration with a high-fat meal increased ripretinib AUC0-24 and Cmax by 30% and 22%, respectively. DP-5439 AUC0-24 and Cmax were higher by 47% and 66%, respectively.

Distribution.

Both ripretinib and its active metabolite DP-5439 bind to plasma proteins at ≥ 99%. The apparent volume of distribution (Vss/F) is approximately 307 L.

Metabolism.

Ripretinib was metabolised in vitro. CYP3A4/5 is the major metaboliser of ripretinib and its active metabolite, DP-5439, while CYP2C8 and CYP2D6 are only minor metabolisers.

Excretion.

Following oral administration of ripretinib 150 mg once daily, the mean apparent oral clearance (CL/F) of ripretinib at steady-state is 15.3 L/hr and the mean plasma elimination half-life is 14.8 hours.
In preclinical species, 14C-labeled ripretinib dosed to Sprague-Dawley rats (oral) and beagle dogs (intravenous [iv]), resulted in greater than 87% of the radioactive dose being excreted in faeces and 1.8% or less in the urine.
PK analyses obtained from urine and faeces samples in 10 healthy volunteers showed that systemic elimination of ripretinib was not primarily attributed to the kidney. Through 1 week (168 hours) after a single oral administration of 50 mg ripretinib (given alone), 0.02% of the ripretinib dose was excreted as ripretinib in urine and 34.2% of the ripretinib dose was excreted as ripretinib in faeces.

Pharmacokinetics in special patient populations.

Population pharmacokinetic analyses of demographic data indicate that no clinically meaningful differences in the pharmacokinetics of ripretinib were observed based on age (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), tumour type (GIST or other solid tumour), prior gastrectomy, mild to moderate renal impairment (CrCl 30 to < 90 mL/min estimated by Cockcroft-Gault) and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 x ULN and any AST).
The effects of severe renal impairment (CrCl 15 to 29 mL/min) on the pharmacokinetics of ripretinib have not been studied.

Patients with hepatic impairment.

In subjects with mild hepatic impairment, there were no clinically significant changes in AUC0-last and Cmax when compared to matched healthy subjects.
In subjects with moderate hepatic impairment, ripretinib AUC0-last increased 2-fold while Cmax was unchanged when compared to matched healthy subjects. The combined AUC0-last of ripretinib and DP-5439 increased 1.5-fold.
In subjects with severe hepatic impairment, ripretinib AUC0-last increased 2.6-fold and Cmax decreased by 24% when compared to matched healthy subjects. The combined AUC0-last of ripretinib and DP-5439 increased by 1.4-fold.
The observed magnitude of increase in ripretinib and the combination of ripretinib and DP-5439 exposures in subjects with hepatic impairment is unlikely to be clinically relevant based on the known safety profile of ripretinib.
The unbound fraction for both ripretinib and DP-5439 showed high variability and no clear trend was apparent between protein binding and the degrees of hepatic impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Ripretinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vivo rat bone marrow micronucleus assay. Ripretinib was weakly positive in an in vitro clastogenicity assay in human lymphocytes without metabolic activation. Ripretinib's active metabolite (DP-5439) was not mutagenic in an in vitro bacterial reverse mutation test or clastogenic in an in vitro chromosomal aberration assay in isolated human lymphocytes. Ripretinib is not expected to pose a genotoxic risk.

Carcinogenicity.

Carcinogenicity studies have not been conducted with ripretinib.

Phototoxicity.

Ripretinib indicates a potential for photoirritation/phototoxicity based on absorption in the UV visible range (above 290 nanometer). In vitro phototoxicity assessment in 3T3 mouse fibroblast cells suggest that ripretinib exhibits a potential for phototoxicity at clinically relevant concentrations following exposure to UVA and UVB radiation.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Qinlock tablet contains the following inactive ingredients: crospovidone; hypromellose acetate succinate; lactose monohydrate; magnesium stearate; microcrystalline cellulose; silicon dioxide.

6.2 Incompatibilities

No incompatibilities have been identified.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Qinlock 50 mg tablets are packaged with silica gel desiccant into white high-density polyethylene (HDPE) bottles. The bottles are closed with polypropylene child resistant closures with a polyethylene-faced induction heat seal liner. Each HDPE bottle contains 90 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The chemical structure of ripretinib is shown below:
Chemical name: 1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl)-3-phenylurea.
Molecular formula: C24H21BrFN5O2.
Molecular weight: 510.36 g/mol.

CAS number.

1442472-39-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes