QINLOCK Tablet Ref.[28085] Active ingredients: Ripretinib

Palmar-Plantar Erythrodysaesthesia Syndrome (PPES)

PPES occurred in patients treated with ripretinib (see section 4.8). Based on severity, ripretinib should be withheld and then resumed at the same or reduced dose (see section 4.2).

Hypertension

Hypertension was observed with ripretinib (see section 4.8). Ripretinib must not be initiated unless blood pressure is adequately controlled. Blood pressure is to be monitored as clinically indicated. Based on severity, ripretinib should be withheld and then resumed at same or reduced dose or permanently discontinue (see section 4.2).

Cardiac failure

Cardiac failure (including cardiac failure, cardiac failure acute, acute left ventricular failure, and diastolic dysfunction) was observed with ripretinib (see section 4.8). Ejection fraction should be assessed by echocardiogram or multiple-gated acquisition (MUGA) scan prior to initiating ripretinib and during treatment, as clinically indicated. Ripretinib should be permanently discontinued for Grade 3 or 4 left ventricular systolic dysfunction (see section 4.2). The safety of ripretinib has not been assessed in patients with a baseline left ventricular ejection fraction below 50%.

Cutaneous squamous cell carcinoma (CuSCC)

CuSCC was reported in patients receiving ripretinib (see section 4.8). Dermatological evaluations should be performed when initiating ripretinib and routinely during treatment. Suspicious skin lesions should be managed with excision and dermatopathological evaluation. Ripretinib should be continued at the same dose.

Wound healing complications

No formal studies to evaluate the effect of ripretinib on wound healing have been conducted. Impaired wound healing complications may occur in patients who receive medicinal products that inhibit the vascular endothelial growth factor (VEGF) signalling pathway. Therefore, ripretinib has the potential to adversely affect wound healing.

Treatment with ripretinib is to be withheld for at least 3 days prior to and after minor surgery and at least 5 days prior to and after major surgery. Ripretinib may then be resumed after surgery based on clinical judgement of adequate wound healing.

Embryo-foetal toxicity

Based on findings from animal studies, ripretinib can cause foetal harm when administered to pregnant women (see sections 4.6 and 5.3). It is recommended to advise women to avoid pregnancy while taking ripretinib. The pregnancy status of females of reproductive potential must be verified prior to initiating ripretinib and during treatment. Females of reproductive potential and males with female partners of reproductive potential must use effective contraception during treatment and for at least 1 week after the final dose of ripretinib (see sections 4.6 and 5.3). Effects of ripretinib on contraceptive steroids have not been studied. A barrier method contraception should be added if systemic contraceptive steroids are used.

Phototoxicity

Ripretinib exhibits a potential for phototoxicity (see section 5.3). It is recommended to advise patients to avoid or minimise exposure to direct sunlight, sunlamps, and other sources of ultraviolet radiation due to the risk of phototoxicity associated with ripretinib. Patients should be instructed to use measures such as protective clothing (long sleeves and hat) and sunscreen with high sun protection factor (SPF).

CYP3A inhibitors and inducers

Ripretinib is a CYP3A substrate. Concurrent administration of ripretinib with the strong CYP3A and P-glycoprotein (P-gp) inhibitor itraconazole resulted in an increase in ripretinib plasma exposure (see section 4.5). Caution is required when administering ripretinib with agents that are strong CYP3A and P-gp inhibitors.

Concurrent administration of ripretinib with the strong CYP3A inducer rifampicin resulted in a decrease in ripretinib plasma exposure. Therefore, chronic administration of agents that are strong or moderate CYP3A inducers with ripretinib should be avoided (see sections 4.2 and 4.5).

Important information about some excipients

QINLOCK contains lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Both ripretinib and its active metabolite DP-5439 are mainly cleared by CYP3A4/5 and are substrates of P-gp and Breast Cancer Resistance Protein (BCRP).

Effect of other medicinal products on ripretinib

Effect of strong CYP3A/P-gp inhibitors

Co-administration of itraconazole (a strong CYP3A inhibitor) and also a P-gp inhibitor increased ripretinib C_max by 36% and AUC_0-∞ by 99%. DP-5439 C_max was unchanged; AUC_0-∞ increased by 99%. Strong inhibitors of CYP3A/P-gp (e.g. ketoconazole, erythromycin, clarithromycin, itraconazole, ritonavir, posaconazole, and voriconazole) are to be used with caution and patients should be monitored. Ingestion of grapefruit juice is not recommended.

Effect of CYP3A inducers

Co-administration of QINLOCK with the strong CYP3A inducer rifampicin decreased ripretinib C_max by 18% and AUC_0-∞ by 61%, decreased DP-5439 AUC_0-∞ by 57%, and increased DP-5439 C_max by 37%.

Concomitant use of QINLOCK with strong CYP3A inducers (e.g. carbamazepine, phenytoin, rifampicin, phenobarbital and St. John’s wort) and moderate CYP3A inducers (e.g. efavirenz and etravirine) must therefore be avoided. If a strong or moderate CYP3A inducer must be co-administered, the QINLOCK dosing frequency may be increased during the co-administration period. For strong inducers, the dose may be increased from 150 mg once daily to 150 mg twice daily. For patients taking QINLOCK twice daily, if the patient misses a dose within 4 hours of the time it is usually taken, the patient should be instructed to take the missed dose as soon as possible and then take the next dose at the regularly scheduled time. If a patient misses a dose by more than 4 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. Monitor for clinical response and tolerability.

Effect of acid-reducing agents

No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observed when QINLOCK was co-administered with pantoprazole (a proton pump inhibitor).

Drug transporter systems

Based on in vitro data, medicinal products that are inhibitors of BCRP (e.g. cyclosporine A, eltrombopag) should be used with caution in combination with QINLOCK, as increased plasma concentrations of ripretinib or DP-5439 may be possible.

Effect of ripretinib on other medicinal products

CYP isoform-selective substrates

In vitro studies suggested ripretinib may inhibit CYP2C8. QINLOCK is to be used with caution in combination with substrates of CYP2C8 (e.g. repaglinide, paclitaxel), as co-administration may lead to increased exposure of CYP2C8 substrates.

The in vivo net effect of inhibition of CYP3A4 in the intestine and systemic CYP3A4 induction is unknown. Caution is recommended when co-administering ripretinib with sensitive CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, tacrolimus) or that are mostly metabolised in the intestine (e.g. midazolam).

Ripretinib and DP-5439 induced CYP2B6 in vitro. Co-administration of ripretinib with CYP2B6 substrates with narrow therapeutic index (e.g. efavirenz) may lead to loss of their efficacy.

Ripretinib and DP-5439 down-regulated CYP1A2 in vitro. Co-administration of ripretinib with CYP1A2 substrates with narrow therapeutic index (e.g. tizanidine) may lead to increased concentrations and monitoring is recommended.

It is unknown whether ripretinib may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a barrier method.

Drug transporter systems

In vitro studies suggested ripretinib is an inhibitor of P-gp and BCRP. DP-5439 is a substrate for P-gp and BCRP. DP-5439 is an inhibitor of BCRP and Multidrug And Toxin Protein 1 (MATE-1).

Medicinal products that are P-gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with QINLOCK due to the likelihood of increased plasma concentrations of these substrates.

QINLOCK is to be used with caution in combination with BCRP substrates (e.g. rosuvastatin, sulfasalazine and irinotecan) and MATE-1 substrates (e.g. metformin) as co-administration of QINLOCK with BCRP and MATE-1 substrates may lead to an increase of their exposure. Clinical studies with BCRP or MATE-1 substrates have not been conducted.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential and men with female partners of reproductive potential must be informed that QINLOCK may cause foetal harm and must ensure effective contraception during treatment and for at least 1 week after the final dose of QINLOCK (see section 4.4).

The pregnancy status of females of reproductive potential is to be verified prior to initiating QINLOCK and during treatment.

Effects of QINLOCK on contraceptive steroids have not been studied. Add a barrier method if systemic steroids are used for contraception.

Pregnancy

There are no data on the use of ripretinib in pregnant women.

Based on its mechanism of action, ripretinib is suspected to cause foetal harm when administered during pregnancy and animal studies have shown reproductive toxicity (see sections 4.4 and 5.3). QINLOCK should not be used during pregnancy unless the clinical condition of the woman requires treatment with ripretinib.

Breast-feeding

It is unknown whether ripretinib/metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Breast-feeding should be discontinued during treatment with QINLOCK and for at least 1 week after the final dose.

Fertility

There are no data on the effect of ripretinib on human fertility. Based on findings from animal studies, male and female fertility may be compromised by treatment with QINLOCK (see section 5.3).

QINLOCK has no influence on the ability to drive and use machines. In some patients, fatigue has been reported following administration of QINLOCK. If a patient experiences fatigue, this may influence their ability to drive or use machines.

Summary of the safety profile

In the Phase 3 double-blind, randomised (2:1), placebo-controlled study (INVICTUS), 129 participants with a diagnosis of advanced GIST who had failed at least 3 approved prior lines of treatment were randomised to QINLOCK (n=85) or placebo (n=44) (see section 5.1). In the Phase 1 Study DCC-2618-01-001, a total of 277 patients with advanced malignancies were enrolled, and 218 patients were treated at the recommended Phase 2 dose of 150 mg QINLOCK once daily.

The median duration of treatment for QINLOCK in the double-blind period of the INVICTUS study was 5.49 months.

The most frequently observed adverse reactions (≥25%) in patients treated with QINLOCK in the pooled safety population (n=392) were fatigue (51.0%), alopecia (50.8%), nausea (39.8%), myalgia (37.8%), constipation (37.2%), diarrhoea (32.7%), PPES (29.8%), weight decreased (26.5%) and vomiting (25.8%).

The adverse reactions (≥10 to <25%) observed in patients treated with QINLOCK in the pooled safety population (n=392) were lipase increased (23.7%), muscle spasms (23.7%), arthralgia (21.2%), headache (20.7%), dyspnoea (20.2%), hypertension (19.4%), dry skin (17.6%), back pain (15.6%), cough (15.6%), blood bilirubin increased (14.0%), oedema peripheral (13.8%), hypophosphataemia (12.2%), pain in extremity (12.0%), pruritus (11.0%) and seborrhoeic keratosis (11.0%).

Grade ¾ adverse reactions (≥2%) observed in patients treated with QINLOCK in the pooled safety population (n=392) were lipase increased (14.8%), anaemia (14.0%), abdominal pain (8.2%), hypertension (6.9%), fatigue (4.1%), hypophosphataemia (4.1%), vomiting (2.6%), dyspnoea (2.0%), diarrhoea (2.0%) and blood bilirubin increased (2.0%). Serious adverse reactions (≥1%) observed in patients treated with QINLOCK were anaemia (3.8%), dyspnoea (2.3%), vomiting (2.0%), nausea (1.8%), fatigue (1.5%), blood bilirubin increased (1.3%), constipation (1.0%), and muscular weakness (1.0%).

Tabulated list of adverse reactions

The overall safety profile of QINLOCK is based on pooled data from 392 patients (pooled safety population) who received at least 1 dose of QINLOCK. Two clinical studies with QINLOCK in adult patients with advanced malignancies were conducted and form the primary basis of the overall evaluation of safety: a pivotal phase 3 study in adult patients with GIST, Study DCC-2618-03-001 (INVICTUS) (see section 5.1) and an open-label, first-in-human study in adult patients with advanced malignancies (Study DCC-2618-01-001).

The double-blind period of the INVICTUS study formed the primary basis of the determination of adverse reactions. The treatment emergent adverse events that were at least 5% higher in QINLOCK arm as compared to the placebo arm and those that were at least 1.5 times greater in the QINLOCK arm than those compared to placebo arm in INVICTUS were considered adverse drug reactions. Treatment emergent adverse events identified within the INVICTUS study were also evaluated across the pooled safety population (n=392). These events were considered adverse drug reactions per the Sponsor assessment. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

The severity of adverse drug reactions was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defining Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4=life threatening, and Grade 5=death.

Frequencies are defined as: 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), not known (cannot be estimated from the available data) and are shown in Table 2. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse drug reactions reported in INVICTUS and study DCC-2618-01-001:

^a Squamous cell carcinoma of skin (Squamous cell carcinoma of skin, Keratoacanthoma, Squamous cell carcinoma of head and neck)
^b Cardiac Failure (Cardiac failure, Acute left ventricular failure, Cardiac failure acute, Diastolic dysfunction)
^c Hypertension (Hypertension, Blood pressure increased)

Description of selected adverse drug reactions

Palmar-plantar erythrodysaesthesia syndrome (PPES)

In the double-blind period of the INVICTUS study, PPES was reported in 19 of 85 (22.4%) patients in the QINLOCK arm and no patients in the placebo arm. PPES led to dose discontinuation in 1.2% of patients, dose interruption in 3.5% of patients, and dose reduction in 2.4% of patients. All events were mild or moderate in severity (58% Grade 1 and 42% Grade 2).

In the pooled safety population, PPES occurred in 29.8% of 392 patients, including Grade 3 adverse reactions in 0.5%. The median time to onset and duration of the first event was 8.1 weeks (range: 0.3 week to 112.1 weeks) and 24.3 weeks (range: 0.9 week to 191.7 weeks), respectively. See sections 4.2 and 4.4 for additional information.

Hypertension

In the double-blind period of the INVICTUS study, there was a higher incidence of hypertension (all events regardless of causality) in patients treated with QINLOCK (15.3%) vs. 4.7% of patients who received placebo.

In the pooled safety population, hypertension occurred in 19.4% of 392 patients, including Grade 3 adverse reactions in 6.9%. See sections 4.2 and 4.4 for additional information.

Cardiac failure

In the double-blind period of the INVICTUS study, cardiac failure (all events regardless of causality) occurred in 1.2% of the 85 patients who received QINLOCK. Cardiac failure led to dose discontinuation in 1.2% of the 85 patients who received QINLOCK.

In the pooled safety population, cardiac failure occurred in 1.5% of 392 patients, including Grade 3 adverse reactions in 1.0%.

In the pooled safety population, 299 of 392 patients had a baseline and at least one post-baseline echocardiogram. Grade 3 decreased left ventricular ejection fraction occurred in 4.0% of the 299 patients.

See section 4.4 for additional information.

Cutaneous malignancies

In the double-blind period of the INVICTUS study, CuSCC (all events regardless of causality) was reported in 5.9% of the 85 patients receiving QINLOCK. CuSCC of the skin was not reported in placebo-treated patients. See sections 4.2 and 4.4 for additional information.

In the pooled safety population, CuSCC occurred in 8.7% of 392 patients including Grade 3 adverse reactions in 0.5%. Melanoma (all events regardless of causality) occurred in 0.3% of 392 patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

Not applicable.