4.1. Therapeutic indications

Gavreto is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previously treated with a RET inhibitor.

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the administration of anticancer medicinal products.

Patient selection for treatment of RET fusion-positive advanced NSCLC should be based on a validated test method.

Posology

The recommended dose is 400 mg pralsetinib once daily on an empty stomach (see method of administration). Treatment should be continued until disease progression or unacceptable toxicity.

If vomiting occurs after taking a dose of pralsetinib, the patient should not take an additional dose but continue with the next scheduled dose.

Missed doses

If a dose of pralsetinib is missed, the patient should make up for the missed dose as soon as possible on the same day. The regular daily dose schedule for pralsetinib should be resumed the next day.

Dose modifications for adverse reactions

Interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.

Patients may have their dose reduced by 100 mg decrements to a minimum dose of 100 mg once daily. Gavreto should be permanently discontinued in patients who are unable to tolerate 100 mg orally once daily.

Recommended dose modifications for adverse reactions are indicated in Table 1.

Table 1. Recommended dose modifications for Gavreto for adverse reactions

Adverse reaction

Severitya

Dose modification

Pneumonitis/Interstitial lung disease (ILD)

(see section 4.4)

Grade 1 or 2

Interrupt treatment with Gavreto until resolution. Resume at a reduced dose.

Permanently discontinue Gavreto for recurrent pneumonitis/ILD.

Grade 3 or 4

Permanently discontinue for pneumonitis/ILD.

Hypertension

Grade 3

Interrupt treatment with Gavreto for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled.

Grade 4

Permanently discontinue Gavreto.

Transaminase elevations

Grade 3 or 4

Interrupt treatment with Gavreto and monitor aspartate aminotransferase (AST) and alanine aminotransferase (ALT) once weekly until resolution to Grade 1 or baseline.

Resume at a reduced dose.

If the transaminase elevation recurs at Grade 3 or higher, permanently discontinue treatment with Gavreto.

Haemorrhagic events

Grade 3 or 4

Interrupt treatment with Gavreto until resolution to Grade 1.

Resume at a reduced dose.

Permanently discontinue Gavreto for life-threatening or recurrent severe haemorrhagic events.

QT prolongation

Grade 3

Interrupt treatment with Gavreto for QTc intervals >500 ms until QTc interval returns to <470 ms.

Resume at the same dose if risk factors that cause QT prolongation are identified and corrected.

Resume treatment at a reduced dose if other risk factors that cause QT prolongation are not identified.

Grade 4

Permanently discontinue Gavreto if the patient has life-threatening arrhythmia.

Other clinically significant adverse reactions (see section 4.8)

Grade 3 or 4

Interrupt treatment with Gavreto until improvement to ≤Grade 2. Resume at a reduced dose.

Permanently discontinue for recurrent Grade 4 adverse reactions.

a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03

Dose modification for use with strong cytochrome P-450 (CYP)3A4 inhibitors or combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors

Concomitant use of pralsetinib with known strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors should be avoided (see section 4.4 and section 4.5). If co-administration with a strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor cannot be avoided, the current dose of pralsetinib should be reduced as recommended in Table 2. After the strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor have been discontinued for 3 to 5 elimination half-lives, the pralsetinib dose that was taken prior to the use of the inhibitor should be resumed.

Table 2. Recommended dose modifications for Gavreto for co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors

Current Gavreto dose

Recommended Gavreto dose

400 mg orally once daily

200 mg orally once daily

300 mg orally once daily

200 mg orally once daily

200 mg orally once daily

100 mg orally once daily

Dose modification for use with strong CYP3A4 inducers

Concomitant use of pralsetinib with strong CYP3A4 inducers should be avoided (see section 4.4 and section 4.5).

If concomitant use with a strong CYP3A4 inducer cannot be avoided, the dose of pralsetinib should be increased to double the current pralsetinib dose starting on Day 7 of co-administration of pralsetinib with the strong CYP3A4 inducer. After the strong CYP3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose that was taken prior to the use of the inducer should be resumed.

Special populations

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLCR] 30 to 89 mL/min estimated by Cockcroft-Gault). Pralsetinib has not been studied in patients with severe renal impairment (CLCR 15 to 29 mL/min) or end-stage renal disease (CLCR <15 mL/min). Since pralsetinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment or end-stage renal disease (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin > 1 to 1.5 times ULN and any AST), moderate (total bilirubin > 1.5 to 3 times ULN and any AST) or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) (see section 5.2).

Elderly

No dose adjustment is recommended for patients aged 65 years and above (see section 5.1).

Paediatric population

The safety and efficacy of pralsetinib in paediatric patients below 18 years of age with RET fusion-positive advanced NSCLC have not been established. No data are available.

Method of administration

Gavreto is for oral use. Patients should swallow the hard capsules whole with a glass of water, on an empty stomach. They should not eat for at least two hours before and at least one hour after taking pralsetinib (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Pneumonitis/ILD

Severe, life-threatening or fatal cases of pneumonitis/ILD have been reported in patients who received pralsetinib in clinical trials (see section 4.8). Patients who present with clinically symptomatic pneumonitis or ILD were excluded from clinical trials.

Patients should be advised to contact their healthcare provider immediately to report new or worsening respiratory symptoms.

Patients who present with acute or worsening of respiratory symptoms indicative of pneumonitis/ILD (e.g., dyspnoea, cough, and fever) should be investigated to exclude other potential causes. If pneumonitis/ILD is considered to be related to pralsetinib, the dose of Gavreto should be interrupted, reduced or permanently discontinued based on severity of confirmed pneumonitis/ILD (see section 4.2).

Hypertension

Hypertension was observed in pralsetinib-treated patients in clinical trials (see section 4.8). Treatment-related hypertension was most commonly managed with anti-hypertensive medicinal products.

Treatment with Gavreto should not be initiated in patients with uncontrolled hypertension. Pre-existing hypertension should be adequately controlled before starting Gavreto treatment. Monitoring of blood pressure is recommended after 1 week, at least monthly thereafter and as clinically indicated. Anti-hypertensive therapy should be initiated or adjusted as appropriate. The dose should be interrupted, reduced, or permanently discontinued based on the severity of hypertension observed during treatment with Gavreto (see section 4.2).

Transaminase elevations

Severe cases of transaminase elevations have been reported in patients who received pralsetinib in clinical trials (see section 4.8).

ALT and AST should be monitored prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Treatment with Gavreto should be interrupted, reduced or permanently discontinued based on severity of the transaminase elevation observed during treatment with Gavreto (see section 4.2).

Haemorrhagic events

Severe, including fatal, haemorrhagic events can occur with Gavreto. In patients with life-threatening or recurrent severe haemorrhage, Gavreto should be permanently discontinued (see section 4.2).

QT prolongation

Prolongation of the QT interval has been observed in patients who received Gavreto in clinical trials (see section 4.8). Therefore, before starting Gavreto treatment, patients should have a QTc interval ≤470 ms and serum electrolytes within normal range. Hypokalaemia, hypomagnesaemia, and hypocalcaemia should be corrected both prior and during Gavreto treatment. Electrocardiograms (ECGs) and serum electrolytes should be monitored at the end of the first week and of the first month of Gavreto treatment, then periodically, as clinically indicated, depending also on presence of other risk factors (e.g. intercurrent diarrhoea, vomiting, nausea, concomitant medications).

Pralsetinib should be used with caution in patients with medical history of cardiac arrhythmias or QT interval prolongation, as well as in patients on strong CYP 3A4 inhibitors or on medicinal products known to be associated with QT/QTc prolongation.

Gavreto may require interruption, dose modification, or discontinuation (see section 4.2).

Tuberculosis

Tuberculosis, mostly extrapulmonary, has been reported in patients receiving Gavreto. Before starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. In patients with active or latent tuberculosis, standard antimycobacterial therapy should be initiated before treatment with Gavreto is started.

Drug interactions

Co-administration of Gavreto with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors should be avoided because they may increase the plasma concentration of pralsetinib (see sections 4.2 and 4.5).

Co-administration of Gavreto with strong CYP3A4 inducers should be avoided because they may decrease the plasma concentration of pralsetinib (see section 4.2 and section 4.5).

Fertility and pregnancy

During treatment with Gavreto and for at least 1 week after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a barrier method (see section 4.6).

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Gavreto. A highly effective non-hormonal method of contraception is required for female patients during treatment with pralsetinib, because pralsetinib can render hormonal contraceptives ineffective. If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 2 weeks after the final dose (see section 4.6).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

In vitro data indicate that pralsetinib is primarily metabolised by CYP3A4 and transported by P-gp. Therefore, inducers and inhibitors of CYP3A4 and P-gp may alter the plasma concentrations of pralsetinib.

Active substances that may have an effect on pralsetinib

Strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors

Co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors can increase pralsetinib plasma concentrations, which may increase the incidence and severity of adverse reactions of pralsetinib. Co-administration of 200 mg pralsetinib once daily with itraconazole 200 mg once daily (a strong CYP3A4 and P-gp inhibitor) increased pralsetinib Cmax by 84% and AUC0-∞ by 251%, compared to pralsetinib administered alone.

Therefore, co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges) should be avoided (see section 4.4). If co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors cannot be avoided, reduce the current dose of pralsetinib (section 4.2).

Strong CYP3A4 inducers

Co-administration of pralsetinib with strong CYP3A4 inducers can decrease pralsetinib plasma concentrations, which may decrease the efficacy of pralsetinib. Co-administration of 400 mg pralsetinib as a single dose with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased pralsetinib Cmax by 30% and AUC0-∞ by 68%. Based on a population PK analysis, CYP3A4 weak inducers decreased pralsetinib exposures, but were not clinically significant in patients with NSCLC.

Therefore, co-administration of pralsetinib with strong CYP3A4 inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort [Hypericum perforatum]) should be avoided (see section 4.4). If co-administration cannot be avoided, increase the pralsetinib dose (see section 4.2).

Sensitive substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1 and MATE2-K with narrow therapeutic index

Co-administration of pralsetinib can alter the exposure of sensitive substrates of CYP enzymes (CYP3A4, CYP2C9 and CYP2C8) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1 and MATE2-K). Substrate drugs of these CYP enzymes and transporters with narrow therapeutic index (including, but not limited to cyclosporine, paclitaxel and warfarin) should be avoided.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females and males

Women of childbearing potential should be informed that pralsetinib may cause foetal harm (see section 5.3).

The pregnancy status of women of childbearing potential should be verified prior to initiating Gavreto treatment.

Women of childbearing potential have to use highly effective non-hormonal contraception during treatment and for at least 2 weeks following the last dose of Gavreto (see section 4.4).

Males with female partners of childbearing potential must use effective contraception during, including a barrier method, treatment with Gavreto and for at least 1 week following the last dose of Gavreto.

Patients should be advised to contact their healthcare provider immediately if they become pregnant, or if pregnancy is suspected, while taking Gavreto.

Pregnancy

There are no data from the use of pralsetinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Based on its mechanism of action and findings in animals, pralsetinib may cause foetal harm when administered to pregnant women.

Gavreto should not be used during pregnancy unless the clinical condition of the woman requires treatment with pralsetinib.

Breast-feeding

It is unknown whether pralsetinib or its metabolites are excreted in human milk.

A risk to the breast-fed child cannot be excluded.

Breast-feeding should be discontinued during treatment with Gavreto and for 1 week following the final dose.

Fertility

There is no clinical data on the effects of pralsetinib on fertility.

Based on non-clinical safety findings, fertility may be compromised during treatment with pralsetinib (see section 5.3). Men and women should seek advice on effective fertility preservation before treatment.

4.7. Effects on ability to drive and use machines

Gavreto has minor influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience fatigue while taking Gavreto (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions were anaemia (53.0%), aspartate aminotransferase increased (49.1%), neutropenia (46.7%), musculoskeletal pain (44.4%), constipation (43.9%), fatigue (42.2%), alanine aminotransferase increased (37.0%), leukopenia (37.0%), and hypertension (35.0%).

The most common serious adverse reactions were pneumonia (15.6%), pneumonitis (5.7%) and anaemia (5.2%).

The most common severe adverse reactions were anaemia (22.4%), neutropenia (21.1%), hypertension (17.6%), pneumonia (15.4%), and lymphopenia (17.4%).

Based on the data from clinical trials, exposure-response relationships for any Grade 3 or 4 adverse reaction were observed at higher exposures, with a faster time to onset for adverse reactions with increasing pralsetinib exposure.

Dose reductions due to adverse reactions occurred in 46.7% of patients treated with Gavreto. The most common adverse reactions resulting in dose reductions were neutropenia (15.6%), anaemia (10.6%), lymphopenia (7.2%), pneumonitis (5.7%), blood creatine phosphokinase increased (5.2%), leukopenia (4.6%), hypertension (4.8%), and fatigue (4.1%).

Permanent discontinuation due to adverse reactions occurred in 10.6% of patients treated with Gavreto. The most common adverse reactions that led to permanent discontinuation of Gavreto were pneumonia and pneumonitis (2.6% and 2.2%, respectively).

Tabulated list of adverse reactions

The safety population includes a total of 540 patients, including 281 patients with advanced NCSLC, as well as patients with other solid tumours (including RET fusion thyroid cancer and RET mutation medullary thyroid cancer), who received pralsetinib at a starting dose of 400 mg, see section 5.1. No clinically relevant differences in the safety profile across indications have been observed.

Adverse reactions reported in patients treated with Gavreto in the ARROW trial are listed below (Table 3), according to the MedDRA System Organ Class and frequency.

Frequencies are defined using 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 the available data).

Within each system organ class, adverse reactions are presented in order of decreasing frequency and severity.

Table 3. Adverse reactions reported in all patients treated with 400 mg Gavreto in the ARROW trial (N=540)

System organ class / Adverse reactions

Frequency category

All grades

%

Grades 3-4

%

Infections and infestations

Pneumonia1

Urinary tract infection

Very common

22.4

14.8

13.1

4.4

Blood and lymphatic system disorders

Anaemia2

Neutropenia3

Leukopenia4

Lymphopenia5

Thrombocytopenia6

Very common

53.0

46.7

37.0

26.9

19.6

22.421.1

8.9

17.4

4.8

Metabolism and nutrition disorders

Hypocalcaemia

Hyperphosphataemia

Hypoalbuminaemia

Hypophosphataemia

Hyponatraemia

Very common

23.1

17.4

14.8

13.0

12.2

3.9

0.2

-

5.7

4.4

Nervous system disorders

Headache7

Taste disorder8

Very common

18.0

16.7

0.6

-

Vascular disorders

Hypertension9

Haemorrhage10

Very common

35.0

20.6

17.6

3.9

Respiratory, thoracic and mediastinal disorders

Cough11

Dyspnoea

Pneumonitis12

Very common

28.1

20.4

12.2

0.6

2.0

3.3

Gastrointestinal disorders

Constipation

Diarrhoea

Nausea

Abdominal pain13

Dry mouth

Vomiting

Very common

43.9

33.1

19.6

17.8

16.5

14.8

0.6

3.1

0.2

1.5

-

1.1

Stomatitis14

Common

6.9

1.3

Hepatobiliary disorders

Aspartate aminotransferase increased*

Alanine aminotransferase increased*

Hyperbilirubinaemia15

Very common

49.1

37.0

14.4

6.9

4.8

1.7

Skin and subcutaneous tissue disorders

Rash16

Very common

19.1

-

Musculoskeletal and connective tissue disorders

Musculoskeletal pain17

Blood creatine phosphokinase increased

Very common

44.4

16.7

2.6

7.6

General disorders and administration site conditions

Fatigue18

Oedema19

Pyrexia

Very common

42.2

31.5

27.8

4.1

0.2

1.5

Cardiac disorders

QT prolongation20

Common

5.2

0.4

Renal and urinary disorders

Blood creatinine increased

Very common

25.4

0.6

Investigations

Blood alkaline phosphatase increased

Very common

12.0

1.5

1 includes pneumonia, pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, atypical pneumonia, lung infection, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, pneumonia streptococcal, pneumonia moraxella, pneumonia staphylococcal, pneumonia pseudomonal, atypical mycobacterial pneumonia, pneumonia legionella

2 includes anaemia, haematocrit decreased, red blood cell count decreased, haemoglobin decreased, aplastic anaemia

3 includes neutrophil count decreased, neutropenia

4 includes white blood cell count decreased, leukopenia

5 includes lymphopenia, lymphocyte count decreased

6 includes thrombocytopenia, platelet count decreased

7 includes headache, tension headache

8 includes ageusia, dysgeusia

9 includes hypertension, blood pressure increased

10 includes 39 preferred terms from the SMQ Haemorrhage (excl laboratory terms) narrow, with the exclusion of terms related to invasive drug administration, terms related to rupture, disseminated intravascular coagulopathy, terms related to traumatic haemorrhages, and haemorrhagic terms related to pregnancy, birth or neonatal

11 includes cough, productive cough

12 includes pneumonitis, interstitial lung disease

13 includes abdominal pain, abdominal pain upper

14 includes stomatitis, aphthous ulcer

15 includes blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased, blood bilirubin unconjugated increased

16 includes rash, rash maculo-papular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pustular, rash macular, rash erythematous

17 includes musculoskeletal chest pain, myalgia, arthralgia, pain in extremity, neck pain, musculoskeletal pain, back pain, bone pain, spinal pain, musculoskeletal stiffness

18 includes asthenia, fatigue

19 includes oedema, swelling face, peripheral swelling, oedema peripheral, face oedema, periorbital oedema, eyelid oedema, generalised oedema, swelling, localised oedema

20 includes electrocardiogram QT prolonged, long QT syndrome

* additionally, transaminases increased were reported in 3.7% (0.6% Grades 3-4)

Description of selected adverse reactions

Pneumonitis/ILD

Pneumonitis and ILD occurred in 12.2% of 540 patients with NSCLC or other solid tumours, enrolled in the ARROW Study who received Gavreto (see section 4.4). Among the patients who had pneumonitis/ILD, the median time to onset was 16.1 weeks.

Serious adverse reactions of pneumonitis/ILD were reported for 5.7% of patients, including Grade 3 events (2.8%), Grade 4 (0.6%) and one fatal (Grade 5) event (0.2%).

In clinical trials, the majority of the patients with Grade 1 or Grade 2 pneumonitis were able to continue treatment without recurrent pneumonitis/ILD following dose interruption and dose reduction. Dose interruption occurred in 8.9%, dose reduction in 5.7% and permanent dose discontinuation in 2.2% of patients due to ILD/pneumonitis. The median time to resolution was 4.3 weeks.

Hypertension

Hypertension (including blood pressure increased) occurred in 35.0% of 540 patients with NSCLC or other solid tumours, including Grade ≤2 events in 17.4% and Grade 3 in 17.6% of patients. No Grade 4 or Grade 5 events were reported. Among the patients who had hypertension, the median time to onset was 2.1 weeks.

Serious adverse reactions of hypertension were reported in 1.3% of all patients (all Grade 3 events).

Dose interruption occurred in 8.0% of patients, dose reduction in 4.8% and one patient (0.2%) required permanent dose discontinuation. The median time to resolution was 4.0 weeks.

Transaminase elevations

Increased AST occurred in 49.1% of 540 patients, including Grade 3 or 4 in 6.9% of patients. Increased ALT occurred in 37.0% of patients, including Grade 3 or 4 events in 4.8% of patients. The median time to first onset for increased AST was 2.1 weeks and increased ALT was 3.5 weeks.

Serious adverse reactions of increased AST and ALT were reported in 0.7% and 0.6% of patients, respectively.

Dose interruption due to increased AST or ALT occurred in 5.0% and 3.9% of patients, respectively and dose reduction in 2.0% and 1.5%, respectively. No patients required permanent dose discontinuation. The median time to resolution was 6.0 and 5.1 weeks for increased AST and ALT, respectively.

Haemorrhagic events

Haemorrhagic events occurred in 20.6% of the 540 patients, including Grade 3 events in 3.7% of patients and a Grade 4 or fatal (Grade 5) event each occurred in one patient (0.2%).

Serious adverse reactions of haemorrhage were reported for 3.9% of patients.

Seventeen patients (3.1%) required dose interruption Dose reduction or permanent dose discontinuation due to haemorrhage occurred in 0.4% and 0.2% of patients, respectively.

QT prolongation

QT prolongation occurred in 5.2% of 540 patients with NSCLC or other solid tumours. In 2 patients (0.4%) the event was assessed as serious. The majority of patients experienced non-severe events – i.e. Grade 1, in 21 (3.9%) and Grade 2, in 5 patients (0.9%). Two patients (0.4%) experienced Grade 3 events of Electrocardiogram QT prolonged, which both resolved. There was no life-threatening or fatal QT prolongation. Three patients (0.6%) had an event that remained unresolved by time of data cut-off. Dose reductions or interruptions were required by two Electrocardiogram QT prolonged patients, each. No QT prolongation event led to permanent discontinuation of pralsetinib.

Infections

Infections were commonly experienced by 66.1% of 540 patients during the median treatment time of 15.9 months. Most frequently (>10%), pneumonia and urinary tract infection were reported (22.4% and 14.8%, respectively). The majority of infections were mild (Grade 1 or 2) and resolved; severe infection (Grade ≥3) occurred in 30.4% patients (with fatal events reported for 4.1%).

Infections reported as serious occurred for 18.5% of patients. The most common (>2%) serious infection was pneumonia (15.6%), followed by urinary tract infection (3.7%) and sepsis (3.7%). The majority of patients experiencing sepsis had concurrent pneumonia or urinary tract infection reported.

Dose interruption due to infection occurred in 12.8% of patients (mainly due to pneumonia [10.9%] and urinary tract infection [2.6%]). Dose was reduced due to infections in 3.7% of patients (mainly due to pneumonia [3.5%]). Permanent treatment discontinuation was required by 2.6% of patients due to infections (mainly due to pneumonia [2.6%]).

Elderly

In ARROW (N=540), 30.9% of patients were 65 years of age and older. Compared with younger patients (<65), more patients of ≥65 years old reported adverse reactions that led to permanent dose discontinuation (29.3% versus 18.8%). Of the commonly reported events with higher incidence in elderly patients (≥65), hypertension has the greatest difference in comparison with patients <65 years of age. However, hypertension is also expected to occur more frequently in the elderly population. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (89.8% versus 78.3%).

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

No cases of overdose have been reported in clinical trials with pralsetinib. The maximum dose of pralsetinib studied clinically is 600 mg orally once daily. Adverse reactions observed at this dose were consistent with the safety profile at 400 mg once daily (see section 4.8).

Management

There is no known antidote for Gavreto overdose. In the event of suspected overdose, Gavreto should be interrupted and supportive care instituted. Based on the large volume of distribution of pralsetinib and extensive protein binding, dialysis is unlikely to result in significant removal of pralsetinib.