GAVRETO Hard capsule Ref.[28155] Active ingredients: Pralsetinib

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). Treatmentrelated hypertension was most commonly managed with anti-hypertensive medicinal products.

Treatment with Gavreto should not be initiated in patients with uncontrolled hypertension. Preexisting 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).

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 (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”.

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 C_max by 84% and AUC_0-∞ 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 C_max by 30% and AUC_0-∞ 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.

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 have to use effective contraception during 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.

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).

Summary of the safety profile

The most common adverse reactions were anaemia (47.2%), aspartate aminotransferase increased (46.0%), neutropenia (43.9%), constipation (41.9%), musculoskeletal pain (39.8%), fatigue (37.3%), leukopenia (35.4%), alanine aminotransferase increased (33.9%), and hypertension (33.0%). The most common serious adverse reactions were pneumonia (11.7%), pneumonitis (5.3%) and anaemia (3.8%).

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 41.5% of patients treated with Gavreto. The most common adverse reactions resulting in dose reductions were neutropenia (14.0%), anaemia (8.5%), lymphopenia (5.3%), pneumonitis (5.3%), leukopenia (4.2%), blood creatine phosphokinase increased (4.0%), hypertension (4.0%), and fatigue (3.8%).

Permanent discontinuation due to adverse reactions occurred in 8.1% of patients treated with Gavreto. The most common adverse reactions that led to permanent discontinuation of Gavreto were pneumonia and pneumonitis (1.9% for each).

Tabulated list of adverse reactions

The safety population includes a total of 528 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=528):

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 ageusia, dysgeusia
⁸ includes headache, tension headache
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, 3.0% transaminases increased were reported (0.6% Grades 3-4)

Description of selected adverse reactions

Pneumonitis/ILD

Pneumonitis and ILD occurred in 11.6% of 528 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 15.6 weeks.

Serious adverse reactions of pneumonitis/ILD were reported for 5.3% of patients, including Grade 3 events (2.5%), 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 5.3% and permanent dose discontinuation in 1.9% of patients due to ILD/pneumonitis. The median time to resolution was 3.7 weeks.

Hypertension

Hypertension (including blood pressure increased) occurred in 33.0% of 528 patients with NSCLC or other solid tumours, including Grade ≤2 events in 16.9% and Grade 3 in 16.1% 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 7.4% of patients, dose reduction in 4.0% and one patient (0.2%) required permanent dose discontinuation. The median time to resolution was 3.1 weeks.

Transaminase elevations

Increased AST occurred in 46.0% of 528 patients, including Grade 3 or 4 in 5.7% of patients. Increased ALT occurred in 33.9% of patients, including Grade 3 or 4 events in 4.2% of patients. The median time to first onset for increased AST was 2.1 weeks and increased ALT was 3.1 weeks.

Serious adverse reactions of increased AST and ALT were each reported for 0.6% of all patients.

Dose interruption due to increased AST or ALT occurred in 4.4% and 3.4% of patients, respectively and dose reduction in 1.3% for both events. No patients required permanent dose discontinuation. The median time to resolution was 5.3 and 4.1 weeks for increased AST and ALT, respectively.

Haemorrhagic events

Haemorrhagic events occurred in 18.8% of the 528 patients, including Grade 3 events in 2.8% 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 3.2% of patients.

Fourteen patients (2.7%) required dose interruption and dose reduction or permanent dose discontinuation due to haemorrhage each occurred in one patient.

QT prolongation

QT prolongation occurred in 5.1% of 528 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 (4.0%) and Grade 2, in 4 patients (0.8%). 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 57.2% of 528 patients during the median treatment time of 9.5 months. Most frequently (>10%), the preferred terms of pneumonia and urinary tract infection were reported (14.2% and 12.7%, respectively). The majority of infections were mild (Grade 1 or 2) and resolved; severe infection (Grade ≥3) occurred in 23.5% patients (with fatal events reported for 1.9%).

Infections reported as serious occurred for 24.2% of patients. The most common (>2%) serious infection preferred term was pneumonia (9.8%), followed by urinary tract infection (3.4%) and sepsis (2.8%). The majority of patients experiencing sepsis had concurrent pneumonia or urinary tract infection reported.

Dose interruption due to infection occurred for 19.5% of patients (mainly due to the preferred terms of pneumonia [6.8%] and urinary tract infection [2.7%]). Dose was reduced due to infections in 3.2% of patients (mainly due to the preferred term of pneumonia [1.9%]). Permanent treatment discontinuation was required by 3.4% of patients due to infections (mainly due to the preferred term of pneumonia [1.7%]).

Elderly

In ARROW (N=528), 37.8% 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 (25.8% versus 13.4%). 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 (87.1% versus 72.3%).

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 national reporting system listed in Appendix V.

Not applicable.