OJEMDA Powder for oral suspension Ref.[116575] Active ingredients: Tovorafenib

Intratumoural haemorrhage

Intratumoural haemorrhage (including the terms tumour haemorrhage and intracranial tumour haemorrhage) events have been reported very commonly in patients treated with tovorafenib (see section 4.8). Patients and caregivers should be advised of the risk of intratumoural haemorrhage during treatment with tovorafenib. The risk of tumour haemorrhage may be increased with concomitant use of anticoagulants and antiplatelet therapy. Monitoring for signs and symptoms of haemorrhage and evaluation as clinically indicated should be done routinely. The occurrence of haemorrhagic events should be managed with dose interruption or treatment discontinuation (see section 4.2).

Other haemorrhage events

Haemorrhagic events have been reported very commonly in patients taking tovorafenib. If haemorrhage occurs, patients should be treated as clinically indicated (see section 4.8). Patients and caregivers should be advised of the risk of haemorrhage during treatment with tovorafenib. The risk of haemorrhage may be increased with concomitant use of anticoagulants and antiplatelet therapy. Monitoring for signs and symptoms of haemorrhage, and evaluation as clinically indicated should be done routinely. The occurrence of haemorrhagic events should be managed with dose interruption, dose reduction or treatment discontinuation (see section 4.2).

Effect on growth

Reductions in growth velocity have been reported very commonly in patients treated with tovorafenib (see section 4.8). Patients and caregivers should be advised of the risk of effect on growth during treatment with tovorafenib. Monitoring for growth and development should be done prior to initiation, routinely during and following discontinuation of treatment with tovorafenib.

Liver related events

Liver related events specifically increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin have been reported very commonly in patients treated with tovorafenib (see section 4.8).

Monitoring of liver function tests including AST, ALT, bilirubin levels should be done prior to initiation, 1 month after initiation and routinely during treatment with tovorafenib. Treatment should be withheld and resumed at the same or reduced dose upon improvement or permanently discontinued based on the severity (see section 4.2).

Skin toxicity including photosensitivity

Rash, including photosensitivity events, have been reported very commonly in patients treated with tovorafenib (see section 4.8). Patients should be monitored for new or worsening skin reactions. Dermatologic consultation and initiation of supportive care should be considered as clinically indicated. Patients and caregivers should be advised of the risk of rash and photosensitivity during treatment with tovorafenib. The use of precautionary measures against ultraviolet exposure such as use of sunscreen (SPF ≥50), sunglasses, and/or protective clothing during treatment with tovorafenib is recommended. Treatment should be withheld, resumed at reduced dose, or permanently discontinued based on severity of adverse reaction (see section 4.2 and section 4.8).

Women of childbearing potential/ Contraception in females and males

Before initiating treatment in women of childbearing potential, appropriate advice on effective methods of contraception should be provided. Women of childbearing potential must use effective non-hormonal contraception such as a barrier method during therapy and for 28 days after the last dose of tovorafenib (see section 4.5 and section 4.6). Male patients with female partners of reproductive potential must use condoms and effective contraception during treatment with tovorafenib and for 2 weeks after the last dose (see section 4.6).

Neurofibromatosis type 1 (NF1) associated tumours

Based on non-clinical data in NF1 models without BRAF alterations, tovorafenib may promote tumour growth in patients with NF1-associated tumours (see section 5.3). Evidence of a BRAF alteration prior to initiation of treatment with tovorafenib should be confirmed.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per 100 mg film-coated tablet, that is to say essentially 'sodium-free'.

Effects of other medicinal products on tovorafenib

Tovorafenib is a substrate for the metabolising enzyme CYP2C8.

Strong or moderate CYP2C8 inhibitors

Strong or moderate CYP2C8 inhibitors are predicted to increase tovorafenib exposure based on a mechanistic understanding of its elimination, which may increase the risk of adverse reactions with tovorafenib (see section 5.2). Coadministration of tovorafenib with a strong or moderate CYP2C8 inhibitor (e.g. gemfibrozil) should be avoided.

Strong or moderate CYP2C8 inducers

Strong or moderate CYP2C8 inducers are predicted to decrease tovorafenib exposure based on a mechanistic understanding of its elimination, which may reduce tovorafenib efficacy (see section 5.2). Coadministration of tovorafenib with a strong or moderate CYP2C8 inducer (e.g. carbamazepine) should be avoided.

Effects of tovorafenib on other medicinal products

CYP3A substrates

Tovorafenib is a CYP3A inducer. Coadministration of tovorafenib is expected to decrease exposure of certain CYP3A substrates, which may reduce the effectiveness of these substrates (see section 5.2). Coadministration of tovorafenib with certain CYP3A substrates (e.g. tacrolimus) where minimal concentration changes may lead to serious therapeutic failures should be avoided. If coadministration cannot be avoided, monitor patients for loss of efficacy unless otherwise recommended in the SmPC for CYP3A substrates.

Coadministration of tovorafenib with hormonal contraceptives (CYP3A substrates) may render hormonal contraceptives ineffective (see sections 4.4, 4.6 and 5.2). Coadministration of hormonal contraceptives with tovorafenib should be avoided. If coadministration cannot be avoided, an additional effective non-hormonal contraceptive method must be used during coadministration and for 28 days following discontinuation of tovorafenib.

CYP1A2, CYP2B6, CYP2C8 and CYP2C9 substrates

In vitro data indicated that tovorafenib may have the potential to induce CYP1A2 and CYP2B6 and to inhibit CYP2C8, CYP2C9. The clinical relevance of these findings is unknown. When tovorafenib is co-administered with medicinal products metabolised by these enzymes, appropriate monitoring is recommended.

Transporters substrates

In vitro data indicated that tovorafenib may have the potential to inhibit BCRP, OATP1B1, OATP1B3 and MATE1, the clinical relevance of these findings is unknown. When tovorafenib is co-administered with medicinal products that are substrates of these transporters, appropriate monitoring is recommended.

Women of childbearing potential/Contraception in females and males

Women of childbearing potential should have a pregnancy test prior to starting treatment with tovorafenib.

Women of childbearing potential must use effective methods of contraception during therapy and for 28 days following discontinuation of tovorafenib. Tovorafenib may decrease the efficacy of hormonal contraceptives, and effective non-hormonal contraception such as a barrier method should be used (see section 4.5). Male patients with female partners of reproductive potential must use condoms and effective methods of contraception during treatment with tovorafenib and for 2 weeks after the last dose.

Pregnancy

There are no data on the use of tovorafenib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Tovorafenib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. Pregnant women should be advised of the potential risk to a foetus. If a patient becomes pregnant while taking tovorafenib, the patient should be informed of the potential hazard to the foetus.

Breastfeeding

It is not known whether tovorafenib is excreted in human milk. A risk to the breastfed child cannot be excluded, therefore breastfeeding should be discontinued during treatment with tovorafenib and for 2 weeks after the last dose.

Fertility

There are no data on the effects of tovorafenib on fertility in humans. Based on findings in animals, tovorafenib may impact fertility in males and females of reproductive potential and may not be reversible (see section 5.3).

Tovorafenib has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of tovorafenib should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should be made aware of the potential for tovorafenib to cause fatigue, which may affect these activities.

Summary of the safety profile

The safety profile of tovorafenib is based on pooled data from 137 patients 6 months of age and older with relapsed or refractory paediatric LGG harbouring a BRAF alteration in one clinical study (FIREFLY-1, Arm 1 and 2). The median duration of treatment was 22.5 months (range 0.7 to 32.1 months). The safety population characteristics were comprised of patients with a median age of 9 years (range 1 to 24 years); 3 (2%) patients were 6 months to <2 years of age, 93 (68%) patients were 2 years to <12 years of age, and 41 (30%) patients were >12 years of age.

The most common adverse drug reactions by individual MedDRA preferred term were hair colour changes (77.4%), blood creatine phosphokinase increased (62.0%), fatigue (60.6%), anaemia (60.6%), vomiting (56.2%), hypophosphataemia (52.6%), headache (52.6%), rash maculo-papular (50.4%), pyrexia (46.7%), growth retardation (43.1%), dry skin (40.9%), aspartate aminotransferase increased (38.0%), blood lactate dehydrogenase increased (38.0%), nausea (37.2%), constipation (36.5%), upper respiratory tract infection (35.8%), dermatitis acneiform (34.3%), epistaxis (32.1%), decreased appetite (29.9%) and paronychia (29.9%).

The most common serious adverse drug reactions were growth retardation (6.6%), vomiting (6.6%), and tumour haemorrhage (5.1%).

The most commonly reported adverse reaction leading to dose reduction of tovorafenib in >5% of patients was rash maculo-papular (5.1%). The most commonly reported adverse reactions leading to dose interruption of tovorafenib in >5% of patients were pyrexia (13.9%), rash maculo-papular (10.2%), vomiting (10.2%), fatigue (5.8%), nausea (5.1%), headache (5.1%) and alanine aminotransferase increased (5.1%).

Adverse reactions which resulted in permanent discontinuation of tovorafenib in more than one patient were growth retardation (2.9%) and tumour haemorrhage (2.9%).

Tabulated list of adverse reactions

Adverse reactions reported in patients treated with tovorafenib monotherapy in FIREFLY-1 (n=137) are listed in Table 4. Adverse reactions are listed below by MedDRA body system organ class and the following frequency convention: very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4. Adverse drug reactions reported in paediatric LGG patients in FIREFLY-1 (n=137):

^a Includes term haemoglobin decreased
^b Includes terms epistaxis, contusion, gingival bleeding, haematoma, petechiae, gastrointestinal haemorrhage, haematemesis, haematochezia, lower gastrointestinal haemorrhage, purpura, subdural haemorrhage, vaginal haemorrhage
^c Includes terms tumour haemorrhage, intracranial tumour haemorrhage
^d Includes term abdominal pain upper
^e Includes terms aphthous ulcer, mouth ulceration, cheilitis, angular cheilitis, lip ulceration
^f Includes term enterocolitis
^g Includes terms rash maculo-papular, eczema, rash erythematous, rash papular, rash pustular, dermatitis, drug eruption, skin exfoliation, dermatitis bullous, rash follicular, rash macular, rash pruritic, erythema multiforme, rash vesicular
^h Includes terms chapped lips, lip dry, xeroderma
ⁱ Includes term acne
^j Includes terms skin depigmentation, skin hyperpigmentation, skin hypopigmentation, melanocytic nevus
^k Includes term growth failure
^l Includes terms face oedema, swelling face, periorbital oedema, eye swelling, oedema peripheral, peripheral swelling, lip oedema, vulval oedema
^m Includes term hypophosphataemia

Description of selected adverse reactions

Intratumoural haemorrhage (ITH)

In FIREFLY-1, intratumoural haemorrhage (Including terms tumour haemorrhage and intracranial tumour haemorrhage) were observed in 13.9% patients, 3.6% patients reported Grade ≥3 events, 0.7% patient reported a Grade 5 event. Tovorafenib was permanently discontinued due to ITH events in 2.9% of patients. The mean time to onset since initiating treatment with tovorafenib was 239.2 days (median: 206 days; range: 23-671 days) and the mean duration of the initial occurrence of ITH was 30.8 days (median: 19.5 days; range: 1 day to 88 days).

Other haemorrhage events

In FIREFLY-1, other haemorrhage events were observed in 40.1% of paediatric patients, with Grade ≥3 events occurring in 2.2%. The most frequent haemorrhagic event (epistaxis) was reported in 32.1% of patients and the majority were Grade 1. 1 patient had a Grade 3 event of epistaxis. The mean time to onset since initiating treatment with tovorafenib was 124.5 days (median: 77 days; range: 4 days-617 days), and the mean duration of the initial occurrence of haemorrhage was 78.1 days (median: 9 days; range: 1 day-428 days).

Growth retardation

Patients treated with tovorafenib for up to 24 months showed reductions from baseline in Z-scores for height compared to age and sex-matched normative data, although children with paediatric LGG may be expected to have altered growth rates compared to children without cancer. In FIREFLY-1, growth retardation was reported in 44.5% of patients 18 years of age or younger. Growth retardation resulted in dose interruption in 5.1% of patients and dose reduction in 2.2% of patients. Among those patients who experienced growth retardation who had hand radiographs taken to assess bone age, there was no evidence of premature closure of the epiphyseal growth plates or advancement of bone age. Growth retardation resulted in permanent discontinuation in 2.9% of patients. Patients followed after interruption of treatment with tovorafenib showed recovery of growth velocity and increase in Z-scores.

Liver related events

In FIREFLY-1, increased ALT was reported in 24.8% of patients taking tovorafenib. Increased AST occurred in 38% of patients taking tovorafenib. Grade ≥ 3 elevations in ALT and AST were observed in 5.8% and 2.9% of patients, respectively. Additionally, increased bilirubin was reported in 14.6% of patients. The mean time to onset of increased ALT was 215.3 days (range: 1-672 days), increased AST was 123.4 days (range: 12-813 days), and increased bilirubin was 79.6 days (range: 13-645 days). Increased ALT leading to dose interruption occurred in 5.1% of patients and dose reduction in 1.5% of patients, and increased AST leading to dose interruption occurred in 2.9% of patients, and dose reduction in 0.7% of patients. Increased bilirubin leading to dose interruption occurred in 0.7% of patients, with no dose reduction required in any patients.

Blood creatine phosphokinase increased

In FIREFLY-1, 62% of patients reported events of blood creatine phosphokinase (CPK) increased. 12.4% of patients reported Grade ≥3 events. All events were non-serious. Of those who reported an increase in CPK, the majority (61.2%), reported an increase within the first 4 weeks of initiation of tovorafenib. Some patients had multiple episodes. Increased CPK led to a dose interruption in 3.6% of patients. The mean time to onset since initiating treatment with tovorafenib was 98.5 days (median: 29 days; range: 4 days to 701 days). The mean duration of the of the initial occurrence of the event was 238.4 days (median: 122 days; range: 8 days-926 days).

Anaemia

In FIREFLY-1, anaemia was reported in 61.3% of patients. 13.1% of patients reported anemia events Grade ≥3. The majority of these patients (54.8%) reported an event of anaemia within 60 days of tovorafenib initiation. One patient experienced a serious event. No patients discontinued treatment due to anaemia; 2.2% of patients reported anaemia which required dose interruption or dose modification. The mean time to onset since initiating treatment with tovorafenib was 107.4 days (median: 57 days; range: 8 days-737 days) The mean duration of the initial occurrence of the anaemia was 207.1 days (median 89.5 days; range: 1 day-826 days).

Skin toxicity, including photosensitivity

In FIREFLY-1, rash occurred in 83.2% of patients. Most events were mild, with Grade ≥3 events reported in 12.4% of patients. Rash resulted in dose interruption in 16.1% of patients and dose reduction in 8.8% of patients, and 1 (0.7%) patient discontinued treatment due to rash pruritic. The mean time to onset of rash since initiating treatment with tovorafenib was 87.6 days (median: 14.5 days; range: 1 day-617. days), and the mean duration of the initial occurrence of rash was 103 days (median: 43 days; range: 1 day-777 days). Photosensitivity occurred in 14.6% of patients, including one Grade 3 event in a single patient (0.7%) and resulted in dose interruption in one patient (0.7%).

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.