Leaflet OJEMDA 25mg / ml powder for oral suspension
Indicated for: relapsed or refractory BRAF-altered pediatric low-grade glioma
Route of administration: oral
Substance: tovorafenib (RAF inhibitor)
ATC: L01EC04 (Antineoplastic and immunomodulating agents | Protein kinase inhibitors | B-raf serine-threonine kinase (BRAF) inhibitors)
This medicine may affect fertility.
Effective contraception is required during treatment.
Do not use this medicine while breastfeeding.
Avoid excessive exposure to sunlight or UV radiation.
This medicine may affect the liver.
This medicine may have important interactions with other medicines.
This medicine is subject to additional monitoring.
Periodic laboratory tests may be required during treatment.
Use in children only as recommended in the leaflet or by a doctor.
This medicine may increase the risk of bleeding.
This medicine may affect fetal development.
Tovorafenib is a targeted medicine used in patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma when the tumour has certain BRAF gene changes. It belongs to the RAF inhibitor class and acts on signalling pathways that drive tumour-cell growth. The aim is to slow down, stop or shrink the tumour.
It is taken by mouth, usually once weekly, as tablets or an oral suspension, exactly as prescribed by the oncology team. The dose may depend on body weight, tolerability and laboratory results. Treatment should be taken consistently; missed doses, vomiting after a dose or troublesome side effects should be discussed with the care team rather than managed independently.
Common side effects include skin rash, dry skin, sensitivity to sunlight, hair colour changes, tiredness, vomiting, nausea, constipation, headache, fever and viral infections. Bleeding, liver test changes, increased muscle enzymes and abnormal blood test results may also occur. Regular check-ups, blood tests and imaging assessments are usually needed during treatment.
Sun protection is important because skin reactions and photosensitivity can be clinically significant. Contact the doctor promptly if unusual bleeding, large bruises, yellowing of the skin or eyes, dark urine, severe rash, persistent fever, dehydration or worsening general condition occur. In children, growth in height may also be monitored throughout treatment.
General data about OJEMDA 25mg / ml
- Substance: tovorafenib
- Commercial code: W71919001
- Concentration: 25mg / ml
- Pharmaceutical form: powder for oral suspension
- Quantity: 1
- Product type: generic
- Prescription restrictions: S - Medicines prescription reserved for use in certain specialized fields.
Pharmaceutical forms available for tovorafenib
Concentrations available for tovorafenib
- 100mg
- 25mg/ml
EMA leaflet
Leaflet OJEMDA 25mg/ml
Contents of the package leaflet for the medicine OJEMDA 25mg / ml powder for oral suspension
1. NAME OF THE MEDICINAL PRODUCT
Ojemda 25 mg/ml powder for oral suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One bottle of Ojemda contains 300 mg of tovorafenib. After reconstitution, one bottle of oralsuspension delivers 12 ml of tovorafenib at a concentration of 25 mg/ml.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for oral suspension.
White to off-white powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Ojemda is indicated as monotherapy for the treatment of patients 6 months of age and older withpaediatric low-grade glioma (LGG) harbouring a BRAF fusion or rearrangement, or BRAF V600mutation, who have progressed after one or more prior systemic therapies (for biomarkers-basedpatient selection, see section 4.2).
4.2 Posology and method of administration
Treatment with tovorafenib should be initiated and supervised by a qualified physician experienced inthe use of anti-cancer medicinal products.
Patient selection
Before taking tovorafenib, patients must have confirmation of BRAF fusion or rearrangement, or
BRAF V600 mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with thecorresponding intended purpose. If the CE-marked IVD is not available, confirmation of BRAF fusionor rearrangement, or BRAF V600 mutation should be assessed by an alternative validated test.
PosologyThe recommended dose of tovorafenib based on body surface area (BSA) is 380 mg/m2 once weekly.
The maximum recommended dose is 600 mg once weekly (see Table 1).
Ojemda may be administered as an oral suspension (see Table 1) or as an immediate release tablet (seetovorafenib 100 mg film-coated tablets SmPC).
A recommended dose for patients with BSA less than 0.3 m2 has not been established.
Table 1: Recommended dose based on body surface area:
Body surface area Dose volume* Recommended dose (once weekly)0.30-0.35 m2 5 ml 125 mg0.36-0.42 m2 6 ml 150 mg0.43-0.48 m2 7 ml 175 mg0.49-0.54 m2 8 ml 200 mg0.55-0.63 m2 9 ml 225 mg0.64-0.77 m2 11 ml 275 mg0.78-0.83 m2 12 ml 300 mg0.84-0.89 m2 14 ml 350 mg0.90-1.05 m2 15 ml 375 mg1.06-1.25 m2 18 ml 450 mg1.26-1.39 m2 21 ml 525 mg≥ 1.40 m2 24 ml 600 mg
*The maximum dose per bottle is 300 mg (12 ml).
Duration of treatmentTreatment with tovorafenib should be continued once weekly until disease progression, loss of clinicalbenefit, or unacceptable toxicity.
Missed or delayed doses
If a dose is missed by 3 days or less, the missed dose should be taken as soon as possible, and the nextdose should be taken on its regularly scheduled day.
If a dose is missed by more than 3 days, the missed dose should be skipped, and the next dose shouldbe taken on its regularly scheduled day.
A minimum of 4 days should occur between doses.
VomitingIf vomiting occurs immediately after taking a dose, the dose should be repeated.
Dose modificationsThe management of adverse reactions may require dose reduction, treatment interruption or treatmentdiscontinuation.
The recommended dose reductions for adverse reactions for tovorafenib oral suspension are providedin Table 2.
Table 2: Recommended dose reductions for adverse reactions
Body surface area First dose reduction Second dose reduction
Volume Dose Volume Dose0.30-0.35 m2 4 ml 100 mg 3 ml 75 mg0.36-0.42 m2 5 ml 125 mg 4 ml 100 mg0.43-0.48 m2 6 ml 150 mg 5 ml 125 mg0.49-0.54 m2 7 ml 175 mg 6 ml 150 mg0.55-0.63 m2 8 ml 200 mg 6 ml 150 mg0.64-0.77 m2 9 ml 225 mg 8 ml 200 mg0.78-0.83 m2 10 ml 250 mg 8 ml 200 mg0.84-0.89 m2 12 ml 300 mg 10 ml 250 mg0.90-1.05 m2 13 ml 325 mg 11 ml 275 mg1.06-1.25 m2 15 ml 375 mg 13 ml 325 mg1.26-1.39 m2 18 ml 450 mg 15 ml 375 mg≥ 1.40 m2 20 ml 500 mg 16 ml 400 mg
The recommended dose modifications for adverse reactions for tovorafenib are in Table 3.
Table 3: Recommended dose modifications for adverse reactions
Severity of ADRa Dose modificationb
Haemorrhage and intratumoural haemorrhage
* Intolerable Grade 2 Withhold administration.
* Grade 3 - If improved to Grade 0-1, resume atreduced dose.
- If not improved, consider permanentdiscontinuation.
* First occurrence of any Grade 4 Withhold administration.
- If improved to Grade 0-1, resume atreduced dose.
- If not improved, consider permanentdiscontinuation.
* Recurrent Grade 4 Permanent discontinuation.
Skin toxicity, including photosensitivity
* Intolerable Grade 2 Withhold administration.
* Grade 3 or 4 - If improved to Grade 0-1, resume atreduced dose.
- If not improved, consider permanentdiscontinuation.
Liver related events
* Grade 3 AST or ALT Withhold administration.
* Grade 3 bilirubin If improved to Grade ≤ 2 or baseline resume asfollows:
- If laboratory abnormality resolves within8 days, resume at the same dose.
- If laboratory abnormality does not resolvewithin 8 days, resume at lower dosage
* First occurrence of any Grade 4 Withhold administration.
- If improved to Grade 0-1, resume at lowerdosage.
- If not improved, consider permanentdiscontinuation.
* Recurrent Grade 4 Permanent discontinuation.
Other adverse reactions
* Intolerable Grade 2 Withhold administration.
* Grade 3 - If improved to Grade 0-1, resume atreduced dose.
- If not improved, consider permanentdiscontinuation.
* Grade 4 Withhold administration.
- If improved to Grade 0-1, resume atreduced dose.
- If not improved, consider discontinuationa National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version5.0.b See Table 2 for recommended dose reductions.
Special populationsHepatic impairment
No dose adjustment is recommended for patients with mildly abnormal liver function tests (defined asbilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN orbilirubin > 1x to 1.5x ULN and any AST). Tovorafenib has not been studied in patients withmoderately abnormal liver function tests (defined as bilirubin > 1.5x to 3x ULN and any AST) orseverely abnormal liver function tests (defined as bilirubin > 3x ULN and any AST) (see section 5.2).
Patients with moderately or severely abnormal liver function tests should be monitored carefully whentreated with tovorafenib.
Renal impairmentNo dose adjustment is recommended for patients with mild-to-moderate (eGFR ≥ 30 ml/min/1.73 m²calculated by Schwartz equation or MDRD equation) renal impairment. Tovorafenib has not beenstudied in patients with severe (eGFR <30 ml/min/1.73 m2) renal impairment (see section 5.2).
Paediatric populationTovorafenib paediatric clinical experience is limited, particularly in the specific age range 6 months to2 years. The safety and efficacy of tovorafenib in children below 6 months of age have not beenestablished. No data are available.
Method of administrationOjemda is for oral use.
If the patient is unable to swallow and has a nasogastric tube in situ, the powder for oral suspensioncan be administered via the tube (see section 6.6).
Ojemda can be taken with or without food (see section 5.2) and should be taken at a regularlyscheduled time once weekly.
Ojemda should be administered to paediatric patients under adult supervision.
Ojemda powder for oral suspension must be reconstituted prior to being administered (see section 6.6).
Prior to first time use of the oral suspension, caregivers (and if appropriate, patients) should beinstructed on the proper preparation, dose, and administration of Ojemda.
Detailed instructions on the preparation and administration of the powder for oral suspension are givenin section 6.6 and at the end of the package leaflet.
The powder for oral suspension and the film-coated tablets may be used interchangeably (seetovorafenib 100 mg film-coated tablets SmPC). For patients who are not able to swallow or with BSAless than 0.9 m2 the oral suspension should be provided.
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
Intratumoural haemorrhage
Intratumoural haemorrhage (including the terms tumour haemorrhage and intracranial tumourhaemorrhage) events have been reported very commonly in patients treated with tovorafenib (seesection 4.8). Patients and caregivers should be advised of the risk of intratumoural haemorrhage duringtreatment with tovorafenib. The risk of tumour haemorrhage may be increased with concomitant useof anticoagulants and antiplatelet therapy. Monitoring for signs and symptoms of haemorrhage andevaluation as clinically indicated should be done routinely. The occurrence of haemorrhagic eventsshould 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. Ifhaemorrhage occurs, patients should be treated as clinically indicated (see section 4.8). Patients andcaregivers should be advised of the risk of haemorrhage during treatment with tovorafenib. The risk ofhaemorrhage may be increased with concomitant use of anticoagulants and antiplatelet therapy.
Monitoring for signs and symptoms of haemorrhage, and evaluation as clinically indicated should bedone 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 duringtreatment 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), aspartateaminotransferase (AST), and bilirubin have been reported very commonly in patients treated withtovorafenib (see section 4.8).
Monitoring of liver function tests including AST, ALT, bilirubin levels should be done prior toinitiation, 1 month after initiation and routinely during treatment with tovorafenib. Treatment shouldbe withheld and resumed at the same or reduced dose upon improvement, or permanently discontinuedbased on the severity (see section 4.2).
Skin toxicity including photosensitivity
Rash, including photosensitivity events, have been reported very commonly in patients treated withtovorafenib (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 clinicallyindicated. Patients and caregivers should be advised of the risk of rash and photosensitivity duringtreatment with tovorafenib. The use of precautionary measures against ultraviolet exposure such as useof sunscreen (SPF ≥ 50), sunglasses, and/or protective clothing during treatment with tovorafenib isrecommended. Treatment should be withheld, resumed at reduced dose, or permanently discontinuedbased 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 effectivemethods of contraception should be provided. Women of childbearing potential must use effectivenon-hormonal contraception such as a barrier method during therapy and for 28 days after the last doseof tovorafenib (see section 4.5 and section 4.6). Male patients with female partners of reproductivepotential must use condoms and effective contraception during treatment with tovorafenib and for2 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 promotetumour growth in patients with NF1-associated tumours (see section 5.3). Evidence of a BRAFalteration prior to initiation of treatment with tovorafenib should be confirmed.
Sodium contentThis medicine contains less than 1 mmol sodium (23 mg) per bottle, that is to say essentially‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
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 amechanistic understanding of its elimination, which may increase the risk of adverse reactions withtovorafenib (see section 5.2). Coadministration of tovorafenib with a strong or moderate CYP2C8inhibitor (e.g. gemfibrozil) should be avoided.
Strong or moderate CYP2C8 inducers
Strong or moderate CYP2C8 inducers are predicted to decrease tovorafenib exposure based on amechanistic 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 substratesTovorafenib is a CYP3A inducer. Coadministration of tovorafenib is expected to decrease exposure ofcertain 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 minimalconcentration changes may lead to serious therapeutic failures should be avoided. If coadministrationcannot be avoided, monitor patients for loss of efficacy unless otherwise recommended in the SmPCfor CYP3A substrates.
Coadministration of tovorafenib with hormonal contraceptives (CYP3A substrates) may renderhormonal contraceptives ineffective (see sections 4.4, pct. 4.6 and 5.2). Coadministration of hormonalcontraceptives with tovorafenib should be avoided. If coadministration cannot be avoided, anadditional effective non-hormonal contraceptive method must be used during coadministration and for28 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 toinhibit CYP2C8, CYP2C9. The clinical relevance of these findings is unknown. When tovorafenib isco-administered with medicinal products metabolised by these enzymes, appropriate monitoring isrecommended
Transporters substrates
In vitro data indicated that tovorafenib may have the potential to inhibit BCRP, OATP1B1, OATP1B3and MATE1, the clinical relevance of these findings is unknown. When tovorafenib is co-administeredwith medicinal products that are substrates of these transporters, appropriate monitoring isrecommended.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in females and males
Women of childbearing potential should have a pregnancy test prior to starting treatment withtovorafenib.
Women of childbearing potential must use effective methods of contraception during therapy and for28 days following discontinuation of tovorafenib. Tovorafenib may decrease the efficacy of hormonalcontraceptives, and effective non-hormonal contraception such as a barrier method should be used (seesection 4.5). Male patients with female partners of reproductive potential must use condoms andeffective methods of contraception during treatment with tovorafenib and for 2 weeks after the lastdose.
PregnancyThere are no data on the use of tovorafenib in pregnant women. Animal studies have shownreproductive toxicity (see section 5.3). Tovorafenib should not be administered to pregnant womenunless the potential benefit to the mother outweighs the possible risk to the foetus. Pregnant womenshould be advised of the potential risk to a foetus. If a patient becomes pregnant while takingtovorafenib, the patient should be informed of the potential hazard to the foetus.
BreastfeedingIt is not known whether tovorafenib is excreted in human milk. A risk to the breastfed child cannot beexcluded, therefore breastfeeding should be discontinued during treatment with tovorafenib and for2 weeks after the last dose.
FertilityThere 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 bereversible (see section 5.3).
4.7 Effects on ability to drive and use machines
Tovorafenib has minor influence on the ability to drive and use machines. The clinical status of thepatient and the adverse reaction profile of tovorafenib should be borne in mind when considering thepatient's ability to perform tasks that require judgement, motor or cognitive skills. Patients should bemade aware of the potential for tovorafenib to cause fatigue, which may affect these activities.
4.8 Undesirable effects
The safety profile of tovorafenib is based on pooled data from 137 patients 6 months of age and olderwith 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 to32.1 months). The safety population characteristics were comprised of patients with a median age of9 years (range: 1 to 24 years); 3 (2%) patients were 6 months to < 2 years of age, 93 (68%) patientswere 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 colourchanges (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 aminotransferaseincreased (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% ofpatients was rash maculo-papular (5.1%). The most commonly reported adverse reactions leading todose interruption of tovorafenib in > 5% of patients were pyrexia (13.9%), rashmaculo-papular (10.2%), vomiting (10.2%), fatigue (5.8%), nausea (5.1%), headache (5.1%) andalanine aminotransferase increased (5.1%).
Adverse reactions which resulted in permanent discontinuation of tovorafenib in more than one patientwere growth retardation (2.9%) and tumour haemorrhage (2.9%).
Tabulated list of adverse reactionsAdverse 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 thefollowing frequency convention: very common ( ≥ 1/10) and common ( ≥ 1/100 to < 1/10). Withineach 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)
Infections and infestationsVery common Upper respiratory tract infection, paronychia, viral infection
Blood and lymphatic system disordersVery common Anaemiaa
Metabolism and nutrition disordersVery common Decreased appetite, hypokalaemia, hypoalbuminemia,hyponatraemia
Nervous system disordersVery common Headache
Eye disordersCommon Blepharitis, dry eye
Vascular disordersVery common Haemorrhageb, intratumoural haemorrhagec, flushing
Gastrointestinal disordersVery common Vomiting, nausea, constipation, abdominal paind, stomatitise,diarrhoeaf
Skin and subcutaneous tissue disordersVery common Rashg, hair colour changes, dry skinh, dermatitis acneiformi, pruritus,skin discolourationj, alopecia, photosensitivity reaction
Musculoskeletal and connective tissue disordersVery common Growth retardationk, pain in extremity, myalgia, arthralgia
General disorders
Very common Fatigue, pyrexia, oedemal
InvestigationsVery common Blood phosphorus decreasedm, blood creatine phosphokinaseincreased, blood lactate dehydrogenase increased, aspartateaminotransferase increased, weight decreased alanineaminotransferase increased, lymphocyte count decreased, bloodbilirubin increased,, white blood cell count decreased
Common Eosinophiliaa Includes term haemoglobin decreasedb Includes terms epistaxis, contusion, gingival bleeding, haematoma, petechiae, gastrointestinal haemorrhage,haematemesis, haematochezia, lower gastrointestinal haemorrhage, purpura, subdural haemorrhage, vaginalhaemorrhagec Includes terms tumour haemorrhage, intracranial tumour haemorrhaged Includes term abdominal pain uppere Includes terms aphthous ulcer, mouth ulceration, cheilitis, angular cheilitis, lip ulcerationf Includes term enterocolitisg Includes terms rash maculo-papular, eczema, rash erythematous, rash papular, rash pustular, dermatitis, drugeruption, skin exfoliation, dermatitis bullous, rash follicular, rash macular, rash pruritic, erythema multiforme,rash vesicularh Includes terms chapped lips, lip dry, xerodermai Includes term acnej Includes terms skin depigmentation, skin hyperpigmentation, skin hypopigmentation, melanocytic nevusk Includes term growth failurel Includes terms face oedema, swelling face, periorbital oedema, eye swelling, oedema peripheral, peripheralswelling, lip oedema, vulval oedemam Includes term hypophosphataemia
Description of selected adverse reactionsIntratumoural haemorrhage (ITH)
In FIREFLY-1, intratumoural haemorrhage (Including terms tumour haemorrhage and intracranialtumour 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 in2.9% 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 was30.8 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 in32.1% of patients and the majority were Grade 1. 1 patient had a Grade 3 event of epistaxis. The meantime 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 was78.1 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 forheight compared to age and sex-matched normative data, although children with paediatric LGG maybe expected to have altered growth rates compared to children without cancer. In FIREFLY-1, growthretardation was reported in 44.5% of patients 18 years of age or younger. Growth retardation resultedin dose interruption in 5.1% of patients and dose reduction in 2.2% of patients. Among those patientswho experienced growth retardation who had hand radiographs taken to assess bone age, there was noevidence of premature closure of the epiphyseal growth plates or advancement of bone age. Growthretardation resulted in permanent discontinuation in 2.9% of patients. Patients followed afterinterruption 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 ASToccurred in 38% of patients taking tovorafenib. Grade ≥ 3 elevations in ALT and AST were observedin 5.8% and 2.9% of patients, respectively. Additionally, increased bilirubin was reported in 14.6% ofpatients. 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 anddose 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 interruptionoccurred 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 anincrease in CPK, the majority (61.2%), reported an increase within the first 4 weeks of initiation oftovorafenib. Some patients had multiple episodes. Increased CPK led to a dose interruption in 3.6% ofpatients. 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 eventwas 238.4 days (median: 122 days; range: 8 days-926 days).
AnaemiaIn 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 oftovorafenib initiation. One patient experienced a serious event. No patients discontinued treatment dueto 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 eventsreported in 12.4% of patients. Rash resulted in dose interruption in 16.1% of patients and dosereduction in 8.8% of patients, and 1 (0.7%) patient discontinued treatment due to rash pruritic. Themean 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 was103 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 reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no information on overdose with tovorafenib. If overdose occurs, tovorafenib should bewithheld and the patient should be treated supportively with appropriate monitoring as necessary.
Since tovorafenib is highly bound to plasma proteins, haemodialysis is likely to be ineffective in thetreatment of overdose with tovorafenib.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agent, protein kinase inhibitor, B-Raf serine-threoninekinase (RAF) inhibitor, ATC code: L01EC04
Mechanism of actionTovorafenib is a central nervous system (CNS)-penetrant, selective small molecule Type II RAFkinase inhibitor of mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, including
RAF monomers and dimers and BRAF fusion, suppressing activation of the mitogen-activated proteinkinase (MAPK) pathway (see section 5.3).
Pharmacodynamic effectsCardiac Electrophysiology
At the recommended tovorafenib dose of 380 mg/m2 orally once weekly (not to exceed 600 mg), amean increase in the QT interval > 20 milliseconds was not observed.
Clinical efficacy and safetyThe efficacy of tovorafenib was evaluated in patients 6 months of age and older in a multicentre,open-label, single-arm clinical study (FIREFLY-1 [Arm 1]). Eligible patients (n=76), from 6 monthsto 25 years of age, were required to have a relapsed or refractory paediatric low-grade glioma (LGG)harbouring an activating BRAF alteration based on local laboratory testing. Patients were also requiredto have at least one measurable lesion as defined by RANO 2010 criteria. All patients had received atleast one line of prior systemic therapy and had documented evidence of radiographic progression.
Patients with tumours harbouring additional activating molecular alteration(s) (e.g., IDH1/2 mutations,
FGFR mutations) or patients with known or suspected diagnosis of neurofibromatosis type 1 (NF1)were excluded.
Patients received tovorafenib approximately 420 mg/m2 orally once weekly (range: 290 to 476 mg/m2,0.76-1.25 times the recommended dose) according to body surface area with a maximum dose of600 mg until disease progression, loss of clinical benefit, or unacceptable toxicity.
Tumour assessments were performed every 12 weeks.
The major efficacy endpoints were overall response rate (ORR) of patients assessed by independentreview based on RANO-HGG (Response Assessment in Neuro-Oncology for High-Grade Glioma),the primary endpoint, and RAPNO-LGG (Response Assessment in Paediatric Neuro-Oncology)criteria. Additional efficacy outcome measures were duration of response, time to response, ORR andprogression-free survival (PFS) by independent review based on RANO-LGG (2011) criteria.
The median age was 8.5 years (range: 2 to 21 years); 14 patients were below 6 years old, 42 between6 and 12 years old, 15 between 12 and 16 years old and 6 patients older than 16, and below25 years-old; 53% were male; 61% were White, and 93% had Karnofsky/Lansky performance statusof 80 to 100. Patients received a median of 3 prior systemic regimens (range: 1 to 9), including 22%,26%, 21%, and 30% who received 1, 2, 3, and > 3 prior systemic regimens, respectively. Mostcommon prior systemic therapies were chemotherapy regimens (carboplatin and vincristine).46 patients (60%) received prior treatment with a MAP kinase pathway inhibitor. The most commontumour locations were the optic pathway (51%), deep midline structures (12%), brain stem (8%),cerebellum (7%), and cerebral hemisphere (5%). 63 patients (83%) had a BRAF fusion orrearrangement and 13 patients (17%) had a V600 mutation.
The median duration of treatment was 23.7 months (range: 0.7 to 32.1 months).
Per protocol, patients could also enter an optional drug holiday after completing 26 cycles oftherapy/24 months of treatment and at the investigator discretion: 43% (33/76) patients were on a drugholiday, 14% (11/76) patients remained on treatment. Out of the patients who entered a drug-holiday,3 patients (9.1%) were retreated with tovorafenib following clinical or radiographic evidence ofdisease progression.
Based on RANO-HGG criteria per independent review, out of the 69 evaluable patients, the ORR was71.0% (58.8, 81.3; 95% CI), with 23.2% of patients were in complete response, 47.8% in partialresponse and 21.7% in stable disease. The median duration of response was 19.7 months(95% CI: 13.7, NE [not estimable]).
Efficacy results based on RAPNO-LGG are shown in Table 5.
Table 5: Efficacy results based on independent review in FIREFLY-1 (Arm-1)
Efficacy parameter RAPNO-LGG
N=76*
Overall response rate
ORR (CR+PR+MR) 95% CIa 52.6% (40.8, 64.2)
Best overall response
Complete response (CR), n (%) 0 (0)
Partial response (PR), n (%) 29 (38.2%)
Minor response (MR), n (%) 11 (14.5%)
Stable disease (SD), n (%) 22 (28.9%)
Progressive disease (PD), n (%) 13 (17.1%)
Duration of response (DoR) N=40
Median (95% CI)b, months 18.0 (12.0, 22.8)
DoR rate at ≥ 12 months (95% CI)b 65.0% (48.2%, 77.6%)
DoR rate at ≥ 24 months (95% CI)b 25.6% (11.4%, 42.6%)
Abbreviations RAPNO-LGG = Response Assessment in Paediatric Neuro-Oncology for Low-Grade Glioma; CI= confidence interval.
*At least one measurable lesion by the relevant imaging criteria at baseline based on RAPNO-LGGaBased on Clopper-Pearson exact confidence interval.bBased on Kaplan-Meier estimate.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of FIREFLY-2study until July 2030 with Ojemda in one or more subsets of the paediatric population in the treatmentof paediatric low-grade glioma (see section 4.2 for information on paediatric use).
Conditional approvalThis medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.
5.2 Pharmacokinetic properties
Tovorafenib pharmacokinetic parameters are presented as mean (CV%) unless otherwise indicated.
Based on pop-PK modelling, tovorafenib steady state maximum concentration (Cmax) is6.9 µg/ml(23%) and the area under the concentration-time curve (AUC) is 508 µg.h/ml (31%). Timeto reach steady state of tovorafenib is 12 days (33%). Tovorafenib exposure increases in adose-proportional manner. No clinically significant tovorafenib accumulation occurs.
AbsorptionBased on clinical study in healthy volunteers, tovorafenib median (minimum, maximum) time toachieve peak plasma concentration (Tmax) is 3 hours (1.5, 4 hours), following a single dose with tabletsor oral suspension.
Effect of foodBased on clinical study in healthy volunteers, no clinically significant differences in tovorafenib Cmaxand AUC were observed following administration of tablets with a high-fat meal (approximately859 total calories, 54% fat) compared to fasted conditions, but the Tmax was delayed to 6.5 hours.
DistributionBased on pop-PK modelling, tovorafenib apparent volume of distribution is 60 L/m2 (23%).
Tovorafenib is 97.5% bound to human plasma proteins in vitro. Tovorafenib is highly protein-boundto albumin (≈ 95%) and moderately bound to alpha-1 acid glycoprotein (AAG) (≈ 42%).
BiotransformationTovorafenib is primarily metabolised by aldehyde oxidase and CYP2C8 in vitro. CYP3A, CYP2C9and CYP2C19 metabolise tovorafenib to a minor extent.
Drug interaction studiesIn vitro studies
CYP450 Enzymes: Tovorafenib inhibits CYP2C8, CYP2C9, CYP2C19 and CYP3A, but does notinhibit CYP1A2, CYP2B6 and CYP2D6 potentially at clinically relevant concentrations.
Tovorafenib induces CYP3A, CYP2C8, CYP1A2, CYP2B6, CYP2C9 and CYP2C19potentially at clinically relevant concentrations.
Transporter systems: Tovorafenib is not a substrate of breast cancer resistance protein (BCRP),
P-glycoprotein (P-gp), OATP1B1 and OATP1B3. Tovorafenib has not been evaluated as a substrate of
OAT1, OAT3, MATE1, MATE2-K and OCT2. Tovorafenib inhibits BCRP, OATP1B1, OATP1B3and MATE1 potentially at clinically relevant concentrations.
EliminationBased on pop-PK modelling, tovorafenib terminal half-life is approximately 56 hours (33%) and theapparent clearance is 0.7 L/h/m2 (31%). Based on clinical study in healthy volunteers, following asingle oral dose of radiolabelled tovorafenib, 66.1% of the total radiolabelled dose was recovered inthe faeces (8.6% unchanged) and 28.7% of the dose was recovered in the urine (0.2% unchanged).
Special populationsPaediatric population
Based on pop-PK modelling, no clinically significant differences in the pharmacokinetics oftovorafenib were observed based on age (range: 1 to 94 years). Cmax and AUC in paediatric patientsaged 11 months to 17 years were within the range of values observed in adults given the same dose perbody surface area.
Patients with renal impairmentBased on pop-PK modelling, no clinically significant differences of tovorafenib were observed inpatients with mild-to-moderate renal impairment (eGFR ≥ 30 ml/min/1.73 m2 calculated by Schwartzequation or MDRD equation). Tovorafenib has not been studied in patients with severe (eGFR<30 ml/min/1.73 m²) renal impairment
Patients with hepatic impairmentBased on pop-PK modelling of PK data derived from clinical studies, no clinically significantdifferences of tovorafenib were observed in patients with mildly abnormal liver functions tests(defined as bilirubin ≤ upper limit of normal [ULN] and Aspartate Aminotransferase (AST) > ULN orbilirubin > 1 to 1.5x ULN and any AST). Tovorafenib has not been studied in patients with moderatelyabnormal liver functions tests (defined as bilirubin > 1.5x to 3x ULN and any AST) or severelyabnormal liver functions tests (defined as total bilirubin >3 x ULN and any AST) (see section 4.2).
RaceNo clinically significant differences in the pharmacokinetics of tovorafenib were observed based onrace (White, Black, Asian).
GenderNo clinically significant differences in the pharmacokinetics of tovorafenib were observed based onsex.
Pharmacokinetic/pharmacodynamic relationshipTovorafenib exposure is associated with reduction in height-for-age Z-scores in paediatric patients.
Reduced height-for-age risk persists during treatment with tovorafenib. Higher tovorafenib exposurewas associated with increased risk of adverse reactions such as skin rash and elevated liver enzymes(AST and ALT) (see section 4.8). The exposure-response relationship for overall response rate basedon RAPNO-LGG was not clinically significant over the dose range of 290 to 476 mg/m2(0.76-1.25 times the recommended dose).
5.3 Preclinical safety data
In vitro, tovorafenib increased phosphorylation of extracellular signal-regulated kinase (ERK) atclinically relevant concentrations in cells with neurofibromatosis Type 1-loss of function (NF1-LOF)suggesting activation, rather than inhibition, of the MAP kinase pathway. In an NF1 geneticallyengineered mouse model of plexiform neurofibroma without BRAF alteration, tovorafenib did nothave antitumour activity (see section 4.4) and while not statistically significant, an increase in tumourvolume was noted in 2/12 mice (approximately 17%).
In hERG-transfected HEK293 cells, hERG channel was inhibited indicating potential for QTprolongation. Half-maximal inhibitory concentration was 8.9 μM which is 32-fold higher than theclinical plasma unbound concentration in adults.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows:
Tovorafenib was not carcinogenic in a 26-week (or 6-month) study in transgenic mice at exposuresapproximately 0.6-fold the human exposure (AUC) at the recommended human dose. Based on invitro and in vivo studies, tovorafenib is not considered genotoxic at clinically relevant exposures.
In a preliminary embryofetal development study in rats, total litter loss due to early resorptions wasobserved in all females at exposure levels lower than the recommended dose in human. This resultedin no foetus available for further examination, and explains the absence of further developmentalstudies (pivotal embryofetal development studies and prenatal and postnatal development study).
In a fertility and early embryonic development study in female rats, tovorafenib decreased the numberof pregnancies, corpora lutea, and live embryos, as well as increased post-implantation losses at dosesas low as approximately 0.8-fold the human exposure at the recommended dose based on AUC.
In repeat-dose toxicology studies in rats of up to 3 months duration, tovorafenib-related findings infemale rats included reversible increased thickness of the vaginal mucosa, increased size and/ornumbers of corpora haemorrhagicum and haemorrhage, and non-reversible cystic follicles, decreasedcorpora lutea, and interstitial cell hyperplasia were observed in ovaries at doses approximately 0.4-foldthe human exposure at the recommended dose based on AUC. In male rats, tovorafenib reducedweights of epididymis and testes, which correlated with reversible tubular degeneration/atrophy of thetestes and reduced epididymal sperm at doses approximately 0.3-fold the human exposure at therecommended dose based on AUC.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Copovidone
Cellulose, microcrystalline
Mannitol (E421)
Sodium Lauril sulfate
Simeticone
Maltodextrin
Silica, colloidal anhydrous
Sucralose
Artificial strawberry flavour (containing maltodextrin, triacetin, artificial flavour)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Powder for oral suspension:3 years.
Reconstituted oral suspension:15 minutes
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
30 ml clear Type III glass bottle with induction-seal and a white polypropylene cap.
Each pack contains one bottle, a 20 ml oral dosing syringe, and a bottle adaptor.
6.6 Special precautions for disposal and other handling
* The instructions for use should be read carefully each time before preparing a dose of Ojemda.
* The doctor or pharmacist should show the patient or the caregiver how to prepare, measureand give a dose of Ojemda correctly.
* The bottle is made of glass. This medicine should not be used if the bottle is broken ordamaged, or if the safety seal under the cap is broken or missing.
* Only 14 ml of room temperature water should be used for preparing Ojemda.
* Only use up to 12 ml of Ojemda from each prepared bottle. If the prescribed dose is more than12 ml (300 mg), split the dose as equally as possible between each prepared bottle (e.g., 6 mland 7 ml for a 325 mg dose). Prepare the first bottle and administer dose prior to preparing thesecond bottle.
* Each dose must be given within 15 minutes after the medicine has been prepared.
Instruction for reconstitution of Ojemda powder for oral suspension
Note: if more than one bottle is needed for the prescribed dose, bottles should be constituted one byone. Split the dose as equally as possible between each prepared bottle.
This procedure should be performed on a clean and flat work surface with clean hands.
Step 1: Fill a cup half-way with room temperature water. Do not use cold water.
Step 2: Pull up on the plunger of the oral dosing syringe to draw water exactly until the 14 ml mark.
Step 3: Turn the oral dosing syringe tip upward and check for air bubbles. If large air bubbles appearin the oral dosing syringe, push the water back into the cup and then draw up the water again to the14 ml mark. Repeat this step until there are no large air bubbles present. Small air bubbles are fine(see Figure 1)
Figure 1
Step 4: Open the bottle with powder by pushing down firmly on the cap and turning it to the left(counterclockwise). Do not use the product if the bottle is broken, damaged or if the safety seal underthe cap is broken or missing. Do not throw away the cap.
Step 5: Using the oral dosing syringe, inject exactly 14 ml of water into the bottle (see Figure 2). Rightaway, replace the cap back onto the bottle by pushing down while twisting the cap to the right(clockwise). Shake the bottle well for 60 seconds in all directions.
Turn the bottle upside down to check for any powder stuck to the inside of the bottle (see Figure 3). Ifyou still see powder in the bottle, continue to shake the bottle for another 15 seconds until you nolonger see the powder inside the bottle. Do not shake the bottle for more than 2 minutes total time.
If you still see powder in the bottle, ask for a new bottle.
Figure 2 Figure 3
Step 6: Turn the bottle upside down again and swirl for 30 seconds (see Figure 4). Remove the cap andcheck that no solids are stuck in the bottle neck. If you see solids in the bottle neck when removing thecap, recap the bottle, turn the bottle upside down, and swirl for an additional 15 seconds.
Allow the bottle to sit for 60 seconds to allow most of the foam to settle. Note: Foaming in the bottlewill reduce the amount of Ojemda for oral suspension.
Figure 4
Step 7: Firmly insert the bottle adaptor into the bottle by pushing it tightly into the top of the bottle.
The top edge of the bottle adaptor should be even with the bottle top.
Do not remove the bottle adaptor after it is inserted into the bottle.
Step 8: Check the prescribed dose in millilitres (ml). Draw air into the oral dosing syringe by pullingthe plunger out until the prescribed dose is reached.
Step 9: Insert the tip of the oral dosing syringe into the bottle adaptor. The tip of the oral dosingsyringe should fit snugly into the hole of the bottle adaptor. With the oral dosing syringe in place andholding the bottle where the oral dosing syringe tip inserts into bottle adaptor, swirl the oralsuspension for 30 seconds (see Figure 5).
Figure 5
Step 10: Inject the air from the oral dosing syringe into the bottle (see Figure 6). Hold the oral dosingsyringe in place and turn the bottle upside down. To measure the prescribed dose, keep the tip of theoral dosing syringe facing up and pull down on the plunger until the top of the plunger lines up withthe prescribed dose in millilitres.
Figure 6
Step 11: While the syringe is still inserted into the adapter in the bottle, remove any air bubbles in theoral dosing syringe by gently pushing the Ojemda back into the bottle and then pulling down on theplunger again to draw up your prescribed dose.
Repeat this step until you see that few or no air bubbles remain or if you draw up the wrong dose inthe oral dosing syringe. Only use up to 12 ml of Ojemda from each prepared bottle.
Step 12: Leave the tip of the oral dosing syringe in the bottle adaptor and carefully turn the bottleupright. Put the bottle onto a flat work surface again. Slowly remove the oral dosing syringe tip fromthe bottle adaptor by gently pulling straight up. Ojemda is ready for administration.
Administration using an oral syringe
Once the suspension is prepared, place the tip of the oral dosing syringe towards the inside of themouth with the tip touching the inside of either cheek then slowly push the medicine into the mouth bypressing down on the plunger.
Do not forcefully push the plunger. This may cause choking. Allow the child to swallow while giving
Ojemda
Administration using a feeding tube
Only use a feeding tube with a minimum size of 12 French. Flush the feeding tube according to themanufacturer’s instructions before administering the suspension. Use an ENFit syringe to draw up thesuspension from the bottle then dispense the suspension into the feeding tube with an ENFit adaptor.
Finally, flush the feeding tube after administering as per the manufacturer’s instructions.
If 2 bottles are required to prepare the required dose, repeat Step 1 to 12 and give the remainder of thedose right away. Be sure to give the entire dose of Ojemda.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.