Spexotras

HOS-288715 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile In clinical studies of paediatric patients treated with trametinib in combination with dabrafenib, the most common adverse reactions (reported at a frequency ≥20%) were: pyrexia (70%), rash (49%), headache (47%), vomiting (40%), fatigue (36%), dry skin (35%), diarrhoea (34%), haemorrhage (34%), nausea (29%), dermatitis acneiform (29%), abdominal pain (28%), neutropenia (26%), cough (24%) and transaminases increased (22%). The most frequently reported severe (Grade 3/4) adverse reactions were: neutropenia (15%), pyrexia (11%), transaminases increased (6%) and weight increased 12 (5%). Long-term data on growth and skeletal maturation in paediatric patients are currently limited (see section 5.3). The safety profile in paediatric patients was largely consistent with the safety profile previously established in adult patients. The following additional adverse reactions have so far only been reported in adult patients treated with trametinib tablets and dabrafenib capsules: cutaneous squamous cell carcinoma, seborrhoeic keratosis, peripheral neuropathy (including sensory and motor neuropathy), lymphoedema, dry mouth, actinic keratosis, renal failure, potentiation of radiation toxicity (common), melanoma, acrochordon, sarcoidosis, chorioretinopathy, pneumonitis, acute renal failure, nephritis, cardiac failure, left ventricular dysfunction, interstitial lung disease, rhabdomyolysis (uncommon), gastrointestinal perforation, haemophagocytic lymphohistiocytosis (rare), tumour lysis syndrome, myocarditis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, tattoo-associated skin reactions (frequency not known). Tabulated list of adverse reactions The safety of trametinib in combination with dabrafenib has been evaluated in a pooled safety set of 171 paediatric patients across two studies in patients with BRAF V600 mutation-positive advanced solid tumours. Four (2.3%) patients were 1 to <2 years of age, 39 (22.8%) patients were 2 to <6 years of age, 54 (31.6%) patients were 6 to <12 years of age and 74 (43.3%) patients were 12 to <18 years of age at enrolment. The mean treatment duration was 2.3 years. Adverse reactions (Table 5) are listed below by MedDRA system organ class ranked by frequency 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

Auszug; vollständigen Abschnitt im Original lesen.

HOS-288711 · has-contraindication-information · PDF-Seite 6

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

HOS-288710 · has-indication-information · PDF-Seite 2

Low-grade glioma Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. High-grade glioma Spexotras in combination with dabrafenib is indicated for the treatment of paediatric patients aged 1 year and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment.

HOS-288713 · has-interaction-information · PDF-Seite 11

Interaction studies have only been performed in adults. Effect of other medicinal products on trametinib As trametinib is metabolised predominantly via deacetylation mediated by hydrolytic enzymes (e.g. carboxyl-esterases), its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions (see section 5.2). Drug-drug interactions via these hydrolytic enzymes cannot be ruled out and could influence the exposure to trametinib. Trametinib is an in vitro substrate of the efflux transporter P-gp. As it cannot be excluded that strong inhibition of hepatic P-gp may result in increased levels of trametinib, caution is advised when co- administering trametinib with medicinal products that are strong inhibitors of P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole). Effect of trametinib on other medicinal products Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the pharmacokinetics of other medicinal products via interaction with CYP enzymes or transporters (see section 5.2). Trametinib may result in transient inhibition of BCRP substrates (e.g. pitavastatin) in the gut, which may be minimised with staggered dosing (2 hours apart) of these agents and trametinib. Based on clinical data, no loss of efficacy of hormonal contraceptives is expected when co- administered with trametinib (see section 5.2). However, use with dabrafenib may render hormonal contraceptives less effective. Effect of the excipient sulfobutylbetadex sodium on other oral medicinal products with low bioavailability and narrow therapeutic index The trametinib oral solution contains 100 mg/ml of sulfobutylbetadex sodium which may have the potential to affect the solubility and bioavailability of other oral medicinal products. Caution should be taken when the trametinib oral solution is administered with oral medicinal products that have low bioavailability and a narrow therapeutic index (e.g. imipramine, desipramine). Also refer to the guidance for medicinal product interactions for dabrafenib found in sections 4.4 and 4.5 of the dabrafenib dispersible tablets SmPC. 11

HOS-288714 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/Contraception in females Women of childbearing potential must use effective methods of contraception during treatment with trametinib and for 16 weeks after stopping treatment. Use with dabrafenib may decrease the efficacy of oral or any systemic hormonal contraceptives and an effective alternative method of contraception, such as a barrier method, should be used during trametinib/dabrafenib combination therapy. Please refer to the dabrafenib dispersible tablets SmPC for further information. Pregnancy There are no data from the use of trametinib in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Trametinib should not be administered to pregnant women unless the potential benefit to the mother outweighs the possible risk to the foetus. If trametinib is used during pregnancy, or if the patient becomes pregnant while taking trametinib, the patient should be informed of the potential hazard to the foetus. Breast-feeding It is not known whether trametinib is excreted in human milk. A risk to the breast-feeding child cannot be excluded. Trametinib should not be administered to breast-feeding mothers. A decision should be made whether to discontinue breast-feeding or discontinue trametinib, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data in humans for trametinib. In animals, no fertility studies have been performed, but effects were seen on female reproductive organs (see section 5.3). Trametinib may impair fertility in humans. Men taking trametinib in combination with dabrafenib Effects on spermatogenesis have been observed in animals given dabrafenib. Male patients taking trametinib in combination with dabrafenib should be informed of the potential risk for impaired spermatogenesis, which may be irreversible. Please refer to the dabrafenib dispersible tablets SmPC for further information.

HOS-288712 · has-warning-information · PDF-Seite 6

Spexotras is intended for use in combination with dabrafenib dispersible tablets as there are limited efficacy data for trametinib monotherapy and for dabrafenib monotherapy in BRAF V600 mutation- positive glioma. The dabrafenib dispersible tablets SmPC must be consulted prior to initiation of treatment. For additional information on warnings and precautions associated with dabrafenib treatment, please refer to the dabrafenib dispersible tablets SmPC. 6 BRAF V600E testing The efficacy and safety of trametinib in combination with dabrafenib have not been evaluated in patients whose glioma tested negative for the BRAF V600E mutation. New malignancies New malignancies, cutaneous and non-cutaneous, can occur when trametinib is used in combination with dabrafenib. Cutaneous malignancies Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma and new primary melanoma have been observed in adult patients treated with trametinib in combination with dabrafenib (see section 4.8). It is recommended that skin examination be performed prior to initiation of therapy with trametinib and monthly throughout treatment and for up to six months after treatment. Monitoring should continue for 6 months following discontinuation of trametinib or until initiation of another anti-neoplastic therapy. Suspicious skin lesions should be managed with dermatological excision and do not require treatment modifications. Patients should be instructed to inform their physicians immediately if new skin lesions develop. Non-cutaneous malignancies Based on its mechanism of action, dabrafenib may increase the risk of non-cutaneous malignancies when RAS mutations are present. Please refer to the dabrafenib dispersible tablets SmPC (section 4.4). No dose modification of trametinib is required for RAS mutation-positive malignancies when taken in combination with dabrafenib. Haemorrhage Haemorrhagic events have been reported in adult and paediatric patients taking trametinib in combination with dabrafenib (see section 4.8). Major haemorrhagic events and fatal haemorrhages have occurred in adult patients taking trametinib in combination with dabrafenib. The potential for these events in patients with low platelet counts (<75 000/mm3) has not been established as such patients were excluded from clinical studies. The risk of haemorrhage may be increased with concomitant use of antiplatelet or a

Auszug; vollständigen Abschnitt im Original lesen.