Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use

When dabrafenib is given in combination with trametinib, the Prescribing Information of trametinib must be consulted prior to intiation of combination treatment. For additional information on warnings and precautions associated with trametinib treatment, please refer to the trametinib Prescribing Information.

BRAF V600 testing

The efficacy and safety of dabrafenib have not been established in patients with wild-type BRAF solid tumors therefore dabrafenib should not be used in patients with wild-type BRAF solid tumors(see sections 4.2 and 5.1).

Dabrafenib in combination with trametinib in patients with melanoma who have progressed on a BRAF inhibitor

There are limited data in patients taking the combination of dabrafenib with trametinib who have progressed on a prior BRAF inhibitor. These data show that the efficacy of the combination will be lower in these patients (see section 5.1). Therefore, other treatment options should be considered before treatment with the combination in this prior BRAF inhibitor treated population. The sequencing of treatments following progression on a BRAF inhibitor therapy has not been established.

New malignancies

New malignancies, cutaneous and non-cutaneous, can occur when dabrafenib is used as monotherapy or in combination with trametinib.

Cutaneous malignancies

Cutaneous squamous cell carcinoma (cuSCC)
Cases of cuSCC (including keratoacanthoma) have been reported in patients treated with dabrafenib alone and in combination with trametinib (see section 4.8). In the Phase III clinical trials MEK115306 and MEK116513 in patients with unresectable or metastatic melanoma, cuSCC occurred in 10% (22/211) of patients receiving dabrafenib as a monotherapy and in 18% (63/349) of patients receiving vemurafenib as a monotherapy, respectively. In the integrated safety population of patients with melanoma and advanced NSCLC, cuSCC occurred in 2% (19/1076) of patients receiving dabrafenib in combination with trametinib.
The median time to diagnosis of the first occurrence of cuSCC in study MEK115306 was 223 days (range 56 to 510 days) in the combination therapy arm and 60 days (range 9 to
653 days) in the dabrafenib monotherapy arm. In the Phase III study BRF115532 (COMBI- AD) in the adjuvant treatment of melanoma, 1% (6/435) of patients receiving dabrafenib in combination with trametinib as compared to 1% (5/432) of patients receiving placebo had developed cuSCC at the time of the primary analysis. During the long-term (up to 10 years) 
off-treatment follow-up, 2 additional patients reported cuSCC in each treatment arm. Overall, the median time to onset of the first occurrence of cuSCC in the combination arm of the adjuvant treatment study was approximately 21 weeks and was 34 weeks in the placebo arm.

It is recommended that skin examination be performed prior to initiation of therapy with dabrafenib and monthly throughout treatment and for up to six months after treatment for cuSCC. Monitoring should continue for 6 months following discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy.

Cases of cuSCC should be managed by dermatological excision and dabrafenib treatment or, if taken in combination, dabrafenib and trametinib should be continued without any dose adjustment. Patients should be instructed to immediately inform their physician if new lesions develop.

New primary melanoma

New primary melanomas have been reported in clinical trials in patients treated with dabrafenib. In clinical trials in unresectable or metastatic melanoma, these cases were identified within the first 5 months of dabrafenib as monotherapy. Cases of new primary melanoma can be managed with excision and do not require treatment modification.
Monitoring for skin lesions should occur as described for cuSCC.

Non-cutaneous malignancies

In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAP kinase) signalling in BRAF wild-type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure (see section 4.8) when RAS mutations are present. RAS-associated malignancies have been reported in clinical trials, both with another BRAF inhibitor (chronic myelomonocytic leukaemia and non-cutaneous SCC of the head and neck) as well as with dabrafenib monotherapy (pancreatic adenocarcinoma, bile duct adenocarcinoma) and with dabrafenib in combination with the MEK inhibitor, trametinib (colorectal cancer, pancreatic cancer).

Prior to initiation of treatment patients should undergo a head and neck examination with minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen computerised tomography (CT) scan. During treatment patients should be monitored as clinically appropriate which may include a head and neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations are recommended before and at the end of treatment or when considered clinically indicated. Complete blood cell counts and blood chemistry should be performed as clinically indicated.

The benefits and risks should be considered before administering dabrafenib in patients with a prior or concurrent cancer associated with RAS mutations. No dose modification of trametinib is required when taken in combination with dabrafenib.

Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.

Haemorrhage

Haemorrhagic events, including major haemorrhagic and fatal haemorrhages, have occurred 
in patients taking the combination of dabrafenib with trametinib (see section 4.8). Please refer to the trametinib Prescribing Information (see section 4.4) for additional information.

Visual impairment

In clinical trials ophthalmologic reactions, including uveitis, iridocyclitis and iritis, have been reported in patients treated with dabrafenib as monotherapy and in combination with trametinib. Patients should be routinely monitored for visual signs and symptoms (such as change in vision, photophobia and eye pain) while on therapy.

No dose modifications are required as long as effective local therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, withhold dabrafenib until resolution of ocular inflammation and then restart dabrafenib reduced by one dose level. No dose modification of trametinib is required when taken in combination with dabrafenib following diagnosis of uveitis.

RPED and RVO may occur with dabrafenib in combination with trametinib. Please refer to the trametinib Prescribing Information (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib following diagnosis of RVO or RPED.

Pyrexia

Fever has been reported in clinical trials with dabrafenib as monotherapy and in combination with trametinib (see section 4.8). In 1% of patients in clinical trials with dabrafenib monotherapy, serious non-infectious febrile events were identified (defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency of pre-renal origin in patients with normal baseline renal function) (see section 4.8). The onset of these serious non-infectious febrile events was typically within the first month of dabrafenib as monotherapy. Patients with serious non-infectious febrile events responded well to dose interruption and/or dose reduction and supportive care.

The incidence and severity of pyrexia are increased with combination therapy. In the combination therapy arm of study MEK115306 in patients with unresectable or metastatic melanoma, pyrexia was reported in 57% (119/209) of patients with 7% Grade 3, as compared to the dabrafenib monotherapy arm with 33% (69/211) of patients reporting pyrexia, 2% Grade 3. In the Phase II study BRF113928 in patients with advanced NSCLC the incidence and severity of pyrexia were increased slightly when dabrafenib was used in combination with trametinib (48%, 3% Grade 3) as compared to dabrafenib monotherapy (39%, 2% Grade 3). In the Phase III study BRF115532 in the adjuvant treatment of melanoma, the incidence and severity of pyrexia were higher in the dabrafenib in combination with trametinib arm (67%; 6% Grade 3/4) as compared to the placebo arm (15%; <1% Grade 3).

Dabrafenib administered with Trametinib (Pediatric): In the pooled safety population, pyrexia occurred in 66% of patients.

For patients with unresectable or metastatic melanoma who received dabrafenib in combination with trametinib and developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy and approximately one- third of the patients had 3 or more events.

Therapy (dabrafenib when used as monotherapy, and both dabrafenib and trametinib when used in combination) should be interrupted if the patient’s temperature is ≥38ºC (see section 5.1). In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia. Treatment with anti-pyretics such as ibuprofen or acetaminophen/paracetamol should 
be initiated. The use of oral corticosteroids should be considered in those instances in which anti-pyretics are insufficient. Patients should be evaluated for signs and symptoms of infection. Therapy can be restarted once the fever resolves. If fever is associated with other severe signs or symptoms, therapy should be restarted at a reduced dose once fever resolves and as clinically appropriate (see section 4.2).

LVEF reduction/Left ventricular dysfunction

Dabrafenib in combination with trametinib has been reported to decrease LVEF (see section 4.8). Please refer to the trametinib Prescribing Information for additional information (see section 4.4). No dose modification of dabrafenib is required when taken in combination with trametinib.

Renal failure

Renal failure has been identified in <1% of patients treated with dabrafenib alone and in ≤1% of patients treated with dabrafenib in combination with trametinib. Observed cases were generally associated with pyrexia and dehydration and responded well to dose interruption and general supportive measures. Granulomatous nephritis has been reported (see section 4.8). Patients should be routinely monitored for serum creatinine while on therapy. If creatinine increases, dabrafenib may need to be interrupted as clinically appropriate.
Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine >1.5 x ULN) therefore caution should be used in this setting (see section 5.2).

Hepatic events

Hepatic adverse events have been reported in clinical trials with dabrafenib in combination with trametinib (see section 4.8). It is recommended that patients receiving treatment with dabrafenib in combination with trametinib have liver function monitored every four weeks for 6 months after treatment initiation with trametinib. Liver monitoring may be continued thereafter as clinically indicated. Please refer to the trametinib Prescribing Information for additional information.

Hypertension

Elevations in blood pressure have been reported in association with dabrafenib in combination with trametinib, in patients with or without pre-existing hypertension (see section 4.8). Please refer to the trametinib Prescribing Information for additional information.

Interstitial lung disease (ILD)/Pneumonitis

Cases of pneumonitis or ILD have been reported in clinical trials with dabrafenib in combination with trametinib. Please refer to the trametinib Prescribing Information section 4.4 for additional information. If dabrafenib is being used in combination with trametinib then therapy with dabrafenib may be continued at the same dose.

Rash

Rash has been observed in about 24% of patients in clinical trials when dabrafenib is used in combination with trametinib (see section 4.8). The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions. Please refer to the trametinib Prescribing Information section 4.4 for additional information.


Rhabdomyolysis

Rhabdomyolysis has been reported in patients taking dabrafenib in combination with trametinib (see section 4.8). Please refer to the trametinib Prescribing Information section 4.4 for additional information.

Pancreatitis

Pancreatitis has been reported in <1% of patients treated with dabrafenib as monotherapy and in combination with trametinib in unresectable or metastatic melanoma clinical trials and about 4% of patients treated with dabrafenib in combination with trametinib in the NSCLC clinical trial. One of the events occurred on the first day of dabrafenib dosing of a metastatic melanoma patient and recurred following re-challenge at a reduced dose. In the adjuvant treatment of melanoma trial, pancreatitis was reported in <1% (1/435) of patients receiving dabrafenib in combination with trametinib, and no patients receiving placebo. Unexplained abdominal pain should be promptly investigated to include measurement of serum amylase and lipase. Patients should be closely monitored when restarting dabrafenib after an episode of pancreatitis.

Deep vein thrombosis /Pulmonary embolism

Pulmonary embolism or deep vein thrombosis can occur when dabrafenib is used in combination with trametinib. If patients develop symptoms of pulmonary embolism or deep vein thrombosis such as shortness of breath, chest pain, or arm or leg swelling, they should immediately seek medical care. Permanently discontinue trametinib and dabrafenib for life- threatening pulmonary embolism.

Severe cutaneous adverse reactions

Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life- threatening or fatal, have been reported during treatment with dabrafenib/trametinib combination therapy. Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should be withdrawn.

Gastrointestinal disorders

Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking dabrafenib in combination with trametinib (see section 4.8). Please refer to the trametinib Prescribing Information for additional information (see section 4.4).

Sarcoidosis

Cases of sarcoidosis have been reported in patients treated with dabrafenib in combination with trametinib, mostly involving the skin, lung, eye and lymph nodes. In the majority of the cases, treatment with dabrafenib and trametinib was maintained. In case of a diagnosis of sarcoidosis, relevant treatment should be considered. It is important not to misinterpret sarcoidosis as disease progression.

Haemophagocytic lymphohistiocytosis

In post-marketing experience, haemophagocytic lymphohistiocytosis (HLH) has been observed in patients treated with dabrafenib in combination with trametinib. Caution should 
be taken when dabrafenib is administered in combination with trametinib. If HLH is confirmed, administration of dabrafenib and trametinib should be discontinued and treatment for HLH initiated.

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of dabrafenib in combination with trametinib (see section 4.8). Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Patients with risk factors for TLS should be closely monitored and prophylactic hydration should be considered. TLS should be treated promptly, as clinically indicated.

Effects of other medicinal products on dabrafenib

Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should be avoided when possible as these agents may decrease the efficacy of dabrafenib (see section 4.5).

Effects of dabrafenib on other medicinal products

Dabrafenib is an inducer of metabolising enzymes which may lead to loss of efficacy of many commonly used medicinal products (see examples in section 4.5). A drug utilisation review (DUR) is therefore essential when initiating dabrafenib treatment. Concomitant use of dabrafenib with medicinal products that are sensitive substrates of certain metabolising enzymes or transporters (see section 4.5) should generally be avoided if monitoring for efficacy and dose adjustment is not possible.

Concomitant administration of dabrafenib with warfarin results in decreased warfarin exposure. Caution should be exercised and additional International Normalised Ratio (INR) monitoring is recommended when dabrafenib is used concomitantly with warfarin and at discontinuation of dabrafenib (see section 4.5).

Concomitant administration of dabrafenib with digoxin may result in decreased digoxin exposure. Caution should be exercised and additional monitoring of digoxin is recommended when digoxin (a transporter substrate) is used concomitantly with dabrafenib and at discontinuation of dabrafenib (see section 4.5).

Effects on Driving

4.7    Effects on ability to drive and use machines

Dabrafenib has minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of dabrafenib 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 fatigue and eye problems to affect these activities.