BRAFTOVI Hard capsule Ref.[8687] Active ingredients: Encorafenib

Encorafenib is to be given in combination with binimetinib. For additional information on warnings and precautions associated with binimetinib treatment, see section 4.4 of binimetinib SmPC.

BRAF mutation testing

Before taking encorafenib in combination with binimetinib, patients must have BRAF V600 mutation confirmed by a validated test. The efficacy and safety of encorafenib have been established only in patients with tumours expressing BRAF V600E and V600K mutations. Encorafenib should not be used in patients with wild type BRAF malignant melanoma.

Encorafenib in combination with binimetinib in patients who have progressed on a BRAF inhibitor

There are limited data for the use of the combination of encorafenib with binimetinib in patients who have progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastatic melanoma with BRAF V600 mutation. These data show that the efficacy of the combination would be lower in these patients.

Encorafenib in combination with binimetinib in patients with brain metastases

There are limited efficacy data with the combination of encorafenib and binimetinib in patients with a BRAF V600 mutant melanoma which have metastasised to the brain (see section 5.1).

Left ventricular dysfunction (LVD)

LVD defined as symptomatic or asymptomatic decreases in ejection fraction has been reported when encorafenib is used in combination with binimetinib. It is recommended that left ventricular ejection fraction (LVEF) is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of encorafenib and binimetinib, one month after initiation, and then at approximately 3-month intervals or more frequently as clinically indicated, while on treatment. If during treatment LVD occurs, see section 4.2 of binimetinib SmPC.

The safety of encorafenib in combination with binimetinib has not been established in patients with a baseline LVEF that is either below 50% or below the institutional lower limits of normal. Therefore, in these patients, binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, Grade 3-4 LVEF or for absolute decrease of LVEF from baseline of ≥ 10%, binimetinib and encorafenib should be discontinued and LVEF should be evaluated every 2 weeks until recovery.

Haemorrhage

Haemorrhages, including major haemorrhagic events, can occur with encorafenib (see section 4.8). The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet therapy. The occurrence of Grade ≥3 haemorrhagic events should be managed with dose interruption or treatment discontinuation (see Table 3 in section 4.2) and as clinically indicated.

Ocular toxicities

Ocular toxicities including uveitis, iritis and iridocyclitis can occur when encorafenib is administered. RPED has also been reported in patients treated with encorafenib in combination with binimetinib (see section 4.8).

Patients should be assessed at each visit for symptoms of new or worsening visual disturbance. If symptoms of new or worsening visual disturbances including diminished central vision, blurred vision or loss of vision are identified, a prompt ophthalmologic examination is recommended. If, uveitis including iridocyclitis and iritis occurs during treatment, see section 4.2. If during treatment patient develops RPED or RVO, see section 4.2 of binimetinib SmPC for guidance.

QT prolongation

QT Prolongation has been observed in patients treated with BRAF-inhibitors. A thorough QT study to evaluate the QT prolongation potential of encorafenib has not been conducted. Overall, results suggest that single agent encorafenib has the potential to cause mild increases in heart rate. Across pooled combination studies of encorafenib and binimetinib at the recommended doses and a single-agent encorafenib study, results suggest that encorafenib has the potential to result in small increases in QTc interval (see section 5.1).

There are insufficient data to exclude a clinically significant exposure dependent QT prolongation.

Due to the potential risk for QT prolongation, it is recommended that serum electrolytes abnormalities, including magnesium and potassium, are corrected and risk factors for QT prolongation controlled (e.g. congestive heart failure, bradyarrhythmias) before treatment initiation and during treatment. It is recommended that an electrocardiogram (ECG) is assessed before initiation of encorafenib, one month after initiation, and then at approximately 3-month intervals or more frequently as clinically indicated, while on treatment. The occurrence of QTc prolongation can be managed with dose reduction, interruption or discontinuation with correction of abnormal electrolytes and control of risk factors (see section 4.2).

New primary malignancies

New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur when encorafenib is administered (see section 4.8).

Cutaneous malignancies

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma has been observed in patients treated with BRAF-inhibitors including encorafenib. New primary melanoma has been observed in patients treated with BRAF inhibitors including encorafenib (see section 4.8). Dermatologic evaluations should be performed prior to initiation of therapy with encorafenib in combination with binimetinib, every 2 months while on therapy and for up to 6 months following discontinuation of the combination. Suspicious skin lesions should be managed with dermatological excision and dermatopathologic evaluation. Patients should be instructed to immediately inform their physicians if new skin lesions develop. Encorafenib and binimetinib should be continued without any dose modification.

Non-cutaneous malignancies

Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Patients receiving encorafenib should undergo a head and neck examination, chest/abdomen computerised tomography (CT) scan, anal and pelvic examinations (for women) and complete blood cell counts prior to initiation, during and at the end of treatment as clinically appropriate. It should be considered to permanently discontinue encorafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. Benefits and risks should be carefully considered before administering encorafenib to patients with a prior or concurrent cancer associated with RAS mutation.

Liver laboratory abnormalities

Liver laboratory abnormalities including AST and ALT elevations have been observed with encorafenib (see section 4.8). Liver laboratory values should be monitored before initiation of encorafenib and binimetinib and monitored at least monthly during the 6 first months of treatment, then as clinically indicated. Liver laboratory abnormalities should be managed with dose interruption, reduction or treatment discontinuation (see section 4.2).

Hepatic impairment

As encorafenib is primarily metabolised and eliminated via the liver, patients with mild to severe hepatic impairment may have increased encorafenib exposure over the range of inter-subject variability exposure (see section 5.2).

In the absence of clinical data, encorafenib is not recommended in patients with moderate or severe hepatic impairment.

Administration of encorafenib should be undertaken with caution at a reduced dose in patients with mild hepatic impairment (see section 4.2).

Closer monitoring of encorafenib related toxicities in patients with mild hepatic impairment is recommended, including clinical examination and liver function tests, with assessment of ECGs as clinically appropriate during treatment.

Renal impairment

There are no data available in patients with severe renal impairment (see sections 4.2 and 5.2). Encorafenib should be used with caution in patients with severe renal impairment. Creatinine elevation has been commonly reported with encorafenib as single agent or in combination with binimetinib. Observed cases of renal failure including acute kidney injury and renal impairment were generally associated with vomiting and dehydration. Other contributing factors included diabetes and hypertension. Blood creatinine should be monitored as clinically indicated and creatinine elevation managed with dose modification or discontinuation (see Table 3 in section 4.2). Patients should ensure adequate fluid intake during treatment.

Effects of other medicinal products on encorafenib.

Concurrent use of strong CYP3A inhibitors during treatment with encorafenib should be avoided. If concomitant use with a strong CYP3A inhibitor is necessary, patients should be carefully monitored for safety (see section 4.5). Caution should be exercised if a moderate CYP3A inhibitor is co-administered with encorafenib.

Effects of other medicinal products on encorafenib

Encorafenib is primarily metabolised by CYP3A4.

CYP3A4 inhibitors

Co-administration of moderate (diltiazem) and strong (posaconazole) CYP3A4 inhibitors with single doses of encorafenib in healthy volunteers resulted in a 2 and 3-fold increase in the area under the concentration-time curve (AUC), respectively and in 44.6% and 68.3% increase in maximum encorafenib concentration (C_max) respectively.

Model based predictions indicate that the effect of posaconazole after repeated administrations could be similar for AUC (3-fold increase) and slightly greater for C_max (2.7-fold increase). Model-based predictions for ketoconazole suggest an increase of approx. 5-fold for encorafenib AUC and 3 to 4-fold for encorafenib C_max.

Therefore, concomitant administration of encorafenib with strong CYP3A4 inhibitors should be avoided (due to increased encorafenib exposure and potential increase in toxicity, see section 5.2). Examples of strong CYP3A4 inhibitors include, but are not limited to, ritonavir, itraconazole, clarithromycin, telithromycin, posaconazole and grapefruit juice. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety. Moderate CYP3A4 inhibitors should be co-administered with caution. Examples of moderate CYP3A4 inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, diltiazem, amprenavir and imatinib. When encorafenib is co-administered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety.

CYP3A4 inducers

Co-administration of encorafenib with a CYP3A4 inducer was not assessed in a clinical study; however, a reduction in encorafenib exposure is likely and may result in compromised efficacy. Examples of moderate or strong CYP3A4 inducers include, but are not limited to carbamazepine, rifampicin, phenytoin and St. John’s Wort. Alternative agents with no or minimal CYP3A induction potential should be considered.

Effects of encorafenib on other medicinal products

CYP substrates

Encorafenib is both an inhibitor and inducer of CYP3A4. Concomitant use with agents that are substrates of CYP3A4 (e.g. hormonal contraceptives) may result in increased toxicity or loss of efficacy of these agents. Agents that are CYP3A4 substrates should be co-administered with caution. Encorafenib is an inhibitor of UGT1A1. Concomitant agents that are substrates of UGT1A1 (e.g. raltegravir, atorvastatin, dolutegravir) may have increased exposure and should be therefore administered with caution.

Effect of encorafenib on binimetinib

While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinib exposure have been observed clinically when binimetinib was co-administered with encorafenib.

Transporter substrates

Encorafenib potentially inhibits a number of transporters. Agents that are substrates of renal transporters OAT1, OAT3, OCT2 (such as furosemide, penicillin) or agents that are substrates of the hepatic transporters OATP1B1, OATP1B3, OCT1 (such as atorvastatin, bosentan) or substrates of BCRP (such as methotrexate, rosuvastatin) or substrates of P-gp (e.g. posaconazole) may have increased exposure and should be therefore co-administered with caution.

Women of childbearing potential/Contraception in females

Women of childbearing potential must use effective contraception during treatment with encorafenib and for at least 1 month following the last dose. Encorafenib may decrease the efficacy of hormonal contraceptives (see section 4.5). Therefore, female patients using hormonal contraception are advised to use an additional or alternative method such as a barrier method (e.g. condom) during treatment with encorafenib and for at least 1 month following the last dose.

Pregnancy

There are no data from the use of encorafenib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Encorafenib is not recommended during pregnancy and in women of childbearing potential not using contraception. If encorafenib is used during pregnancy or if the patient becomes pregnant while taking encorafenib, the patient should be informed of the potential hazard to the foetus.

Breast-feeding

It is unknown whether encorafenib or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue encorafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

There are no data on the effects of encorafenib on fertility in humans. Based on findings in animals, the use of encorafenib may impact fertility in males of reproductive potential (see section 5.3). As the clinical relevance of this is unknown, male patients should be informed of the potential risk for impaired spermatogenesis.

Encorafenib has minor influence on the ability to drive or use machines. Visual disturbances have been reported in some patients treated with encorafenib during clinical studies. Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse reactions that may affect their ability to drive and use machines (see sections 4.4 and 4.8).

Summary of safety profile

The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 274 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the pooled Combo 450 population), based on two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1). At the recommended dose (n=274) in patients with unresectable or metastatic melanoma, the most common adverse reactions (>25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, blood CK increased and myalgia.

The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the Combo 300 population), based on the Phase III study (CMEK162B2301, Part 2). The most common adverse reactions (>25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea.

The encorafenib single agent (300 mg orally once daily) safety profile is based on data from 217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to as the pooled encorafenib 300 population). The most common adverse drug reactions (ADRs) (>25%) reported with encorafenib 300 were hyperkeratosis, alopecia, PPES, fatigue, rash, arthralgia, dry skin, nausea, myalgia, headache, vomiting and pruritus.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA body system organ class and the following frequency 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), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4. Adverse reactions:

* composite terms which included more than one preferred term
^a includes keratoacanthoma, squamous cell carcinoma, lip squamous cell carcinoma and squamous cell carcinoma of skin
^b includes angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis and urticaria
^c includes facial nerve disorder, facial paralysis, facial paresis
^d includes extrasystoles, sinus tachycardia, supraventricular extrasystoles, tachyarrhythmia, tachycardia
^e includes erythema, generalised erythema, plantar erythema
^f includes dermatitis exfoliative, skin exfoliation, exfoliative rash
^g includes myalgia, muscle fatigue, muscle injury, muscle spasm, muscle weakness
^h includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction abnormal
ⁱ includes haemorrhage at various sites including cerebral haemorrhage
^j includes pulmonary embolism, deep vein thrombosis, embolism, thrombophlebitis, thrombophlebitis superficial and thrombosis
^k includes colitis, colitis ulcerative, enterocolitis and proctitis
^l includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis
^m includes fluid retention, peripheral oedema, localised oedema

When encorafenib was used at a dose of 300 mg once daily in combination with binimetinib 45 mg twice daily (Combo 300) in study CMEK162B2301-Part 2, the frequency category was lower compared to the pooled Combo 450 population for the following adverse reactions: anemia, peripheral neuropathy, haemorrhage, hypertension, pruritus (common); and colitis, increased amylase and increased lipase (uncommon).

Description of selected adverse reactions

Cutaneous malignancies

Cutaneous squamous cell carcinoma

In the pooled Combo 450 population, cuSCC including keratoacanthomas was observed in 3.3% (9/274) of patients. The median time to onset of the first event of cuSCC (all grades) was 6.5 months (range 1.0 to 22.8 months).

In the pooled encorafenib 300 population, cuSCC was reported in 7.4% (16/217) patients. For patients in the Phase III study (CMEK162B2301) who developed cuSCC, the median time to onset of the first event of cuSCC (all grades) was 2.3 months (range 0.3 to 12.0 months).

New primary melanoma

In the pooled encorafenib 300 population, new primary melanoma events occurred in 4.1% of patients (9 /217) and was reported as Grade 1 in 1.4% (3/217) of patients, Grade 2 in 2.1% (4/217) of patients, Grade 3 in 0.5% (1/217) of patients and Grade 4 in 0.5% (1/217) of patients.

Ocular events

In the pooled Combo 450 population, uveitis was reported in 4.4% (12/274) of patients, and was Grade 1 in 0.4% (1/274), Grade 2 in 3.6% (10/274) and Grade 3 in 0.4% (1/274). Visual impairment, including blurred vision and reduced visual acuity, occurred in 21.5% (59/274) of patients. Uveitis and visual impairment were generally reversible. RPED occurred in 29.6% (81/274) of patients, most of them had Grade 1-2 and 1.8% (5/274) had Grade 3 events.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, RPED was observed in 12.5% (32/257) of patients with 0.4% (1/257) Grade 4 event.

Left ventricular dysfunction

LVD was reported when encorafenib is used in combination with binimetinib (see section 4.8 of binimetinib SmPC).

Haemorrhage

Haemorrhagic events were observed in 17.9% (49/274) of patients in the pooled Combo 450 population. Most events were Grade 1 or 2 (14.6%) and 3.3% were Grade 3-4 events. Few patients required dose interruptions or dose reductions (0.7% or 2/274). Haemorrhagic events led to discontinuation of treatment in 1.1% (3/274) of patients. The most frequent haemorrhagic events were haematuria in 3.3% (9/274) of patients, rectal haemorrhage in 2.9% (8/274) and haematochezia in 2.9% (8/274) of patients. Fatal gastric ulcer haemorrhage, with multiple organ failure as a concurrent cause of death, occurred in one patient. Cerebral haemorrhage was reported in 1.5% (4/274) of patients, with fatal outcome in 3 patients. All events occurred in the setting of new or progressive brain metastases.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, haemorrhagic events were observed in 6.6% (17/257) of patients and were Grade 3-4 in 1.6% (4/257) of patients.

Hypertension

Hypertension was reported when encorafenib was used in combination with binimetinib (see section 4.8 of binimetinib SmPC).

Venous thromboembolism

VTE was reported when encorafenib is used in combination with binimetinib (see section 4.8 of binimetinib SmPC).

Pancreatitis

Pancreatic enzyme elevation, mostly asymptomatic, was reported in the pooled Combo 450 population. Amylase and lipase elevations were reported in 3.3% (9/274) and 5.1% (14/274) of patients, respectively. Pancreatitis was reported in 0.7% (2/274) of patients. Both patients experienced Grade 3 events. Pancreatitis led to dose interruption or adjustment in (0.4 %) 1/274 of patients.

Dermatologic reactions

Rash

In the pooled Combo 450 population, rash occurred in 19.7% (54/274) of patients. Most events were mild, with Grade 3 or 4 events reported in 0.7% (2/274) of patients. Rash led to discontinuation in 0.4% (1/274) patients and to dose interruption or dose modification in 1.1% (3/274) of patients.

In the pooled encorafenib 300 population, rash was reported in 43.3% (94/217) of patients. Most events were mild, with Grade 3 or 4 events reported in 4.6% (10/217) of patients. Rash led to discontinuation in 0.5% (1/217) of patients and to dose interruption or dose modification in 7.4% (16/217) of patients.

Palmar-plantar erythrodysaesthesia syndrome (PPES)

PPES was reported in 6.2% (17/274) of patients in the pooled Combo 450 population. All the PPES adverse reactions were either Grade 1 (3.3%) or Grade 2 (2.9%). Dose interruption or dose modification occurred in 1.1% (3/274) of patients.

In the Combo 300 arm in Part 2 of the pivotal study, PPES was observed in 3.9% (10/257) of patients with Grade 3 reported in 0.4% (1/257) of patients.

In the pooled encorafenib 300 population, PPES was reported in 51.6% (112/217) of patients. Most events were mild-moderate: Grade 1 in 12.4% (27/217) of patients, Grade 2 in 26.7% (58/217) and Grade 3 in 12.4% (27/217) of patients. PPES led to discontinuation in 4.1% (9/217) of patients and to dose interruption or dose modification in 23.0% (50/217) of patients.

Dermatitis acneiform

Dermatitis acneiform was reported when encorafenib is used in combination with binimetinib (see section 4.8 of binimetinib SmPC).

Photosensitivity

In the pooled Combo 450 population, photosensitivity was observed in 4.0% (11/274) of patients. Most events were Grade 1-2, with Grade 3 reported in 0.4% (1/274) of patients and no event led to discontinuation. Dose interruption or dose modification was reported in 0.4% (1/274) of patients.

In the pooled encorafenib 300 population, photosensitivity was reported in 4.1% (9/217) of patients. All events were Grade 1-2. No event required discontinuation, dose modification or interruption.

Facial paresis

In the pooled Combo 450 population, facial paresis occurred in 0.7% (2/274) of patients including Grade 3 in 0.4% (1/274) of patients. The events were reversible, and no event led to treatment discontinuation. Dose interruption or modification was reported in 0.4% (1/274) of patients.

In the pooled encorafenib 300 population, facial paresis was observed in 7.4% (16/217) of patients. Most events were mild-moderate: Grade 1 in 2.3% (5/217); Grade 2 in 3.7% (8/217) and Grade 3 in 1.4% (3/217) of patients. The median time to onset of the first event of facial paresis was 0.3 months (range 0.1 to 12.1 months). Facial paresis was generally reversible and led to treatment discontinuation in 0.9% (2/217). Dose interruption or modification was reported in 3.7% (8/217) and symptomatic treatment including corticosteroids was reported in 5.1% (11/217) of patients.

CK elevation and rhabdomyolysis

CK elevation and rhabdomyolysis occurred when encorafenib is used in combination with binimetinib (see section 4.8 of binimetinib SmPC).

Renal dysfunction

In the pooled Combo 450 population, mild, mostly Grade 1, asymptomatic blood creatinine elevation was noted in 6.2% (17/274) of patients treated with the Combo 450 mg. The incidence of Grade 3 or 4 elevation was 0.7% (2/274). Renal failure events, including acute kidney injury and renal impairment, were reported in 3.3% (9/274) patients treated with encorafenib and binimetinib with Grade 3 or 4 events in 2.2% (6/274) of patients. Renal failure was generally reversible with dose interruption, rehydration and other general supportive measures.

Liver laboratory abnormality

The incidences of liver laboratory abnormalities reported in the pooled Combo 450 population are listed below:

• Increased transaminases: 15.7% (43/274) overall – Grade 3-4: 5.5% (15/274)
• Increased GGT: 14.6% (40/274) overall – Grade 3-4: 8.4% (23/274)

In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidence of liver laboratory abnormalities was:

• Increased transaminases: 13.2% (34/257) overall – Grade 3-4: 5.4% (14/257)
• Increased GGT: 14.0% (36/257) overall – Grade 3-4: 4.7% (12/257)

Gastrointestinal disorders

In the pooled Combo 450 population, diarrhoea was observed in 38% (104/274) of patients and was Grade 3-4 in 3.3% (9/274) patients. Diarrhoea led to dose discontinuation in 0.4% of patients and to dose interruption or dose modification in 4.4% of patients. Constipation occurred in 24.1% (66/274) of patients and was Grade 1 or 2. Abdominal pain was reported in 27.4% (75/274) of patients and was Grade 3 in 2.6% (7/274) patients. Nausea occurred in 41.6% (114/274) with Grade 3 or 4 observed in 2.6% (7/274) of patients. Vomiting occurred in 28.1% (77/274) of patients with Grade 3 or 4 reported in 2.2% (6/274) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, nausea was observed in 27.2% (70/257) of patients and was Grade 3 in 1.6% (4/257) of patients. Vomiting occurred in 15.2% (39/257) of patients with Grade 3 reported in 0.4% (1/257) of patients. Diarrhoea occurred in 28.4% (73/257) of patients with Grade 3 reported in 1.6% (4/257) of patients.

Gastrointestinal disorders were typically managed with standard therapy.

Anaemia

In the pooled Combo 450 population, anaemia was reported in 19.7% (54/274) of patients; 4.7% (13/274) patients had a Grade 3 or 4. No patients discontinued treatment due to anaemia, 1.5% (4/274) required dose interruption or dose modification.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, anaemia was observed in 9.7% (25/257) of patients with Grade 3-4 reported in 2.7% (7/257) patients.

Headache

In the pooled Combo 450 population, headache occurred in 21.5% (59/274) of patients, including Grade 3 in 1.5% (4/274) of patients. In Study CMEK162B2301-Part 2, in the Combo 300 arm, headache was reported in 12.1% (31/257) of patients and was Grade 3 in 0.4% (1/257) of patients.

Fatigue

In the pooled Combo 450 population, fatigue occurred in 43.8% (120/274) of patients including Grade 3 in 2.9% (8/274) of patients. In Study CMEK162B2301-Part 2, in the Combo 300 arm, fatigue was observed in 33.5% (86/257) of patients with 1.6% (4/257) Grade 3-4 events.

Special populations

Elderly

In patients treated with Combo 450 (n=274), 194 patients (70.8%) were <65 years old, 65 patients (23.7%) were 65-74 years old and 15 patients (5.5%) were aged >75. No overall differences in safety or efficacy were observed between elderly patients (≥65) and younger patients. The proportions of patients experiencing adverse events (AE) and serious adverse events (SAE) were similar in patients aged <65 years and those aged ≥65 years. The most common AEs reported with a higher incidence in patients aged ≥65 years compared to patients aged <65 years included diarrhoea, pruritus, GGT and blood phosphatase alkaline elevation. In the small group of patients aged ≥75 years (n=15), patients were more likely to experience serious adverse events and adverse events leading to discontinuation of treatment.

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.