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Safety and Tolerability

ALUNBRIG  (brigatinib) demonstrated a generally manageable tolerability profile1

Treatment-emergenta AEs in patients treated with ALUNBRIG

Bar chart

Adapted from Kim DW, et al. 20171

aAn adverse event that begins or worsens in severity after the first administration of study drug, regardless of the cause.

bThe recommended daily dose is 180 mg, with a 7-day lead-in of 90 mg.

ALUNBRIG demonstrated a generally manageable tolerability profile2

Treatment-related AEs in patients treated with ALUNBRIGa

Bar chart

Adapted from Huber MH, et al. 20182

  • The most common adverse reactions (≥25%) reported in patients treated with ALUNBRIG at the recommended dosing regimen were increased AST, hyperglycaemia, hyperinsulinaemia, anaemia, increased CPK, nausea, increased lipase, decreased lymphocyte count, increased ALT, diarrhoea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphataemia, increased APTT, rash, vomiting, dyspnoea, hypertension, decreased white blood cell count, myalgia and peripheral neuropathy.3
  • The most common serious adverse reactions (≥2%) reported in patients treated with ALUNBRIG at the recommended dosing regimen, other than events related to neoplasm progression, were pneumonitis, pneumonia and dyspnoea.3
  • For further information please refer to the Summary of Product Characteristics.

aCausality to treatment as assessed by the investigator.

b180 mg once daily with 7-day lead-in at 90 mg once daily.

ALUNBRIG demonstrated a generally manageable tolerability profile3

Frequency catergories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100).


Infections and infestations

Frequency category: Very common

Adverse reactions+ all grades

  • Pneumoniaa
  • Upper respiratory tract infection

Adverse reactions grade 3-4

-

Frequency category: Common

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Pneumoniaa

a Includes atypical pneumonia, pneumonia, pneumonia aspiration, pneumonia pseudomonal, lower respiratory tract infection, lower respiratory tract infection viral, lung infection

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Blood and lymphatic system disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Anaemia
  • Lymphocyte count decreased
  • APTT increased
  • White blood cell count decreased
  • Neutrophil count decreased
  • Decreased platelet count

Adverse reactions Grade 3-4

  • Lymphocyte count decreased

Frequency category: Common

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • APTT increased
  • Anaemia
  • Neutrophil count decreased

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Metabolism and nutrition disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Hyperglycaemia
  • Hyperinsulinaemiab
  • Hypophosphataemia
  • Decreased appetite
  • Hypokalaemia
  • Hypomagnesameia
  • Hyponatraemia
  • Hypercalcaemia

Adverse reactions Grade 3-4

-

Frequency category: Common

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Hypophosphataemia
  • Hyperglycaemia
  • Hyponatraemia
  • Hypokalaemia
  • Decreased appetite

b Grade not applicable

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Psychiatric disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Insomnia

Adverse reactions grade 3-4

-

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Nervous system disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Headachec
  • Peripheral neuropathyd
  • Dizziness

Adverse reactions grade 3-4

-

Frequency category: Common

Adverse reactions+ all grades

  • Memory impairment
  • Dysgeusia

Adverse reactions grade 3-4

  • Peripheral neuropathyd
  • Headachec

c Includes headache, sinus headache, head discomfort, migraine, tension headache

d Includes paraesthesia, peripheral sensory neuropathy, dysaesthesia, hyperaesthesia, hypoesthesia, neuralgia, neuropathy peripheral, neurotoxicity, peripheral motor neuropathy, polyneuropathy

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Eye disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Visual disturbancee

Adverse reactions grade 3-4

-

Frequency category: Common

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Visual disturbancee

e Includes altered visual depth perception, asthenopia, cataract, colour blindness acquired, diplopia, glaucoma, intraocular pressure increased, macular oedema, photophobia, photopsia, retinal oedema, vision blurred, visual activity reduced, visual field defect, visual impairment, vitreous detachment, vitreous floaters, amaurosis fugax

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Cardiac disorders

Frequency category: Common

Adverse reactions+ all grades

  • Tachycardiaf
  • Electrocardiogram QT prolonged
  • Bradycardiag
  • Palpitations

Adverse reactions grade 3-4

-

Frequency category: Uncommon

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Electrocardiogram QT prolonged

f Includes sinus tachycardia

g Includes bradycardia, sinus bradycardia, tachycardia

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Vascular disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Hypertension

Adverse reactions grade 3-4

  • Hypertension

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Respiratory, thoracic and mediastinal disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Cough
  • Dyspnoeah

Adverse reactions grade 3-4

-

Frequency category: Common

Adverse reactions+ all grades

  • Pneumonitisi

Adverse reactions grade 3-4

  • Pneumonitisi
  • Dyspnoeah

h Includes dyspnoea, dyspnoea exertional

i Includes interstitial lung disease, pneumonitis

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Gastrointestinal disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Lipase increased
  • Nausea
  • Diarrhoeaj
  • Amylase increased
  • Vomiting
  • Constipation
  • Abdominal paink
  • Dry mouth
  • Stomatitisl

Adverse reactions grade 3-4

  • Lipase increased

Frequency category: Common

Adverse reactions+ all grades

  • Dyspepsia
  • Flatulence

Adverse reactions grade 3-4

  • Amylase increased
  • Abdominal paink

Frequency category: Uncommon

Adverse reactions+

  • Pancreatitis

Adverse reactions Grade 3-4

  • Nausea
  • Dyspepsia
  • Pancreatitis

j Includes diarrhoea, diarrhoea infectious

k Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort

l Includes aphthous stomatitis, stomatitis, aphthous ulcer, mouth ulceration, oral mucosal blistering

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Hepatobiliary disorders

Frequency category: Very common

Adverse reactions+ all grades

  • AST increased
  • ALT increased
  • Alkaline phosphatase increased

Adverse reactions grade 3-4

-

Frequency category: Common

Adverse reactions+ all grades

  • Blood lactate dehydrogenase increased
  • Hyperbilirubinaemia

Adverse reactions grade 3-4

  • ALT increased
  • AST increased
  • Alkaline phosphatase increased
  • Hyperbilirubinaemia

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Skin and subcutaenous tissue disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Rashm
  • Pruritus

Adverse reactions grade 3-4

-


Frequency category: Common

Adverse reactions+ all grades

  • Dry skin
  • Photosensitivity reaction

Adverse reactions grade 3-4

  • Rashm
  • Photosensitivity reaction

Frequency category: Uncommon

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Dry skin

m Includes dermatitis acneiform, erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo papular, rash papular, rash pruritic, rash pustular, dermatitis, dermatitis allergic, generalised erythema, rash follicular, urticaria

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Musculoskeletal and connective tissue disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Blood CPK increased
  • Myalgian
  • Arthalgia
  • Musculoskeletal chest pain

Adverse reactions grade 3-4

  • Blood CPK increased

Frequency category: Common

Adverse reactions+ all grades

  • Pain in extremity
  • Musculoskeletal stiffness

Adverse reactions grade 3-4

  • Pain in extremity

Frequency category: Uncommon

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Myalgian

n Includes musculoskeletal pain, myalgia, muscle spasms, muscle tightness, muscle twitching, musculoskeletal discomfort

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Renal and urinary disorders

Frequency category: Very common

Adverse reactions+ all grades

  • Blood creatinine increased

Adverse reactions grade 3-4

-

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

General disorders and administration site conditions

Frequency category: Very common

Adverse reactions+ all grades

  • Fatigueo
  • Oedemap
  • Pyrexia

Adverse reactions grade 3-4

-


Frequency category: Common

Adverse reactions+ all grades

  • Pain
  • Non cardiac chest pain
  • Chest discomfort

Adverse reactions grade 3-4

  • Fatigueo

Frequency category: Uncommon

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Non cardiac chest pain
  • Pyrexia

o Includes asthenia, fatigue

p Includes eyelid oedema, face oedema, localised oedema, oedema peripheral, periorbital oedema, swelling face, generalised oedema, peripheral swelling

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Investigations

Frequency category: Common

Adverse reactions+ all grades

  • Weight decreased

Adverse reactions grade 3-4

-

Frequency category: Uncommon

Adverse reactions+ all grades

-

Adverse reactions grade 3-4

  • Weight decreased

+ The frequencies for ADR terms associated with chemistry and haematology laboratory changes were determined based on the frequency of abnormal laboratory shifts from baseline

Interstitial lung disease (ILD)/pneumonitis

Lungs

Incidence

  • Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, can occur in patients treated with ALUNBRIG3
  • In ALTA, Grade ≥ 3 pneumonitis occurred in 2% of the 90 mg arm and 4% of the 180 mg arma,2
Calendar

Early onset pulmonary events

  • In ALTA, 14 patients (6%) experienced pulmonary adverse reactionsb of any grade within 9 days of treatment initiation (median onset 2 days). These adverse events occurred at 90 mg, in both arms, and none occurred after escalation to 180 mg1
    • Of these 14, 7 (3%) had Grade ≥3 pulmonary adverse reactions, including 1 patient with fatal pneumonia1
    • The other 7 patients (3%) had Grade 1-2 pulmonary adverse reactions: 6 were managed with dose interruption and successful reintroduction of ALUNBRIG, and 1 by dose reduction to 60 mgc once daily without needing interruption1
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Factors to consider with initiating treatment3

  • Most pulmonary adverse reactions were observed within the first 7 days of treatment
    • Monitor for new or worsening respiratory symptoms (e.g. dyspnoea, cough), particularly in the first week of treatment. But note that some patients experienced pneumonitis later in treatment with ALUNBRIG
  • Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment of dose modification
  • Factors independently associated with an increased rate of these pulmonary adverse reactions:
    • Increased age
    • Shorter interval (<7 days) between the last dose of crizotinib and the first dose of ALUNBRIG
  • See recommended dose modifications for managing adverse reactions

a 180 mg once daily with 7-day lead-in at 90 mg once daily.

b Dyspnoea, hypoxia, cough, pneumonia or pneumonitis.

c See Summary of Product Characteristics recommended dose modification for adverse reactions.

ALUNBRIG: Special warnings and precautions for use3*

Hypertension Regular monitoring of blood pressure (BP); avoidance of bradycardia-causing medicinal products; dose modification as necessary
Bradycardia Use caution when administering with bradycardia-causing medicinal products; monitor heart rate (HR) and BP; dose modification as necessary
Visual disturbance Consider referral and dose reduction for new or worsening severe visual symptoms
CPK elevation Regular monitoring of CPK levels; dose modification as necessary
Elevated pancreatic enzymes Regular monitoring of lipase and amylase; dose modification as necessary
Hepatoxicity Assess liver function prior to treatment initiation, every 2 weeks during the first 3 months of treatment, then periodically thereafter; dose modification as necessary
Hyperglycaemia Monitor fasting serum glucose prior to initiation of and during treatment; dose modification as necessary
Drug-drug interactions Avoid concomitant use of strong CYP3A inhibitors, or reduce dose of ALUNBRIG if unavoidable. Avoid concomitant use of strong and moderate CYP3A inducers. Avoid grapefruit or grapefruit juice. Avoid coadministration with CYP3A substrates with a narrow therapeutic index (e.g. alfentanil, fentanyl, quinidine, cyclosporine, sirolimus, tacrolimus). Monitor closely if coadministered with substrates of P-gp, BCRP, OCT1, MATE1 or MATE2K transporters with a narrow therapeutic index (e.g. digoxin, dabigatran, methotrexate)
Fertility Women of child-bearing age to use effective non-hormonal contraception during treatment and for a minimum of 4 months after the final dose. Breastfeeding should be stopped during treatment with ALUNBRIG. Men being treated with ALUNBRIG should be advised to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG if they have a female partner of reproductive potential
Lactose ALUNBRIG contains lactose monohydrate, so should be avoided in those with any hereditary galactose/lactose intolerance or malabsorption problems

*For full information please refer to the Summary of Product Characteristics3