Special Warning : אזהרת שימוש

Precautions
(6.1)]          Grade 2                      • If new pulmonary symptoms occur after the first 7 days of treatment, withhold ALUNBRIG until recovery to baseline. If ILD/pneumonitis is suspected, resume at next lower dose (Table 1);
otherwise, resume at same dose.
• If ILD/pneumonitis recurs, permanently discontinue ALUNBRIG.

Grade 3 or 4                 Permanently discontinue ALUNBRIG for
ILD/pneumonitis.

Grade 3 hypertension         • Withhold ALUNBRIG until hypertension has (SBP greater than or             recovered to Grade 1 or less (SBP less than 140 equal to 160 mmHg or             mmHg and DBP less than 90 mmHg), then DBP greater than or              resume ALUNBRIG at the same dose.
equal to 100 mmHg,           • Recurrence: withhold ALUNBRIG until recovery to medical intervention             Grade 1 or less, and resume at next lower dose Hypertension indicated, more than one         (Table 1) or permanently discontinue treatment.
[see Warnings anti-hypertensive drug, or and more intensive therapy
Precautions than previously used
(6.2)] indicated)

• Withhold ALUNBRIG until recovery to Grade 1 or less, and resume at next lower dose (Table 1) or
Grade 4 hypertension             permanently discontinue treatment.
(life- threatening consequences, urgent         • Recurrence: permanently discontinue intervention indicated)          ALUNBRIG for recurrence of Grade 4 hypertension.



                                                     • Withhold ALUNBRIG until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.
• If a concomitant medication known to cause bradycardia is identified and discontinued or dose-
Symptomatic bradycardia          adjusted, resume ALUNBRIG at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.
• If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ALUNBRIG at next lower dose (Table 1) upon recovery to asymptomatic
Bradycardia (HR bradycardia or to resting heart rate of 60 bpm or less than 60 bpm) above.
[see Warnings and                                              • Permanently discontinue ALUNBRIG if no Precautions                                          contributing concomitant medication is (6.3)]                                               identified.
Bradycardia with life-       • If contributing concomitant medication is identified threatening                      and discontinued or dose-adjusted, resume consequences, urgent             ALUNBRIG at next lower dose (Table 1) upon intervention indicated           recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.
• Recurrence: permanently discontinue ALUNBRIG.



Withhold ALUNBRIG until recovery to Grade 1 or
Visual              Grade 2 or 3 visual baseline, then resume at the next lower dose (Table
Disturbance         disturbance
1).
[see Warnings and
Precautions
(6.4)]              Grade 4 visual disturbance Permanently discontinue ALUNBRIG.


•   Withhold ALUNBRIG until recovery to Grade 1
Creatine                                                  or less (less than or equal to 2.5 × ULN) CPK Phosphokinase                                             elevation or to baseline, then resume (CPK) Elevation     Grade 3 or 4 CPK elevation            ALUNBRIG at same dose.
[see Warnings       (greater                          •   Recurrence: Withhold ALUNBRIG until and                 than 5 × ULN)                         recovery to Grade 1 or less (less than or Precautions                                               equal to 2.5 × ULN) CPK elevation or to (6.5)]                                                    baseline, then resume ALUNBRIG at the next lower dose (Table 1).



Grade 3 lipase or                   •   Withhold ALUNBRIG until recovery to Grade amylase elevation                       1 or less (less than or equal to 1.5 × ULN) or Lipase/Amyl
(greater than 2 x ULN)                  to baseline, then resume ALUNBRIG at ase same dose.
Elevation
[see Warnings                                            •   Recurrence: Withhold ALUNBRIG until and                                                          recovery to Grade 1 or less (less than or Precautions                                                  equal to 1.5 × ULN) or to baseline, then (6.6)]                                                       resume ALUNBRIG at next lower dose (Table 1).

Grade 4 lipase or
Withhold ALUNBRIG until recovery to Grade 1 or amylase elevation less (less than or equal to 1.5 x ULN) or to baseline,
(greater than 5 x ULN) then resume ALUNBRIG at next lower dose (Table
1).

Grade 3 or 4 elevation        Withhold ALUNBRIG until recovery to Grade 1 or (greater than 5 × ULN) of      less (less than or equal to 3x ULN) or to baseline, either ALT or AST with         then resume ALUNBRIG at next lower dose Hepatotoxicity bilirubin less than or equal   (Table 1).
(Elevation of alanine to 2 × ULN aminotransferase
(ALT) or aspartate
Permanently discontinue ALUNBRIG.
aminotransferase       Grade 2 to 4 elevation
(AST))                (greater than 3 × ULN) of
ALT or AST with concurrent
[see Warnings and total bilirubin elevation
Precautions (6.7)]    greater than 2 × ULN in the absence of cholestasis or hemolysis

If adequate hyperglycemic control cannot be
Hyperglycemia        Grade 3 (greater than 250 achieved with optimal medical management,
[see Warnings        mg/dL or 13.9 mmol/L) or withhold ALUNBRIG until adequate hyperglycemic and Precautions      4 control is achieved and resume at the next lower
(6.8)] dose (Table 1) or permanently discontinue
ALUNBRIG.

• Withhold ALUNBRIG until recovery to baseline, then resume at same dose.
Grade 3                        • Recurrence: withhold ALUNBRIG until recovery to baseline, then resume at next lower dose or
Other                                                   discontinue ALUNBRIG (Table 1).

• Withhold     ALUNBRIG until recovery to baseline and resume at next lower dose
Grade 4                            (Table 1).
• Recurrence: Permanently discontinue ALUNBRIG.
 bpm = beats per minute; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; ULN = upper limit of normal


*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI 
    CTCAE v4)



    3.4 Dosage Modifications for Strong or Moderate CYP3A Inhibitors
Avoid coadministration of strong or moderate CYP3A inhibitors during treatment with ALUNBRIG [see Drug Interactions (8.1), Clinical Pharmacology (11.3)]. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). If coadministration of a moderate CYP3A inhibitor cannot be avoided, reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong or moderate CYP3A inhibitor, resume the ALUNBRIG dose that was tolerated prior to initiating the CYP3A inhibitor.

3.5 Dosage Modifications for Moderate CYP3A Inducers
Avoid coadministration of moderate CYP3A inducers during treatment with ALUNBRIG [see Drug Interactions (8.1), Clinical Pharmacology (11.3)]. If coadministration of a moderate CYP3A inducer cannot be avoided, increase the ALUNBRIG once daily dose in 30 mg increments after 7 days of treatment with the current ALUNBRIG dose as tolerated, up to a maximum of twice the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

After discontinuation of a moderate CYP3A inducer, resume the ALUNBRIG dose that was tolerated prior to initiating the moderate CYP3A inducer.

3.6 Dosage Modifications for Patients with Severe Hepatic Impairment
Reduce the ALUNBRIG once daily dose by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (9.6), Clinical Pharmacology (11.3)].

3.7 Dosage Modifications for Patients with Severe Renal Impairment
Reduce the ALUNBRIG once daily dose by approximately 50% (i.e. from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min by Cockcroft-Gault] [see Use in Specific Populations (9.7), Clinical Pharmacology (11.3)].

4     DOSAGE FORMS AND STRENGTHS
•   30 mg, round, white to off-white film-coated tablets with “U3” debossed on one side and plain on the other side
•   90 mg, oval, white to off-white film-coated tablets with “U7” debossed on one side and plain on the other side

5     CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients listed in section 10.

6     WARNINGS AND PRECAUTIONS
6.1 Interstitial Lung Disease (ILD)/Pneumonitis
Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG.
In Trial ALTA 1L, ILD/pneumonitis occurred in 5.1% of patients receiving ALUNBRIG. ILD/pneumonitis occurred within 8 days of initiation of ALUNBRIG in 2.9% of patients, with Grade 3 to 4 reactions occurring in 2.2% of patients.
In Trial ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily).
Adverse reactions consistent with possible ILD/pneumonitis occurred within 9 days of initiation of ALUNBRIG (median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%.

Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction according to Table 1 after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis [see Dosage and Administration (3.3,) Adverse Reactions (7)].

6.2 Hypertension
In ALTA 1L, hypertension was reported in 32% of patients receiving ALUNBRIG; Grade 3 hypertension occurred in 13% of patients.
In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall.
Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1, resume ALUNBRIG at the same dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension [see Dosage and Administration (3.3), Adverse Reactions (7)].
Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia [see Warnings and Precautions (6.3)].

6.3 Bradycardia
In ALTA 1L, heart rates less than 50 beats per minute (bpm) occurred in 8.1% of patients receiving ALUNBRIG. Grade 3 bradycardia occurred in 1 patient (0.7%).
In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group.
Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided [see Warnings and Precautions (6.2)].
For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia.
Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (3.3)].


6.4 Visual Disturbance
In ALTA 1L, Grade 1 or 2 adverse reactions leading to visual disturbance including blurred vision, photophobia, photopsia, and reduced visual acuity were reported in 7.4% of patients receiving ALUNBRIG.
In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients receiving ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in 1 patient each in the 90→180 mg group.
Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG  at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances [see Dosage and Administration (3.3), Adverse Reactions (7)].

6.5 Creatine Phosphokinase (CPK) Elevation

In ALTA 1L, creatine phosphokinase (CPK) elevation occurred in 81% of patients who received ALUNBRIG. The incidence of Grade 3 or 4 CPK elevation was 24%. Dose reduction for CPK elevation occurred in 15% of patients.
In ALTA, CPK elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3 to 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group.
Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group.
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 CPK elevation or baseline, resume ALUNBRIG at the same dose or at a reduced dose as described in Table 2 [see Dosage and Administration (3.3), Adverse Reactions (7)].

6.6 Pancreatic Enzymes Elevation

In ALTA 1L, amylase elevation occurred in 52% of patients and Grade 3 or 4 amylase elevation occurred in 6.8% of patients. Lipase elevations occurred in 59% of patients and Grade 3 or 4 lipase elevation occurred in 17% of patients.
In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group.
Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose as described in Table 2 [see Dosage and Administration (3.3), Adverse Reactions (7)].


6.7   Hepatotoxicity
In ALTA 1L, aspartate aminotransferase (AST) elevations occurred in 72% of patients and Grade 3 or 4 AST elevations occurred in 4.5% of patients. Alanine aminotransferase (ALT) elevations occurred in 52% of patients and Grade 3 or 4 ALT elevations occurred in 5.2% of patients. One patient (0.7%) had a serious adverse reaction of hepatocellular injury.
In ALTA, AST elevations occurred in 38% of patients in the 90 mg group and 65% of patients in the 90→180 mg group. ALT elevations occurred in 34% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. Grade 3 or 4 AST elevations occurred in 0.9% of patients in the 90 mg group and did not occur in any patients in the 90→180 mg group. Grade 3 or 4 ALT elevations did not occur in any patients in the 90 mg group and in 2.7% of patients in the 90→180 mg group.
Monitor AST, ALT and total bilirubin during treatment with ALUNBRIG, especially during first 3 months.
Withhold ALUNBRIG for Grade 3 or 4 hepatic enzyme elevation with bilirubin less than or equal to 2 × ULN.
Upon resolution or recovery to Grade 1 or less (less than or equal to 3 × ULN) or to baseline, resume ALUNBRIG at a next lower dose as described in Table 2. Permanently discontinue ALUNBRIG for Grade 2 to 4 hepatic enzyme elevation with concurrent total bilirubin elevation greater than 2 times the ULN in the absence of cholestasis or hemolysis [see Dosage and Administration (3.3), Adverse Reactions (7)].



6.8   Hyperglycemia

In ALTA 1L, 56% of patients who received ALUNBRIG experienced new or worsening hyperglycemia.
Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 7.5% of patients.
In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG.
Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti- hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG as described in Table 1 or permanently discontinuing ALUNBRIG [see Dosage and Administration (3), Adverse Reactions (7)].

6.9   Photosensitivity

In ALTA 1L, photosensitivity occurred in 3.7% of patients who received ALUNBRIG, with 0.7% Grade 3 to 4.

In ALTA, 0.9% of patients who received ALUNBRIG in the 90 mg group experienced photosensitivity and 0.9% of patients in the 90 mg→180 mg group. Grade 3 to 4 photosensitivity was not reported in patients in the 90 mg group or in the 90→180 mg group.

Advise patients to limit sun exposure while taking brigatinib, and for at least 5 days after discontinuation of treatment. Advise patients, when outdoors to wear a hat and protective clothing, and use a broad- spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (SPF ≥30) to help protect against sunburn. Based on the severity withhold ALUNBRIG, then resume at the same dose, or reduce the dose, or permanently discontinue as described in Table 2 [see Dosage and Administration (3.3), Adverse Reactions (7)].

6. 10 Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women.
Administration of brigatinib to pregnant rats during the period of organogenesis resulted in dose-related skeletal anomalies at doses as low as 12.5 mg/kg/day (approximately 0.7 times the human exposure by AUC at 180 mg once daily) as well as increased post implantation loss, malformations, and decreased fetal body weight at doses of 25 mg/kg/day (approximately 1.26 times the human exposure at 180 mg once daily) or higher.
Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 4 months following the final dose.
Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG [see Use in Specific Populations (9.1, 9.3), Clinical Pharmacology (11.3)].


6.11      Lactose & Sodium

Lactose
Alunbrig contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.


Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.




7     ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the prescribing information:
•     Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (6.1)] •     Hypertension [see Warnings and Precautions (6.2)]
•     Bradycardia [see Warnings and Precautions (6.3)]
•     Visual Disturbance [see Warnings and Precautions (6.4)]
•     Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (6.5)] •     Pancreatic Enzymes Elevation [see Warnings and Precautions (6.6)] •     Hepatotoxicity [see Warnings and Precautions (6.7)]
•     Hyperglycemia [see Warnings and Precautions (6.8)]
•     Photosensitivity [see Warnings and Precautions (6.9)]

7.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Advanced ALK-positive NSCLC Without Prior ALK-targeted Therapy
In ALTA 1L, the safety of ALUNBRIG was evaluated in 136 patients with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy [see Clinical Studies (13)]. The median duration of treatment with ALUNBRIG when administered as 90 mg orally once daily for the first 7 days; then increased to 180 mg orally once daily, was 24.3 months. A total of 106 (78%) patients were exposed to ALUNBRIG for greater than or equal to 6 months including 92 (68%) patients exposed for greater than or equal to 1 year. The median relative dose intensity was 97% for ALUNBRIG.
The study population (N = 275) characteristics were: median age 59 years (range: 27 to 89), age less than 65 years (68%), female (55%), White (59%), Asian (39%), Stage IV disease (93%), NSCLC adenocarcinoma histology (96%), never smoker (58%), ECOG Performance Status (PS) 0 or 1 (95%), and CNS metastases at baseline (30%) [see Clinical Studies (13)].
Serious adverse reactions occurred in 33% of patients receiving ALUNBRIG. The most common serious adverse reactions were pneumonia (4.4%), ILD/pneumonitis (3.7%), pyrexia (2.9%), dyspnea (2.2%), pulmonary embolism (2.2%), and asthenia (2.2%). Fatal adverse reactions occurred in 2.9% of patients and included pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).
In ALTA 1L, 13% of patients receiving ALUNBRIG permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (3.7%) and pneumonia (2.2%). In ALTA 1L, 38% of patients required a dose reduction due to adverse reactions.
The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (15%), increased lipase (6.6%), increased amylase (4.4%), increased aspartate aminotransferase (2.2%), ILD/pneumonitis (2.2%) and hypertension (2.2%).
Table 3 and Table 4 summarize the common adverse reactions and laboratory abnormalities observed in ALTA 1L.




Table 3: Adverse Reactions in ≥10% (All Grades*) or ≥2% (Grades 3-4) of Patients by Arm in ALTA 1L (N = 273)
ALUNBRIG                     Crizotinib
N = 136                      N = 137
All Grades     Grades 3-4    All Grades     Grades 3-4
Adverse Reactions                    (%)           (%)            (%)            (%) Gastrointestinal Disorders
Diarrhea                                     53            2.2           57             2.9 Nausea                                       30            2.2           58             2.9 Abdominal pain†                              24            0.7           33             3.6 Vomiting                                     21            0.7           44             2.2 Constipation                                 18             0            42              0 Stomatitis‡                                  13            0.7           8.8             0 Dyspepsia                                     8             0            16             0.7 Gastroesophageal reflux disease              0.7            0            11              0 Skin and Subcutaneous Tissue
Disorders
Rash§                                        40            2.9           17              0 Pruritus¶                                    20            0.7           5.8            0.7 Respiratory, Thoracic and Mediastinal
Disorders
Cough                                        35             0             20             0 Dyspnea#                                     25            2.9           22Ɖ            3.6 ILD/Pneumonitis                              5.1           2.9           2.2            0.7 Pulmonary embolism                           2.2           2.2           5.8Ɖ           2.9 Vascular Disorders
HypertensionÞ                                32             13            8             2.9 General Disorders and Administration
Site Conditions
Fatigueβ                                     32            1.5            40            2.2 Edemaà                                       18            0.7            48            0.7 Pyrexia                                      15            0.7            15             0 Musculoskeletal and Connective Tissue
Disorders
Myalgiaẻ                                     28             0             23             0 Back pain                                    21            0.7            17            1.5 Arthralgia                                   14             0             12             0 Pain in extremity                            5.1            0             15            0.7 Nervous System Disorders
Headacheð                                    22            2.2            17             0 Dizziness                                    15            0.7            20            0.7 Peripheral neuropathyø                       11            0.7            18             0 Dysgeusia                                    2.9            0             14             0 Investigations
Increased Blood cholesterolý                 13             0            0.7             0 Cardiac Disorders
Bradycardia£                                 12            0.7            23             0 Infections and Infestations
Pneumonia¥                                   15Ɖ           5.1           6.6Ɖ           2.9 Upper respiratory tract infectionOE          12             0             10             0 
Nasopharyngitis                                     8               0              11                0 Urinary tract infection                            5.9             0.7             8.8              2.2 Metabolism and Nutrition Disorders
Decreased Appetite                                 8.8             0.7              19              2.9 Eye Disorders
Visual Disturbanceoe                               7.4              0               53              0.7 

* Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 †  Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort
‡ Includes aphthous ulcer, mouth ulceration, oral mucosal blistering and stomatitis 
§ Includes dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis contact, drug eruption, erythema,  palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption, urticaria ¶ Included pruritus, allergic pruritus, and generalized pruritus

# Include dyspnea and exertional dyspnea

Þ Includes hypertension and systolic hypertension
â Includes asthenia and fatigue

à Includes angioedema, eye swelling, eyelid edema, face edema, generalized edema, lip swelling, peripheral  edema, periorbital edema, peripheral swelling, skin swelling, swelling and swelling face ẻ Includes muscle spasms, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, and myalgia 
ð
Includes headache and migraine
ø
Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, peripheral neuropathy, paraesthesia, peripheral sensory neuropathy and polyneuropathy
ý
Includes blood cholesterol increased, hypercholesterolaemia
£
Includes bradycardia, heart rate decreased, sinus bradycardia
¥
Includes lower respiratory tract infection, lung infection, pneumonia, aspiration pneumonia, and cryptococcal pneumonia
OE
Includes upper respiratory tract infection and viral upper respiratory tract infection oe
Includes cataract, glaucoma, hypermetropia, night blindness, papilloedema, photophobia, photopsia, blurred vision, reduced visual acuity, visual field defect, visual impairment, and vitreous floaters Ɖ
Includes Grade 5 events




Table 4: Laboratory Abnormalities in ≥20% (All Grades*) of Patients by Arm in ALTA 1L (N = 273) ALUNBRIG                              Crizotinib
N = 136**                            N = 137**
All Grades          Grades 3-4        All Grades      Grades 3-4
Laboratory Abnormality                  (%)                (%)                (%)            (%) Chemistry
Increased creatine phosphokinase             81                 24                68                 4.8 Increased aspartate                          72                 4.5               70                 5.2 aminotransferase
Increased lipase                             59                 17                36                 9.8 Hyperglycemia†                               56                 7.5               37                 3.7 Increased alanine aminotransferase           52                 5.2               77                 13 Increased amylase                            52                 6.8               25                  3 Decreased phosphorous                        41                 3.7               39                  6 Increased alkaline phosphatase               36                  3                49                 1.5 Increased creatinine                         25                  0                33                  0 Potassium increased                          24                 1.5               31                 3.7 Increased calcium                            22                  0                1.5                 0 Decreased magnesium                          21                  0                6.9                 0 Decreased albumin                            15                 0.8               52                 3.7 Decreased calcium                            15                  0                67                 1.5 Hematology
Hemoglobin decreased                         41                 2.3               36                 1.5 Lymphocyte count decreased                   42                 9.3               30                 5.4 Neutrophil count decreased                   12                  0                34                 6.8 
* Per CTCAE version 4.03
** Denominator for each laboratory parameter may vary and is defined as the number of patients who had both, baseline and post-baseline test
† Elevated blood insulin was also observed in both arms

Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (3.7%).

ALK-positive Advanced or Metastatic NSCLC Previously Treated with Crizotinib The safety of ALUNBRIG was evaluated in 219 patients with locally advanced or metastatic ALK-positive NSCLC who received at least 1 dose of ALUNBRIG in ALTA after experiencing disease progression on crizotinib. Patients received ALUNBRIG 90 mg once daily continuously (90 mg group) or 90 mg once daily for 7 days followed by 180 mg once daily (90→180 mg group). The median duration of treatment was 7.5 months in the 90 mg group and 7.8 months in the 90→180 mg group. A total of 150 (68%) patients were exposed to ALUNBRIG for greater than or equal to 6 months and 42 (19%) patients were exposed for greater than or equal to 1 year.

The study population (N=222) characteristics were: median age 54 years (range: 18 to 82), age less than 65 years (77%), female (57%), White (67%), Asian (31%), Stage IV disease (98%), NSCLC adenocarcinoma histology (97%), never or former smoker (95%), ECOG Performance Status (PS) 0 or 1 (93%), and CNS metastases at baseline (69%) [see Clinical Studies (13)].


Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

In ALTA, 2.8% of patients in the 90 mg group and 8.2% of patients in the 90→180 mg group permanently discontinued ALUNBRIG for adverse reactions. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90 mg group and 1.8% in the 90→180 mg group) and pneumonia (1.8% in the 90→180 mg group only).

In ALTA, 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90 mg group and 20% in the 90→180 mg group). The most common adverse reaction that led to dose reduction was increased creatine phosphokinase for both regimens (1.8% in the 90 mg group and 4.5% in the 90→180 mg group).

Table 5 and Table 6 summarize the common adverse reactions and laboratory abnormalities observed in ALTA.

Table 5: Adverse Reactions in ≥ 10% (All Grades*) or ≥ 2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)
90 mg once                    90→180 mg once daily N = 109                   daily N = 110
Adverse Reactions                 All Grades    Grades 3-        All            Grades 3- (%)           4 (%)             Grades        4 (%)
Gastrointestinal Disorders
Nausea                                           33              0.9            40              0.9 Diarrhea                                         19               0             38               0 Vomiting                                         24              1.8            23               0 Constipation                                     19              0.9            15               0 Abdominal Pain†                                  17               0             10               0 
General Disorders and Administration Site Conditions
Fatigue‡                                      29                 1.8            36               0 Pyrexia                                       14                  0             6.4             0.9 Respiratory, Thoracic and Mediastinal Disorders
Cough                                         18                  0             34               0 Dyspnea§                                      27                 2.8            21             1.8‡‡ ILD/Pneumonitis                               3.7                1.8            9.1             2.7 Hypoxia                                       0.9                 0             2.7             2.7 Nervous System Disorders
Headache¶                                        28               0             27              0.9 Peripheral Neuropathy#                        13                 0.9            13              1.8 Skin and Subcutaneous Tissue Disorders
RashÞ                                         15                 1.8            24              3.6 Vascular Disorders
Hypertension                                  11                 5.5            21              6.4 Musculoskeletal and Connective Tissue Disorders
Muscle Spasms                                 12                  0             17               0 Back pain                                     10                 1.8            15              1.8 

Myalgia**                                             9.2              0              15               0.9 Arthralgia                                            14              0.9             14                0 Pain in extremity                                     11               0              3.6              0.9 Metabolism and Nutrition Disorders
Decreased Appetite                                    22              0.9             15               0.9 Eye Disorders
Visual Disturbance††                                  7.3             0               10               0.9 Infections
Pneumonia                                            4.6           2.8‡‡             10              5.5‡‡ Psychiatric Disorders
Insomnia                                              11              0               7.3               0 
*Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 †Includes abdominal distension, abdominal pain, and epigastric discomfort ‡Includes asthenia and fatigue
§Includes dyspnea and exertional dyspnea
¶Includes headache and sinus headache
#includes peripheral sensory neuropathy and paresthesia
ÞIncludes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash **Includes musculoskeletal pain and myalgia
††Includes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment
‡‡Includes one Grade 5 event


Table 6: Laboratory Abnormalities in ≥20% (All Grades*) of Patients by Regimen in ALTA (N=219) 90 mg once                           90→180 mg once daily N= 109                          daily N=110
Laboratory Abnormality
All Grades        Grades 3-4             All            Grades 3-
(%)               (%)                   Grades         4 (%)
(%)
Chemistry
Increased aspartate aminotransferase             38                   0.9                   65               0 Hyperglycemia†                                   38                   3.7                   49              3.6 Increased creatine phosphokinase                 27                   2.8                   48              12 Increased lipase                                 21                   4.6                   45              5.5 Increased alanine aminotransferase               34                    0                    40              2.7 Increased amylase                                27                   3.7                   39              2.7 Increased alkaline phosphatase                   15                   0.9                   29              0.9 Decreased phosphorous                            15                   1.8                   23              3.6 Prolonged activated partial                      22                   1.8                   20              0.9 thromboplastin time
Hematology
Anemia                                           23                   0.9                   40              0.9 Lymphopenia                                      19                   2.8                   27              4.5 
*Per CTCAE version 4.0
†Elevated blood insulin was observed in both regimens

Clinically relevant adverse reactions in patients who received ALUNBRIG included photosensitivity (0.9%).


Other Adverse Reactions from Multiple Clinical Trials
In a pooled clinical trial population consisting of three studies with 274 patients treated with ALUNBRIG at the recommended dose, the following adverse reactions and laboratory abnormalities were reported: white blood cell count decreased (28%), hyponatremia (20%), hypokalemia (19%), decreased platelet count (10%), dry skin (4.7%), pain (3.3%), and musculoskeletal stiffness (1.1%).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il





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