Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1   Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers 
Severe hepatotoxicity occurred in 10 of 12 healthy subjects receiving a single dose of LORVIQUA with multiple daily doses of rifampin, a strong CYP3A inducer. Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 50% of subjects, Grade 3 ALT or AST elevations occurred in 33% and Grade 2 ALT or AST elevations occurred in 8%. ALT or AST elevations occurred within 3 days and returned to within normal limits after a median of 15 days (7 to 34 days); the median time to recovery was 18 days in subjects with Grade 3 or 4 ALT or AST elevations and 7 days in subjects with Grade 2 ALT or AST elevations [see Drug Interactions (7.1)].

LORVIQUA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORVIQUA [see Contraindications (4), Drug Interactions (7.1)].

Avoid concomitant use of LORVIQUA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor AST, ALT, and bilirubin 48 hours after initiating LORVIQUA and at least 3 times during the first week after initiating LORVIQUA .

5.2   Central Nervous System Effects

A broad spectrum of central nervous system (CNS) effects can occur in patients receiving LORVIQUA . These include seizures, psychotic effects and changes in cognitive function, mood (including suicidal ideation), speech, mental status, and sleep. Overall, CNS effects occurred in 52% of the 476 patients who received 100 mg LORVIQUA once daily in clinical trials [see Adverse Reactions (6.1)]. Cognitive effects occurred in 28% of the 476 patients; 2.9% of these events were severe (Grade 3 or 4). Mood effects occurred in 21% of patients; 1.7% of these events were severe. Speech effects occurred in 11% of patients; 0.6% of these events were severe.
Psychotic effects occurred in 7% of patients; 0.6% of these events were severe. Mental status changes occurred in 1.3% of patients; 1.1% of these events were severe. Seizures occurred in 1.9% of patients, sometimes in conjunction with other neurologic findings. Sleep effects occurred in 12% of patients. The median time to first onset of any CNS effect was 1.4 months (1 day to 3.4 years). Overall, 2.1% of patients required permanent discontinuation of LORVIQUA for a CNS effect; 10% required temporary discontinuation and 8% required dose reduction.

Withhold and resume at the same dose or at a reduced dose or permanently discontinue LORVIQUA based on severity [see Dosage and Administration (2.3)].

5.3   Hyperlipidemia

Increases in serum cholesterol and triglycerides can occur in patients receiving LORVIQUA [see Adverse Reactions (6.1)]. Grade 3 or 4 elevations in total cholesterol occurred in 18% and Grade 3 or 4 elevations in triglycerides occurred in 19% of the 476 patients who received 100 mg LORVIQUA once daily. The median time to onset was 15 days for both hypercholesterolemia and hypertriglyceridemia. Approximately 4% and 7% of patients required temporary discontinuation and 1% and 3% of patients required dose reduction of LORVIQUA for elevations in cholesterol and in triglycerides in Study B7461001 and Study B7461006, respectively. Eighty-three percent of patients required initiation of lipid-lowering medications, with a median time to onset of start of such medications of 17 days.

Initiate or increase the dose of lipid-lowering agents in patients with hyperlipidemia. Monitor serum cholesterol and triglycerides before initiating LORVIQUA , 1 and 2 months after initiating LORVIQUA , and periodically thereafter. Withhold and resume at the same dose for the first occurrence; resume at the same or a reduced dose of LORVIQUA for recurrence based on severity [see Dosage and Administration (2.3)].

5.4   Atrioventricular Block

PR interval prolongation and atrioventricular (AV) block can occur in patients receiving LORVIQUA [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. In 476 patients who received 100 mg LORVIQUA once daily and who had a baseline electrocardiography (ECG), 1.9% experienced AV block and 0.2% experienced Grade 3 AV block and underwent pacemaker placement.

Monitor ECG prior to initiating LORVIQUA and periodically thereafter. Withhold and resume at a reduced dose or at the same dose in patients who undergo pacemaker placement. Permanently discontinue for recurrence in patients without a pacemaker [see Dosage and Administration (2.3)].

5.5   Interstitial Lung Disease/Pneumonitis

Severe or life-threatening pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis can occur with LORVIQUA . ILD/pneumonitis occurred in 1.9% of patients who received 100 mg LORVIQUA once daily, including Grade 3 or 4 ILD/pneumonitis in 0.6% of patients. Four patients (0.8%) discontinued LORVIQUA for ILD/pneumonitis.

Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold LORVIQUA in patients with suspected ILD/pneumonitis. Permanently discontinue LORVIQUA or treatment-related ILD/pneumonitis of any severity [see Dosage and Administration (2.3)].

5.6   Hypertension

Hypertension can occur in patients receiving LORVIQUA [see Adverse Reactions (6.1)]. Hypertension occurred in 13% of patients who received 100 mg LORVIQUA once daily, including Grade 3 or 4 in 6% of patients. The median time to onset of hypertension was 6.4 months (1 day to 2.8 years), and 2.3% of patients temporarily discontinued LORVIQUA for hypertension.

Control blood pressure prior to initiation of LORVIQUA. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with LORVIQUA. Withhold and resume at a reduced dose or permanently discontinue LORVIQUA based on severity [see Dosage and Administration (2.3)].

5.7   Hyperglycemia

Hyperglycemia can occur in patients receiving LORVIQUA [see Adverse Reactions (6.1)]. Hyperglycemia occurred in 9% of patients who received 100 mg LORVIQUA, including Grade 3 or 4 in 3.2% of patients. The median time to onset of hyperglycemia was 4.8 months (1 day to 2.9 years), and 0.8% of patients temporarily discontinued LORVIQUA for hyperglycemia.

Assess fasting serum glucose prior to initiation of LORVIQUA and monitor periodically thereafter. Withhold and resume at a reduced dose or permanently discontinue LORVIQUA based on severity [see Dosage and Administration (2.3)].

5.8   Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, LORVIQUA can cause fetal harm when administered to a pregnant woman. Administration of lorlatinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in malformations, increased post-implantation loss, and abortion at maternal exposures that were equal to or less than the human exposure at the recommended dose of 100 mg once daily based on area under the curve (AUC).

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective non-hormonal method of contraception, since LORVIQUA can render hormonal contraceptives ineffective, during treatment with LORVIQUA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LORVIQUA and for 3 months after the final dose [see Drug Interactions (7.2), Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

5.9      Lactose intolerance

This medicinal product contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

5.10      Dietary sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 25 mg or 100 mg tablet. Patients on low sodium diets should be informed that this product is essentially “sodium-free”.


6 ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the labeling: 
•      Risk of Serious Hepatotoxicity with Concomitant Use of Strong CYP3A Inducers [see Warnings and Precautions (5.1)]
•      Central Nervous System Effects [see Warnings and Precautions (5.2)]
•      Hyperlipidemia [see Warnings and Precautions (5.3)]
•      Atrioventricular Block [see Warnings and Precautions (5.4)]
•      Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.5)]
•      Hypertension [see Warnings and Precautions (5.6)]
•      Hyperglycemia [see Warnings and Precautions (5.7)] 
6.1     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.

The pooled safety population described in the Warnings and Precautions section reflects exposure to LORVIQUA in 476 patients who received 100 mg LORVIQUA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORVIQUA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORVIQUA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). The most frequent Grade 3-4 laboratory abnormalities in ≥ 20% of 476 patients who received LORVIQUA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Previously Untreated ALK-Positive Metastatic NSCLC (CROWN Study)

The safety of LORVIQUA was evaluated in 149 patients with ALK-positive NSCLC in a randomized, open-label, active-controlled trial for the treatment of patients with ALK-positive, locally advanced or metastatic, NSCLC who had not received previous systemic treatment for advanced disease [see Clinical Studies (14)]. The median duration of exposure to LORVIQUA was 16.7 months (4 days to 34.3 months) and 76% received LORVIQUA for at least 12 months.

Serious adverse reactions occurred in 34% of patients treated with LORVIQUA; the most frequently reported serious adverse reactions were pneumonia (4.7%), dyspnea (2.7%), respiratory failure (2.7%), cognitive effects (2.0%), and pyrexia (2.0%). Fatal adverse reactions occurred in 3.4% of patients treated with LORVIQUA and included pneumonia (0.7%), respiratory failure (0.7%), cardiac failure acute (0.7%), pulmonary embolism (0.7%), and sudden death (0.7%).

Permanent discontinuation of LORVIQUA due to adverse reactions occurred in 6.7% of patients. The most frequent adverse reaction that led to permanent discontinuation of LORVIQUA was cognitive effects (1.3%).
Adverse reactions leading to dose interruptions occurred in 49% of patients treated with LORVIQUA. The most frequent adverse reactions that led to dose interruptions of LORVIQUA were hypertriglyceridemia (7%), edema (5%), pneumonia (4.7%) cognitive effects (4.0%), mood effects (4.0%), and hypercholesterolemia (3.4%).
Adverse reactions leading to dose reductions occurred in 21% of patients treated with LORVIQUA. The most frequent adverse reactions that led to dose reductions were edema (5%), hypertriglyceridemia (4.0%), and peripheral neuropathy (3.4%).

Tables 2 and 3 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORVIQUA in Study B7461006.

Table 2 Adverse Reactions (≥10% for all NCI CTCAE Grades or ≥2% for Grades 3-4) in Patients Treated with LORVIQUA in Study B7461006*
Adverse Reaction                   LORVIQUA                 Crizotinib N=149                    N=142
All Grades Grade 3 or 4 All Grades Grade 3 or 4
(%)         (%)         (%)             (%)
Psychiatric
Mood effectsa                               16           2           5               0 Nervous system
Peripheral neuropathyb                      34           2          15              0.7 c
Cognitive effects                           21           2           6               0 Headache                                    17           0          18              0.7 Dizziness                                   11           0          14               0 Sleep effectsd                              11          1.3         10               0 Respiratory
Dyspnea                                      20          2.7         16              2.1 Cough                                       16           0          18               0 Respiratory failure                         2.7          2           0               0 Vascular disorders
Hypertension                                 18          10          2.1              0 Ocular
Vision disordere                            18           0          39              0.7 Gastrointestinal
Diarrhea                                    21          1.3         52              0.7 Nausea                                      15          0.7         52              2.1 Constipation                                17           0          30              0.7 Vomiting                                    13          0.7         39              1.4 Musculoskeletal and connective tissue
Adverse Reaction                                  LORVIQUA                              Crizotinib N=149                                N=142
All Grades Grade 3 or 4               All Grades Grade 3 or 4
(%)         (%)                       (%)            (%)
Arthralgia                                                   19          0.7                       11             0 Myalgiaf                                                     15          0.7                        7             0 Back pain                                                    15          0.7                       11             0 Pain in extremity                                            17           0                         8             0 General
Edemag                                                       56                  4                  40                1.4 Weight gain                                                  38                 17                  13                2.1 Fatigueh                                                     19                 1.3                 32                2.8 Pyrexia                                                      17                 1.3                 13                1.4 Chest pain                                                   11                 1.3                 14                0.7 Infections
Upper respiratory tract infectioni                           11                 0.7                7.7                1.4 Pneumonia                                                    7.4                 2                 8.5                3.5 Bronchitis                                                   6.7                 2                 2.1                 0 Skin
Rashj                                                        11                  0                 8.5                  0 * Adverse reactions were graded using NCI CTCAE version 4.03.
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
a
Mood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress).
b
Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy).
c
Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation).
d
Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism).
e
Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
f
Myalgia (including musculoskeletal pain, myalgia).
g
Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
h
Fatigue (including asthenia, fatigue).
i
Upper respiratory tract infection (including upper respiratory infection).
j
Rash (including dermatitis acneiform, maculopapular rash, rash).
Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were speech effects (6.7%) and psychotic effects (3.4%).

Table 3   Laboratory Abnormalities Worsening from Baseline in >20% of Patients in Study B7461006 Laboratory Abnormality                  LORVIQUA                      Crizotinib N=149                         N=142
All Grades Grade 3 or 4 All Grades Grade 3 or 4
(%)            (%)           (%)             (%)
Chemistry
Hypertriglyceridemiaa,A                    95             22            27               0 a,A
Hypercholesterolemia                       91             19            12               0 Increased creatininea,A                    81             0.7           99              2.1 Increased GGTa,A                           52              6            41               6 Laboratory Abnormality                            LORVIQUA                           Crizotinib N=149                             N=142
All Grades Grade 3 or 4            All Grades Grade 3 or 4
(%)         (%)                    (%)            (%)
Increased ASTa,A                                       48           2                     75             3.5 Hyperglycemiaa,A                                       48           7                     27             2.1 Increased ALTa,A                                       44          2.7                    75             4.3 Increased CPKa,A                                       39           2                     64              5 Hypoalbuminemiaa,A                                     36          0.7                    61              6 Increased lipasea,A                                    28           7                     34              5 Increased alkaline phosphatasea,A                      23           0                     50             0.7 Hyperkalemiaa,A                                        21          1.3                    27             2.1 Increased amylaseb,A                                   20          1.4                    32             1.4 Hematology
Anemiaa,A                                             48                2                38               2.8 Activated PTTc,B                                      25                0                14                0 Lymphopeniaa,A                                        23               2.7               43                6 Thrombocytopeniaa,A                                   23                0                 7               0.7 * Grades using NCI CTCAE version 4.03.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time.
N=number of patients who had at least one on-study assessment for the parameter of interest.
a
N=149 (LORVIQUA).
A
N=141 (crizotinib).
b
N=148 (LORVIQUA).
B
N=135 (crizotinib).
c
N=138 (LORVIQUA).

Previously Treated ALK-Positive Metastatic NSCLC

The data described below reflect exposure to LORVIQUA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORVIQUA 100 mg orally once daily in Study B7461001, a multi-cohort, non-comparative trial [see Clinical Studies (14)]. The median duration of exposure to LORVIQUA was 12.5 months (1 day to 35 months) and 52% received LORVIQUA for ≥12 months. Patient characteristics were: median age of 53 years (19 to 85 years), age ≥65 years (18%), female (58%), White (49%), Asian (37%), and ECOG performance status 0 or 1 (96%).

The most frequent (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Of the worsening laboratory values occurring in ≥20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORVIQUA for adverse reactions occurred in 8% of patients.


The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1.4%), dyspnea (0.7%), myocardial infarction (0.7%), cognitive effects (0.7%) and mood effects (0.7%).
Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4.4%), increased lipase (3.7%), hypercholesterolemia (3.4%), mood effects (3.1%), dyspnea (2.7%), pneumonia (2.7%), and hypertension (2.0%). Approximately 24% of patients required at least 1 dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4.7%), cognitive effects (4.1%), and mood effects (3.1%).

Tables 4 and 5 summarize most frequent adverse reactions and laboratory abnormalities, respectively, in patients treated with LORVIQUA in Study B7461001.

Table 4     Adverse Reactions Occurring in ≥10% of Patients in Study B7461001* LORVIQUA
(N=295)
Adverse Reaction
All Grades                    Grade 3 or 4
(%)                          (%)
Psychiatric
Mood effectsa                                       23                           1.7 Nervous system
Peripheral neuropathyb                              47                           2.7 Cognitive effectsc                                  27                            2 Headache                                            18                           0.7 Dizziness                                           16                           0.7 Speech effectsd                                     12                           0.3 e
Sleep effects                                       10                            0 Respiratory
Dyspnea                                             27                            5 Cough                                               18                            0 Ocular
Vision disorderf                                    15                           0.3 Gastrointestinal
Diarrhea                                            22                           0.7 Nausea                                              18                           0.7 Constipation                                        15                            0 Vomiting                                            12                            1 Musculoskeletal and connective tissue
Arthralgia                                          23                           0.7 Myalgiag                                            17                            0 Back pain                                           13                           0.7 Pain in extremity                                   13                           0.3 General
Edemah                                              57                           3.1 i
Fatigue                                             26                           0.3 Weight gain                                         24                           4.4 Pyrexia                                             12                           0.7 Infections
Upper respiratory tract infectionj                  12                            0 Skin
Table 4      Adverse Reactions Occurring in ≥10% of Patients in Study B7461001* LORVIQUA
(N=295)
Adverse Reaction
All Grades                    Grade 3 or 4
(%)                          (%)
Rashk                                                14                           0.3 * Adverse reactions were graded using NCI CTCAE version 4.03.
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
a
Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation).
b
Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance).
c
Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder).
d
Speech effects (including aphasia, dysarthria, slow speech, speech disorder) e
Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) f
Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
g
Myalgia (including musculoskeletal pain, myalgia).
h
Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
i
Fatigue (including asthenia, fatigue).
j
Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection).
k
Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were psychotic effects (7%).

Table 5   Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001* LORVIQUA
Laboratory Abnormality                 All Grades                       Grade 3 or 4 (%)                              (%)
Chemistry
Hypercholesterolemiaa                        96                               18 a
Hypertriglyceridemia                         90                               18 Hyperglycemiab                               52                                5 a
Increased AST                                37                               2.1 Hypoalbuminemiac                             33                                1 Increased ALTa                               28                               2.1 Increased lipased                            24                               10 Increased alkaline phosphatasea              24                                1 Increased amylase e
22                               3.9
Hypophosphatemiaa                            21                               4.8 Hyperkalemia  b
21                                1
Hypomagnesemiaa                              21                                0 Hematology
Anemiab                                      52                               4.8 b
Thrombocytopenia                             23                               0.3 Lymphopeniaa                                 22                               3.4 
* Grades using NCI CTCAE version 4.03.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
N=number of patients who had at least one on-study assessment for the parameter of interest.
a
N=292.
b
N=293.
c
N=291.
d
N=290.
e
N=284.
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.
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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