Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

5.1 Ocular Disorders
ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.
Ocular adverse reactions occurred in 59% of patients with ovarian cancer treated with ELAHERE. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions, including blurred vision, keratopathy (corneal disorders), dry eye, cataract, photophobia, and eye pain; two patients (0.3%) experienced Grade 4 events (keratopathy and cataract). The most common (≥5%) ocular adverse reactions were blurred vision (48%), keratopathy (36%), dry eye (27%), cataract (16%), photophobia (14%), and eye pain (10%). [see Adverse Reactions (6.1)].
The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution; 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up. Ocular adverse reactions led to permanent discontinuation of ELAHERE in 1% of patients.
Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with ELAHERE are recommended [see Dosage and Administration (2.3)]. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by a healthcare provider.
Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.
Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions. [see Dosage and Administration (2.4)].

5.2 Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ELAHERE.
Pneumonitis occurred in 10% of patients treated with ELAHERE, including 1% with Grade 3 events and 1 patient (0.1%) with a Grade 4 event. One patient (0.1%) died due to respiratory failure in the setting of pneumonitis and lung metastases. One patient (0.1%) died due to respiratory failure of unknown etiology.
Pneumonitis led to permanent discontinuation of ELAHERE in 3% of patients.
Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold ELAHERE for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade 3 or 4 pneumonitis [see Dosage and Administration (2.4)]. Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring.

5.3 Peripheral Neuropathy
Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 3% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (1%), peripheral motor neuropathy (0.9%), polyneuropathy (0.3%), and peripheral sensorimotor neuropathy (0.1%).
The median time to onset of peripheral neuropathy was 5.9 weeks (range 0.1 to 126.7). Of the patients who experienced peripheral neuropathy, 23% had complete resolution and 12% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of ELAHERE in 0.7% of patients.
Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy [see Dosage and Administration (2.4)].

.4 Embryo-Fetal Toxicity
Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose [see Use in Specific Populations (8.1, 8.3)].


5.5 Driving and using machines with Elahere.
Elahere may affect your ability to drive and use machines. If you experience blurred vision or nerve damage causing pain, numbness or weakness in your hands, arms or feet, do not drive, use tools, or operate machines until your symptoms are completely better.

6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling: •     Ocular Disorders [see Warnings and Precautions (5.1)].
•     Pneumonitis [see Warnings and Precautions (5.2)].
•     Peripheral Neuropathy [see Warnings and Precautions (5.3)].

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 Warnings and Precautions reflect exposure to ELAHERE in 682 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer at 6 mg/kg AIBW administered intravenously once every 3 weeks until disease progression or unacceptable toxicity in Study 0416, Study 0417, Study 0403 (NCT02631876), and Study 0401 (NCT01609556). The median duration of treatment was 4.4 months (range: 1.0 to 30.0). In the pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils.
Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Study 0416
The safety of ELAHERE was evaluated in Study 0416, a multicenter, open-label, active-controlled, randomized, two-arm, study in patients (n=453) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14)]. Patients received ELAHERE 6 mg/kg AIBW once every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 5 months (range: 0.69 to 27.4).
Serious adverse reactions occurred in 24% of patients treated with ELAHERE. The most common (≥2%) serious adverse reactions were intestinal obstruction (5%), abdominal pain (3%), and pleural effusion (3%).
Fatal adverse reactions occurred in 3% of patients, including intestinal obstruction, dyspnea in the setting of subileus, neutropenic sepsis, cardiopulmonary failure, respiratory failure, ischemic stroke, and pulmonary embolus.
Permanent discontinuation of ELAHERE due to adverse reactions occurred in 9% of patients. The most common (≥1%) adverse reactions leading to permanent discontinuation were pneumonitis (2%), blurred vision (1%), and peripheral neuropathy (1%).
Dosage delays of ELAHERE due to an adverse reaction occurred in 54% of patients treated with ELAHERE.
Adverse reactions which required dosage delays in ≥3% of patients included blurred vision (22%), keratopathy (19%), dry eye (7%), neutropenia (6%), pneumonitis (6%), photophobia (5%), cataract (4%), and peripheral neuropathy (4%).
Dose reductions of ELAHERE due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dose reductions in ≥3% of patients included blurred vision (14%), keratopathy (10%), peripheral neuropathy (6%), and dry eye (5%).
Tables 4 and 5 summarize adverse reactions and laboratory abnormalities, respectively, occurring in ≥10% of patients who received ELAHERE in Study 0416.
Table 4: Adverse Reactions Occurring in ≥10% of Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0416

Adverse Reaction                                        ELAHERE                          Chemotherapy¥ (n=218)                            (n=207)
All Grades           Grades 3-4   All Grades        Grades 3-4
(%)                 (%)           (%)              (%)
Gastrointestinal disorders
Abdominal pain*                                    34                    3         23                    2 Diarrhea                                           29                    1         17                    0.5 Constipation                                       27                    0         19                    1 Nausea                                             27                    2         29                    2 Vomiting                                           18                    3         18                    1 Eye disorders
Blurred vision※                                    45                    9          3                    0 Keratopathy†                                       37                   11          0                    0 Dry eye‡                                           29                    3          5                    0 Photophobia                                        18                   0.5        0.5                   0 Cataract˄                                          16                    3         0.5                   0 General disorders and administration site conditions
Fatigue⸙                                           47                    3         41                    7 Nervous system disorders
Peripheral neuropathy¶                             37                    4         23                    4 Headache                                           14                    0         10                    0 Musculoskeletal and connective tissue disorders
Musculoskeletal pain♦                              31                    1         21                    2 Metabolism and nutrition disorders
Decreased appetite                                 18                    1         14                    1 Respiratory, thoracic, and mediastinal disorders
Pneumonitis±                                       10                   0.5        0.5                   0 ¥
Chemotherapy: paclitaxel, pegylated liposomal doxorubicin (PLD), topotecan.
※ Blurred vision includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, accommodation disorder, and visual impairment.
† Keratopathy includes corneal disorder, corneal epithelial microcysts, keratitis, keratopathy, corneal deposits, punctate keratitis, and corneal opacity.
‡ Dry eye includes dry eye and lacrimation increased.
˄
Cataract includes cataract and cataract nuclear.
⸙
Fatigue includes fatigue and asthenia.
* Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
¶
Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, neurotoxicity, and peripheral sensorimotor neuropathy.
♦
Musculoskeletal pain includes back pain, myalgia, neck pain, arthralgia, musculoskeletal pain, non-cardiac chest pain, bone pain, pain in extremity, musculoskeletal stiffness, musculoskeletal chest pain, and musculoskeletal discomfort.
±
Pneumonitis includes pneumonitis, interstitial lung disease, respiratory failure, and organizing pneumonia.

Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0416 included infusion related reactions/hypersensitivity (8%).
Table 5: Select Laboratory Abnormalities ≥10% for All Grades, in Patients Who Received ELAHERE in Study 0416
ELAHERE                                      Chemotherapy
(n=218)                                        (n=207)
Laboratory Abnormality
All Grades             Grades 3-4             All Grades             Grades 3-4 %                      %                      %                      % Liver Function Tests
Increased aspartate aminotransferase                   57                      0                     14                      0 Increased alanine aminotransferase                     38                      1                     15                      1 Increased alkaline phosphatase                         30                      1                     13                      1 Chemistry
Decreased albumin                                      21                      1                     27                      2 Decreased magnesium                                    21                      1                     29                      2 Decreased sodium                                       16                      0                     18                      0 Decreased potassium                                    15                      1                     11                      1 Increased calcium                                      12                      0                      5                      0 Decreased bicarbonate                                  11                      0                     11                      0 Increased creatinine                                   10                      0                     11                      0 Hematology*
Decreased lymphocytes                                  27                      3                     42                     11 Decreased leukocytes                                   23                      1                     53                     10 Decreased neutrophils                                  22                      1                     45                     17 Decreased hemoglobin                                   18                      1                     63                      8 Decreased platelets                                    17                      1                     20                      5 * The denominator used to calculate the rate varied from 63 to 214 (ELAHERE); 63 to 194 (IC Chemo) based on the number of patients with a baseline value and at least one post-treatment value.
Study 0417
The safety of ELAHERE was evaluated in Study 0417, a single-arm, open-label study in patients (n=106) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14)].
Patients received ELAHERE 6 mg/kg AIBW once every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7 to 13.3).
Serious adverse reactions occurred in 31% of patients treated with ELAHERE. The most common (≥2%) serious adverse reactions were intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%).
Permanent discontinuation of ELAHERE due to adverse reactions occurred in 11% of patients. The most common (≥2%) adverse reactions leading to permanent discontinuation were intestinal obstruction (2%) and thrombocytopenia (2%). One patient (0.9%) permanently discontinued ELAHERE due to visual impairment (unilateral decrease to BCVA < 20/200 that resolved to baseline after discontinuation).
Dosage delays of ELAHERE due to an adverse reaction occurred in 39% of patients treated with ELAHERE.
Adverse reactions which required dosage delays in ≥3% of patients included blurred vision (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%), and increased gamma-glutamyltransferase (3%).
Dose reductions of ELAHERE due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in ≥3% of patients included blurred vision (9%) and keratopathy (7%).
Table 6 summarizes the adverse reactions (≥10%) in patients treated with ELAHERE in Study 0417.
Table 6: Adverse Reactions (≥10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0417
Adverse Reaction                                  All Grades                             Grade 3-4 N=106                                 N=106
(%)                                  (%)
Eye disorders
Blurred Vision※                                       50                                     7 Keratopathy†                                          37                                     9 Dry eye‡                                              27                                     2 Cataract                                              18                                     3 Photophobia                                           17                                     0 §
Eye pain                                              10                                     0 General disorders
Fatigue                                               49                                     3 Gastrointestinal disorders
Nausea                                                40                                     0 Abdominal pain*                                       36                                     7 Diarrhea                                              31                                     3 Constipation                                          30                                     1 Vomiting                                              19                                     0 Abdominal distension                                  11                                     0 Nervous system disorders
Adverse Reaction                                            All Grades                                   Grade 3-4 N=106                                       N=106
(%)                                        (%)
Peripheral neuropathy¶                                            33                                            2 Metabolism and nutrition disorders
Decreased appetite                                                18                                            1 Musculoskeletal and connective tissue disorders
Arthralgia                                                        17                                            0 Myalgia                                                           10                                            0 Respiratory, thoracic, and mediastinal disorders
Dyspnea^                                                          12                                            0 ※ Blurred vision includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, and refraction disorder.
† Keratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis.
‡ Dry eye includes dry eye and lacrimation increased.
§ Eye pain includes eye pain and ocular discomfort.
⸙
Fatigue includes fatigue and asthenia.
* Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
¶
Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity.
^ Dyspnea includes dyspnea and exertional dyspnea.
Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0417 included infusion related reactions/hypersensitivity (9%), pneumonitis (8%), and uveitis (1%).
Table 7 summarizes the laboratory abnormalities in Study 0417.
Table 7: Select Laboratory Abnormalities ≥10% for All Grades, or ≥2% for Grades 3-4 in Patients Who Received ELAHERE
ELAHERE*
Laboratory Abnormality                                  All Grades                                     Grade 3-4 (%)                                          (%)
Liver Function Tests
Increased aspartate                                          50                                             2 aminotransferase
Increased alanine aminotransferase                           39                                             2 Increased alkaline phosphatase                               30                                             1 Hematology*
Decreased lymphocytes                                        35                                             7 Decreased leukocytes                                         26                                             1 Decreased neutrophils                                        26                                             3 Decreased hemoglobin                                         25                                             3 Decreased platelets                                          18                                             2 Chemistry
ELAHERE*
Laboratory Abnormality                                  All Grades                                     Grade 3-4 (%)                                          (%)
Decreased albumin                                            31                                             1 Decreased magnesium                                          27                                             2 Increased creatinine                                         16                                             0 Decreased potassium                                          15                                             4 * The denominator used to calculate the rate varied from 98 to 101 based on the number of patients with a baseline value and at least one post-treatment value.
Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions
In studies 0416, 0417, 0401, and 0403 in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received ELAHERE at 6 mg/kg AIBW administered intravenously once every 3 weeks, 9% (57/626) developed anti-drug antibodies. Infusion reactions (including bronchospasm, erythema, eyelid erythema, flushing, hypersensitivity, periorbital edema, rash, allergic rhinitis, face edema) occurred in 26% (15/57) of patients with anti-drug antibodies and in 7% (41/569) who did not develop anti-drug antibodies [see Clinical Pharmacology (12.6)].


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/

Effects on Driving