Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following adverse reactions are described in other labeling sections: o Anemia, Neutropenia and Thrombocytopenia [see Warnings and Precautions (5.2)] o Hepatotoxicity in Patients with Severe Pre-existing Hepatic Impairment [see Warnings and Precautions (5.3)]
 o Renal Toxicity [see Warnings and Precautions (5.4)]
 o Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]


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6.1 Clinical Trials Experirnce
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.

MDS

The data described below reflect exposure to Azacitidine in 443 patients with MDS from 4 clinical studies. Study 1 was a supportive-care controlled trial (subcutaneous administration), Studies 2 and 3 were single arm studies (one with subcutaneous administration and one with intravenous administration), and Study 4 was an international randomized trial (subcutaneous administration) [see Clinical Studies (12)].

In Studies 1, 2 and 3, a total of 268 patients were exposed to Azacitidine, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Azacitidine was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the intravenous study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m2.

In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to Azacitidine. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily Azacitidine doses of 75 mg/m2.

Most Commonly Occurring Adverse Reactions (Subcutaneous or Intravenous Route)in patients with MDS : nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by intravenous route also included petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (Subcutaneous or Intravenous Route) in patients with MDS:
Discontinuation: leukopenia, thrombocytopenia, neutropenia.
Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.
Dose Reduced: leukopenia, neutropenia, thrombocytopenia
Table 1 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine (subcutaneous) in Studies 1 and 2. It is important to note that duration of exposure was longer for the Azacitidine-treated group than for the observation group: patients received Azacitidine for a mean of 11.4 months while mean time in the observation arm was 6.1 months.
Table 1: Most Frequently Observed Adverse Reactions (≥ 5.0% in All
Subcutaneous Azacitidine Treated Patients; Studies 1 and 2)
Number (%) of Patients
System Organ Class                           All Azacitidineb           Observationc (N=2
Preferred Terma                                    20)                   (N=92) Blood and lymphatic system disorders
Anemia                                     153 (70)                    59   (64) Anemia aggravated                            12    (6)                  5    (5) Febrile neutropenia                          36 (16)                    4    (4) Leukopenia                                 106 (48)                    27   (29) Neutropenia                                  71 (32)                   10   (11) Thrombocytopenia                           144 (66)                    42   (46) Gastrointestinal disorders
Abdominal tenderness                         26 (12)                    1    (1) Constipation                                 74 (34)                    6    (7) Diarrhea                                     80 (36)                  13    (14) Gingival bleeding                            21 (10)                    4    (4) Loose stools                                 12    (6)                   0 Mouth hemorrhage                             11    (5)                  1    (1) Nausea                                     155 (71)                   16    (17) Stomatitis                                   17    (8)                   0 Vomiting                                   119 (54)                      5   (5) General disorders and administration site conditions
Chest pain                                   36 (16)                     5   (5) Injection site bruising                      31 (14)                     0 Injection site erythema                      77 (35)                     0 Injection site granuloma                     11    (5)                   0 Injection site pain                          50 (23)                     0 Injection site pigmentation changes          11    (5)                   0 Injection site pruritus                      15    (7)                   0 Injection site reaction                      30 (14)                     0 Injection site swelling                      11    (5)                   0 Lethargy                                     17    (8)                  2    (2) Malaise                                      24 (11)                    1    (1) Pyrexia                                    114 (52)                    28   (30) Infections and infestations
Nasopharyngitis                              32 (15)                     3   (3) Pneumonia                                    24 (11)                     5   (5) Upper respiratory tract infection            28 (13)                     4   (4) Injury, poisoning, and procedural complications
Post procedural hemorrhage                   13    (6)                   1   (1) Metabolism and nutrition disorders
Anorexia                                     45 (21)                     6   (7) Musculoskeletal and connective tissue disorders
Arthralgia                                   49 (22)                     3   (3) Chest wall pain                              11    (5)                   0 Myalgia                                      35 (16)                     2   (2) Nervous system disorders
Dizziness                                    41 (19)                    5    (5) Headache                                     48 (22)                  10    (11) Psychiatric disorders
Anxiety                                      29 (13)                     3   (3) Insomnia                                     24 (11)                     4   (4) Respiratory, thoracic and mediastinal disorders
Dyspnea                                      64 (29)                    11 (12) Table 1: Most Frequently Observed Adverse Reactions (≥ 5.0% in All Subcutaneous Azacitidine Treated Patients; Studies 1 and 2)
Number (%) of Patients
Observationc
System Organ Class Preferred Terma All Azacitidineb (N=220)                (N=92) Skin and subcutaneous tissue disorders
Dry skin                                      11 (5)                       1 (1) Ecchymosis                                    67 (31)                    14 (15) Erythema                                      37 (17)                    4 (4) Rash                                          31 (14)                    9 (10) Skin nodule                                      11 (5)                    1 (1) Urticaria                                     13 (6)                       1 (1) Vascular disorders
Hematoma                                      19 (9)                     0 Hypotension                                   15 (7)                     2 (2) Petechiae                                     52 (24)                      8 (9) a
Multiple terms of the same preferred terms for a patient are only counted once within each treatment group.
b Includes adverse reactions from all patients exposed to Azacitidine, including patients after crossing over from observations.
c Includes adverse reactions from observation period only; excludes any adverse events after crossover to Azacitidine.



Table 2 presents adverse reactions occurring in at least 5% of patients treated with Azacitidine in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with Azacitidine was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months).
Table 2: Most Frequently Observed Adverse Reactions (≥ 5.0% in the Azacitidine Treated Patients and the Percentage with NCI CTC Grade 3/4
Reactions; Study 4)
Number (%) of Patients
Any Grade                  Grade 3/4
Best                      Best
Azacitidin    Supportive Azacitidine Supportive e    Care Only        (N=175 Care Only
System Organ Class Preferred Terma (N=175)               (N=102)         )         (N=102) Blood and lymphatic system disorders
Anemia                                     90 (51)      45 (44)       24 (14)      9 (9) Febrile neutropenia                        24 (14)      10 (10)       22 (13)      7 (7) Leukopenia                                 32 (18)        2 (2)       26 (15)      1 (1) Neutropenia                               115 (66)      29 (28)      107 (61)     22 (22) Thrombocytopenia                          122 (70)      35 (34)      102 (58)     29 (28) Gastrointestinal disorders
Abdominal pain                   22 (13)        7 (7)        7 (4)      0 Constipation                               88 (50)        8 (8)        2 (1)      0 Dyspepsia                                   10 (6)        2 (2)        0          0 Nausea                                     84 (48)      12 (12)        3 (2)      0 Vomiting                                   47 (27)        7 (7)        0          0 General disorders and administration site conditions
Fatigue                                    42 (24)      12 (12)        6 (3)      2 (2) Injection site bruising                      9 (5)        0            0          0 Injection site erythema                    75 (43)        0            0          0 Injection site hematoma                     11 (6)        0            0          0 Injection site induration                    9 (5)        0            0          0 Injection site pain               33 (19)        0            0          0 Injection site rash                10 (6)        0            0          0 Injection site reaction                    51 (29)        0            1 (1)      0 Pyrexia                                    53 (30)      18 (18)        8 (5)      1 (1) Infections and infestations
Rhinitis                                    10 (6)        1 (1)        0          0 Upper respiratory tract infection           16 (9)        4 (4)        3 (2)      0 Urinary tract infection                     15 (9)        3 (3)        3 (2)      0 Investigations
Weight decreased                   14 (8)        0            1 (1)      0 Metabolism and nutrition disorders
Hypokalemia                                 11 (6)        3 (3)        3 (2)      3 (3) Nervous system disorders
Lethargy                                    13 (7)        2 (2)        0          1 (1) Psychiatric disorders
Anxiety                                      9 (5)        1 (1)        0          0 Insomnia                                    15 (9)        3 (3)        0          0 Renal and urinary disorders
Hematuria                                   11 (6)        2 (2)        4 (2)      1 (1) Respiratory, thoracic and mediastinal disorders
Dyspnea                                    26 (15)        5 (5)        6 (3)      2 (2) Dyspnea exertional                           9 (5)        1 (1)        0          0 Pharyngolaryngeal pain                      11 (6)        3 (3)        0          0 Skin and subcutaneous tissue disorders
Erythema                                    13 (7)        3 (3)        0          0 Petechiae                                  20 (11)        4 (4)        2 (1)      0 Pruritus                                   21 (12)        2 (2)        0          0 Rash                                       18 (10)        1 (1)        0          0 Vascular disorders
Hypertension                                15 (9)        4 (4)        2 (1)      2 (2) a
Multiple reports of the same preferred term from a patient were only counted once within each treatment.

In Studies 1, 2 and 4 with subcutaneous administration of Azacitidine, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of Azacitidine. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of subcutaneous treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.

Overall, adverse reactions were qualitatively similar between the intravenous and subcutaneous studies. Adverse reactions that appeared to be specifically associated with the intravenous route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage).

In clinical studies of either subcutaneous or intravenous Azacitidine, the following serious adverse reactions occurring at a rate of <5% (and not described in Tables 1 or 2) were reported: 
Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly.

Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy.

Eye disorders: eye hemorrhage

Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.

General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.

Hepatobiliary disorders: cholecystitis.

Immune system disorders: anaphylactic shock, hypersensitivity.
Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.

Metabolism and nutrition disorders: dehydration.

Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain.

Neoplasms benign, malignant and unspecified: leukemia cutis.

Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage.
Renal and urinary disorders: loin pain, renal failure.

Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress.
Skin and subcutaneous tissue disorders: pyoderma gangrenosum, pruritic rash, skin induration.

Surgical and medical procedures: cholecystectomy.

Vascular disorders: orthostatic hypotension.
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
 and e-mailed to the Registration Holder’s Patient Safety Unit at:

6.2 Post marketing Experience

The following adverse reactions have been identified during postmarketing use of Azacitidine.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
-       Interstitial lung disease
-       Tumor lysis syndrome
-       Injection site necrosis
-       Sweet’s syndrome (acute febrile neutrophilic dermatosis)
-       Necrotizing fasciitis (including fatal cases)


-       Differentiation syndrome

-       Pericardial effusion

-       Pericarditis


-       Cutaneous vasculitis


7 USE IN SPECIFIC POPULATIONS

7.1 Pregnancy

Risk Summary
Based on its mechanism of action and findings in animals, Azacitidine can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (10.1)]. There are no data on the use of Azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose (see Data). Advise pregnant women of the potential risk to the fetus.

The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Data
Animal Data
Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis) Azacitidine on gestation day 10.
Developmental abnormalities in the brain have been detected in mice given Azacitidine on or before gestation day 15 at doses of ~3- 12 mg/m2 (approximately 4%-16% the recommended human daily dose on a mg/m2 basis).

In rats, Azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation days 1- 3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study Azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

7.2      Lactation

Risk Summary
There is no information regarding the presence of Azacitidine in human milk, the effects of Azacitidine on the breastfed infant, or the effects of Azacitidine on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology (11)] and the potential for serious adverse reactions in nursing infants from Azacitidine, advise patients not to breastfeed during treatment with Azacitidine and for 1 week after the last dose.
7.3      Females and Males of Reproductive Potential
Based on its mechanism of action and findings in animals, Azacitidine can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (7.1)].

Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating AZADINE.

Contraception
Females
Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential to use effective contraception during treatment with AZADINE and for 6 months after the last dose..

Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with AZADINE and for 3 months after the last dose

Infertility
Based on animal data, Azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology (11)].


7.4     Pediatric Use
Safety and effectiveness of AZADINE in pediatric patients have not been established.

7.5      Geriatric Use
Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.

Of the 179 patients randomized to Azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients <65 years of age and patients 65 years of age and older.

Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see Dosage and Administration (3.6) and Warnings and Precautions (5.4)].