Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The table below provides a listing of adverse drug reactions with frequency based on all- causality data from clinical studies that enrolled more than 6,000 adult patients who received the recommended linezolid doses for up to 28 days.

Those most commonly reported were diarrhoea (8.9%), nausea (6.9%) , vomiting (4.3%) and headache (4.2%).


The most commonly reported drug-related adverse events which led to discontinuation of treatment were headache, diarrhoea, nausea and vomiting. About 3% of patients discontinued treatment because they experienced a drug-related adverse event.

Additional adverse reactions reported from post-marketing experience are included in the table

The following undesirable effects have been observed and reported during treatment with linezolid with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); Not known (cannot be estimated from the available data)


System Organ           Common               Uncommon                   Rare            Very Rare     Frequency not Class                  (≥1/100 to       (≥1/1,000 to <1/100)       (≥1/10,000 to       (<1/10,000)   known (cannot be <1/10)                                    <1/1,000)                         estimated from available data)
Infections and      candidiasis,        antibiotic-associated infestations        oral                colitis, including candidiasis,        pseudomembranous vaginal             colitis*,vaginitis candidiasis,
fungal infections
Blood and the       thrombocytope       pancytopenia*,             sideroblastic                     myelosuppression lymphatic           nia*,               leucopenia*,               anaemia*                          *, system disorders    anaemia*†           neutropenia,
eosinophilia
Immune system                                                      anaphylaxis disorders
Metabolism and                          hyponatraemia              lactic nutrition                                                          acidosis* disorders
Psychiatric         insomnia disorders
Nervous system      headache, taste     convulsions*,                                                serotonin disorders           perversion          peripheral                                                   syndrome**, (metallic taste),   neuropathy*,
dizziness           hypoaesthesia,
paraesthesia
Eye disorders                           optic neuropathy*,         changes in                        optic neuritis*, blurred vision*            visual field                      loss of vision*, defect*                           changes in visual acuity*, changes in colour vision*
Ear and                                 tinnitus labyrinth disorders
Cardiac                                 arrhythmia disorders                               (tachycardia)
Vascular            hypertension        transient ischaemic disorders                               attacks, phlebitis,
thrombophlebitis
Gastrointestinal    diarrhoea,          pancreatitis, gastritis,   superficial disorders           nausea,             abdominal distention,      tooth vomiting,           dry mouth, glossitis,      discolouration

System Organ           Common               Uncommon                  Rare             Very Rare     Frequency not Class                  (≥1/100 to       (≥1/1,000 to <1/100)      (≥1/10,000 to        (<1/10,000)   known (cannot be <1/10)                                   <1/1,000)                          estimated from available data) localised or       loose stools,
general            stomatitis, tongue abdominal          discolouration or pain,              disorder constipation,
dyspepsia
Hepato-biliary      abnormal liver     increased total disorders           function test,     bilirubin increased AST,
ALT or alkaline phosphatase
Skin and            pruritus, rash     angioedema,,               toxic                              alopecia subcutaneous                           urticaria, dermatitis      epidermal tissue disorders                       bullous, dermatitis,       necrolysis#, diaphoresis                Stevens-
Johnson syndrome#,
hypersensitivi ty vasculitis
Musculoskeletal                                                   rhabdomyolys and connective                                                    is* tissue disorders
Renal and           increased BUN      renal failure,
urinary                                increased creatinine,
disorders                              polyuria
Reproductive                           vulvovaginal disorder system and breast disorders
General             fever, localised   chills, fatigue,
disorders and       pain               injection site pain,
administration                         increased thirst site conditions
Investigations      Chemistry          Chemistry
Increased          Increased sodium or
LDH, creatine      calcium. Decreased kinase, lipase,    non fasting glucose.
amylase or non     Increased or fasting            decreased chloride.
glucose.
Decreased total protein,
albumin,
sodium or calcium.
Increased or decreased potassium or bicarbonate.

Haematology
Increased          Haematology

System Organ            Common               Uncommon                  Rare             Very Rare     Frequency not Class                   (≥1/100 to       (≥1/1,000 to <1/100)      (≥1/10,000 to        (<1/10,000)   known (cannot be <1/10)                                   <1/1,000)                          estimated from available data) neutrophils or     Increased eosinophils.       reticulocyte count.
Decreased          Decreased haemoglobin,       neutrophils.
haematocrit or red blood cell count.
Increased or decreased platelet or white blood cell counts.


* See section 4.4.
** See sections 4.3 and 4.5
# ADR frequency estimated using “The Rule of 3”
† See below
The following adverse reactions to linezolid were considered to be serious in rare cases: localised abdominal pain, transient ischaemic attacks and hypertension.
†
In controlled clinical trials where linezolid was administered for up to 28 days, 2.0% of the patients reported anaemia. In a compassionate use program of patients with life-threatening infections and underlying co-morbidities, the percentage of patients who developed anaemia when receiving linezolid for ≤ 28 days was 2.5% (33/1326) as compared with 12.3% (53/430) when treated for >28 days. The proportion of cases reporting drug-related serious anaemia and requiring blood transfusion was 9% (3/33) in patients treated for ≤ 28 days and 15% (8/53) in those treated for >28 days.

Paediatric population
The safety of ZYVOXID® formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients (birth through 11 years) with Grampositive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established.
Of the pediatric patients treated for uSSSIs, 19.2% of ZYVOXID® -treated and 14.1% of comparator- treated patients experienced at least one drug-related adverse event. For all other indications, 18.8% of ZYVOXID® -treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.
Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator- controlled Phase 3 trials.



Table 2. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in > 1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials
Uncomplicated Skin and Skin          All Other Indications†
ADVERSE REACTIONS                   Structure Infections*
Cefadroxil                    Vancomycin
ZYVOXID®             (n=251)     ZYVOXID®          (n=101)
(n=248)                          (n=215)

Diarrhoea                                7.8               8.0             10.8           12.1 Vomiting                                 2.9               6.4              9.4            9.1 Headache                                 6.5               4.0              0.9             0 Anaemia                                   0                 0               5.6            7.1 Thrombocytopenia                          0                 0               4.7            2.0 Nausea                                   3.7               3.2              1.9             0 Generalized abdominal pain               2.4               2.8              0.9            2.0 Localized abdominal pain                 2.4               2.8              0.5            1.0 Loose stools                             1.6               0.8              2.3            3.0 Eosinophilia                             0.4               0.8              1.9            1.0 Pruritus at non-application site         0.8               0.4              1.4            2.0 Vertigo                                  1.2               0.4               0              0 ®
* Patients 5 through 11 years of age received ZYVOXID 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received ZYVOXID® 600 mg by mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours.
†
Patients from birth through 11 years of age received ZYVOXID®10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance.

Of the pediatric patients treated for uSSSIs, 1.6% of ZYVOXID®-treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 0.9% of ZYVOXID®-treated and 6.1% of comparator-treated patients.
ZYVOXID® has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with ZYVOXID® and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with ZYVOXID® and 0.4% with cefadroxil. Thrombocytopenia associated with the use of ZYVOXID® appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for ZYVOXID®; the role of linezolid in these events cannot be determined [see section 4.4]. The incidence of pediatric patients with at least one substantially abnormal haematologic or serum chemistry value is presented in Table 3.

Table 3. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOXID® Uncomplicated Skin and Skin                 All Other Indications‡
†
Laboratory Assay                   Structure Infections
Cefadroxil                              Vancomycin
ZYVOXID®                               ZYVOXID®
Hemoglobin (g/dL)                  0.0                 0.0                 15.7               12.4 Platelet count (x 103/mm3)         0.0                 0.4                 12.9               13.4 WBC (x 103/mm3)                    0.8                 0.8                 12.4               10.3 Neutrophils (x 103/mm3)            1.2                 0.8                  5.9                4.3 *
<75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and <75% (<50% for neutrophils, <90% for hemoglobin if baseline 2 x Upper Limit of Normal (ULN) for values normal at baseline;

>2 x ULN and >2 x baseline for values abnormal at baseline.
† Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously  every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours.


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.