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 2,000 adult patients who received the recommended linezolid doses for up to 28 days.

Those most commonly reported were diarrhoea (8.4%), headache (6.5%),
nausea (6.3%) and vomiting (4.0%).

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 with frequency category ‘Not known’, since the actual frequency cannot be estimated from the available data.
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            Common        Uncommon                    Rare             Very Rare Frequency not Organ Class       (≥1/100       (≥1/1,000           to      (≥1/10,000       (<1/10,000 known (cannot to            <1/100)                     to               )          be    estimated <1/10)                                    <1/1,000)                   from available data)
Infections      candidiasi     vaginitis                   antibiotic- and             s,      oral                               associated infestations    candidiasi                                 colitis,
s, vaginal                                 including candidiasi                                 pseudomem s, fungal                                  br       anous infections                                 colitis*

Blood and       anaemia*†      leucopenia*,                pancytopenia                myelosuppressi the                            neutropenia,                *                           on lymphatic                      thrombocytopenia*,                                      *, system                         eosinophilia                                            sideroblastic disorders                                                                              anaemia* 
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Immune                                                                        anaphylaxis system disorders
Metabolism                        hyponatraemia                               lactic acidosis* and nutrition disorders
Psychiatric       insomnia disorders
Nervous           headache,       convulsions*,                               serotonin system            taste           hypoaesthesi                                syndrome** disorders         perversion      a,                                          , peripheral (metallic       paraesthesia                                neuropathy taste),                                                     * dizziness
Eye disorders                     blurred vision*            changes    in    optic visual  field    neuropathy*,
defect*          optic neuritis*,
loss of vision*,
changes        in visual acuity*,
changes in colour vision*
Ear and                           tinnitus labyrint h disorder s
Cardiac                           arrhythmia disorder                          (tachycardi s                                 a)
Vascula        hypertension       transient ischaemic r                                 attacks, phlebitis,
disorder                          thrombophlebitis s
Gastrointestin diarrhoea,         pancreatitis,          superficial al disorders   nausea,            gastritis, abdominal tooth vomiting,          distention,      dry discolouration localised     or   mouth,      glossitis,
general            loose         stools,
abdominal pain,
stomatitis, tongue constipation,
discolouration      or dyspepsia disorder
Hepato-biliary abnormal liver increased           total disorders      function     test; bilirubin increased AST,
ALT or alkaline phosphatase
Skin       and pruritus, rash     urticaria, dermatitis,                     bullous disorders subcutaneous                      diaphoresis                                such as those tissue                                                                       described      as disorders                                                                    Stevens-Johnson syndrome     and toxic epidermal necrolysis,
angioedema,
alopecia
Renal     and increased BUN renal         failure,
urinary                     increased disorders                   creatinine, polyuria

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Reproductive                        vulvovaginal system      and                     disorder breast disorders
General         fever, localised    chills,      fatigue,
disorders and pain                  injection site pain,
administration                      increased thirst site conditions
Investigations Chemistry            Chemistry
Increased LDH,      Increased sodium creatine kinase,    or        calcium.
lipase, amylase     Decreased      non or non fasting      fasting   glucose.
glucose.
Increased        or
Decreased total decreased chloride.
protein,
albumin,
sodium        or calcium.
Increased     or decreased potassium     or bicarbonate.

Haematology         Haematology
Increased           Increased neutrophils or      reticulocyte count.
eosinophils.
Decreased
Decreased neutrophils.
haemoglobin,
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
† 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 linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 Page 13 of 24
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 Gram- positive 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 linezolid-treated and 14.1% of comparator- treated patients experienced at least one drug-related adverse event. For all other indications, 18.8% of linezolid-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                All Other Indications†
ADVERSE REACTIONS                       Skin           Structure
Infections*
Linezoli         Cefadroxi         Linezoli       Vancomyci d                 l (n=251)        d              n
(n=248)                            (n=215)        (n=101)
Diarrhea                                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 Anemia                            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 linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received linezolid 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 linezolid 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 linezolid-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 linezolid-treated and 6.1% of comparator- treated patients. Linezolid has been associated with thrombocypenia 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 linezolid 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 
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substantially low platelet count was 0% with linezolid and 0.4% with cefadroxil.
Thrombocytopenia associated with the use of linezolid 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 linezolid; 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 hematologic 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 Linezolid
Uncomplicated Skin and Skin     All Other Indications‡
Laboratory Assay                 Structure Infections†
Linezolid       Cefadroxil  Linezolid      Vancomycin


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