Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031, BN Haarlem, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The safety and efficacy of tedizolid phosphate in patients with neutropenia (neutrophil counts <1,000 cells/mm³) have not been investigated. In an animal model of infection, the antibacterial activity of tedizolid was reduced in the absence of granulocytes. The clinical relevance of this finding is unknown. Alternative therapies should be considered when treating patients with neutropenia and ABSSSI (see section 5.1).
Tedizolid inhibits mitochondrial protein synthesis. Adverse reactions such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur as a result of this inhibition. These events have been observed with another member of the oxazolidinone class when administered over a duration exceeding that recommended for tedizolid phosphate.
Decreased platelets, decreased haemoglobin and decreased neutrophils have been observed in a few subjects during treatment with tedizolid phosphate. In cases where tedizolid phosphate was discontinued, the affected haematological parameters have returned back to pre-treatment levels. Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients treated with another member of the oxazolidinone class and the risk of these effects appeared to be related to the duration of treatment.
Peripheral neuropathy, as well as optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with another member of the oxazolidinone class with treatment durations exceeding that recommended for tedizolid phosphate. Neuropathy (optic and peripheral) has not been reported in patients treated with tedizolid phosphate at the recommended treatment duration of 6 days. All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary.
Lactic acidosis has been reported with the use of another member of the oxazolidinone class. Lactic acidosis has not been reported in patients treated with tedizolid phosphate at the recommended treatment duration of 6 days.
Tedizolid phosphate should be administered with caution in patients known to be hypersensitive to other oxazolidinones since cross-hypersensitivity may occur.
Clostridioides difficile associated diarrhoea (CDAD) has been reported for tedizolid phosphate (see section 4.8). CDAD may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
CDAD must be considered in all patients who present with severe diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, tedizolid phosphate and, if possible, other antibacterial agents not directed against C. difficile should be discontinued and adequate therapeutic measures should be initiated immediately. Appropriate supportive measures, antibiotic treatment of C. difficile, and surgical evaluation should be considered. Medicinal products inhibiting peristalsis are contraindicated in this situation.
Tedizolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO) in vitro (see section 4.5).
Spontaneous reports of serotonin syndrome associated with the co-administration of another member of the oxazolidinone class together with serotonergic agents have been reported (see section 4.5).
There is no Phase 3 clinical experience in patients with co-administration of tedizolid phosphate with serotonergic agents such as selective serotonin re-uptake inhibitors [SSRI], serotonin norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, MAO inhibitors, triptans, and other medicines with potential adrenergic or serotonergic activity.
Prescribing tedizolid phosphate in the absence of a proven or strongly suspected bacterial infection increases the risk of the development of drug-resistant bacteria.
Tedizolid is generally not active against Gram-negative bacteria.
The safety and efficacy of tedizolid phosphate when administered for periods longer than 6 days have not been established.
In ABSSSI, the types of infections treated were confined to cellulitis/erysipelas or major cutaneous abscesses, and wound infections only. Other types of skin infections have not been studied.
There is limited experience with tedizolid phosphate in the treatment of patients with concomitant acute bacterial skin and skin structure infections and secondary bacteremia and no experience in the treatment of ABSSSI with severe sepsis or septic shock.
Controlled clinical studies did not include patients with neutropenia (neutrophil counts <1,000 cells/mm³) or severely immunocompromised patients.
In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (Breast Cancer Resistant Protein [BCRP] substrate) alone or in combination with tedizolid phosphate (once-daily 200 mg oral dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when coadministered with tedizolid phosphate. Therefore, orally administered tedizolid phosphate can result in inhibition of BCRP at the intestinal level. If possible, an interruption of the co-administered BCRP substrate medicinal product (such as imatinib, lapatinib, methotrexate, pitavastatin, rosuvastatin, sulfasalazine, and topotecan) should be considered during the 6 days of treatment with oral tedizolid phosphate.
In a clinical study comparing the single dose (2 mg) pharmacokinetics of midazolam (CYP3A4 substrate) alone or in combination with tedizolid phosphate (once-daily 200 mg oral dose for 10 days), midazolam AUC and Cmax when co-administered with tedizolid phosphate were 81% and 83% of midazolam AUC and Cmax when administered alone, respectively. This effect is not clinically meaningful, and no dose adjustment for co-administered CYP3A4 substrates is necessary during tedizolid phosphate treatment.
Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro; however, no interaction is anticipated when comparing the IC50 for MAO-A inhibition and the anticipated plasma exposures in man. Drug interaction studies to determine effects of 200 mg oral tedizolid phosphate at steady state on pseudoephedrine and tyramine pressor effects were conducted in healthy volunteers. No meaningful changes in blood pressure or heart rate with pseudoephedrine were observed in the healthy volunteers, and no clinically relevant increase in tyramine sensitivity was observed.
The potential for serotonergic interactions has not been studied in either patients or healthy volunteers (see section 5.2).
There are no data from the use of tedizolid phosphate in pregnant women. Studies in mice and rats showed developmental effects (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tedizolid phosphate during pregnancy.
It is unknown whether tedizolid phosphate or its metabolites are excreted in human milk. Tedizolid is excreted in the breast milk of rats (see section 5.3). A risk to the breast-feeding infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tedizolid phosphate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effects of tedizolid phosphate on fertility in humans have not been studied. Animal studies with tedizolid phosphate do not indicate harmful effects with respect to fertility (see section 5.3).
Sivextro may have a minor influence on the ability to drive and use machines as it may cause dizziness, fatigue or, uncommonly, somnolence (see section 4.8).
The most frequently reported adverse reactions occurring in patients receiving tedizolid phosphate in the pooled controlled Phase 3 clinical studies (tedizolid phosphate 200 mg once daily for 6 days) were nausea (6.9%), headache (3.5%), diarrhoea (3.2%) and vomiting (2.3%), and were generally mild to moderate in severity.
The safety profile was similar when comparing patients receiving intravenous tedizolid phosphate alone to patients who received oral administration alone, except for a higher reported rate of gastrointestinal disorders associated with oral administration.
The safety of tedizolid phosphate was evaluated in one Phase 3 clinical trial, which included 91 paediatric patients (12 to <18 years of age) with ABSSSI treated with IV and/or oral Sivextro 200 mg for 6 days and 29 patients treated with comparator agents for 10 days.
The following adverse reactions have been identified in two comparative pivotal Phase 3 studies in adults treated with Sivextro (Table 1). Increased ALT, increased AST and liver function tests abnormal were the only adverse drug reactions reported in one comparative Phase 3 study in patients 12 to <18 years of age. Adverse reactions are classified by preferred term and System Organ Class, and by frequency. Frequencies are defined as: 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).
Table 1. Frequency of adverse reactions by System Organ Class in Phase 3 comparative clinical studies:
Uncommon: Vulvovaginal mycotic infection, Fungal infection, Vulvovaginal candidiasis, Abscess, Clostridioides difficile colitis, Dermatophytosis, Oral candidiasis, Respiratory tract infection
Uncommon: Lymphadenopathy
Uncommon: Drug hypersensitivity
Uncommon: Dehydration, Diabetes mellitus inadequate control, Hyperkalaemia
Uncommon: Insomnia, Sleep disorder, Anxiety, Nightmare
Common: Headache, Dizziness
Uncommon: Somnolence, Dysgeusia, Tremor, Paraesthesia, Hypoaesthesia
Uncommon: Vision blurred, Vitreous floaters
Uncommon: Bradycardia
Uncommon: Flushing, Hot flush
Uncommon: Cough, Nasal dryness, Pulmonary congestion
Common: Nausea, Diarrhoea, Vomiting
Uncommon: Abdominal pain, Constipation, Abdominal discomfort, Dry mouth, Dyspepsia, Abdominal pain upper, Flatulence, Gastrooesophageal reflux disease, Haematochezia, Retching
Common: Pruritus generalised
Uncommon: Hyperhidrosis, Pruritus, Rash, Urticaria, Alopecia, Rash erythematous, Rash generalised, Acne, Pruritus allergic, Rash maculo-papular, Rash papular, Rash pruritic
Uncommon: Arthralgia, Muscle spasms, Back pain, Limb discomfort, Neck pain
Uncommon: Urine odor abnormal
Uncommon: Vulvovaginal pruritus
Common: Fatigue
Uncommon: Chills, Irritability, Pyrexia, Peripheral oedema
Uncommon: Grip strength decreased, Transaminases increased, White blood cell count decreased
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. Healthcare professionals are asked to report any suspected. adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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