SIVEXTRO Powder for concentrate for solution for infusion Ref.[9877] Active ingredients: Tedizolid

Patients with neutropenia

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 infec tion, 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).

Mitochondrial dysfunction

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.

Myelosuppression

Thrombocytopenia, decreased haemoglobin and decreased neutrophils have been observed during treatment with tedizolid phosphate. Anaemia, leucopenia and pancytopenia have 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.

Most cases of thrombocytopenia occurred with treatment lasting longer than the recommended duration. There may be an association with thrombocytopenia in patients with renal insufficiency. Patients who develop myelosuppression should be monitored and the benefit-risk should be re-evaluated. If treatment is continued, close monitoring of blood counts and appropriate management strategies should be implemented.

Peripheral neuropathy and optic nerve disorders

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

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.

Hypersensitivity reactions

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

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.

Monoamine oxidase inhibition

Tedizolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO) in vitro (see section 4.5).

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with the co-administration of oxazolidinones, including tedizolid phosphate, together with serotonergic agents (such as antidepressants and opioids) have been reported (see section 4.5).

Caution should be exercised when tedizolid is used with these medicinal products. Patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur, physicians should consider discontinuing either one or both agents.

Non-susceptible microorganisms

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.

Limitations of the clinical data

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 bacteraemia and no experience in the treatment of ABSSSI with severe sepsis or septic shock.

Controlled clinical studies did not include patients with n eutropenia (neutrophil counts <1 000 cells/mm³) or severely immunocompromised patients. Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

Pharmacokinetic interactions

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 C_max increased by approximately 70% and 55%, respectively, when co-administered 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.

Pharmacodynamic interactions

Monoamine oxidase inhibitors

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.

Potential serotonergic interactions

The potential for serotonergic interactions has not been studied in either patients or healthy volunteers (see sections 4.4 and 5.2).

Post-marketing experience: there have been reports of patients experiencing serotonin syndrome while taking tedizolid and serotonergic agents (antidepressants, opioids) which resolved on discontinuation of one or both medications.

Pregnancy

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.

Breast-feeding

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.

Fertility

The effects of tedizolid phosphate on fertility in humans have not been studied. Animal studies with tedizolid phosphate do not indicate harmful effects with res pect 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).

Summary of the safety profile

Adults

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.

Safety was additionally evaluated in a randomised, double-blind, multicenter study conducted in China, the Philippines, Taiwan, and the US, which included a total 292 adult patients treated with tedizolid phosphate 200 mg adminis tered IV and/or oral once daily for 6 days, and 297 patients treated with linezolid 600 mg administered IV and/or oral every 12 hours for 10 days for ABSSSI. The safety profile in this study was similar to the Phase 3 clinical trials; however, infusion site reactions(phlebitis) were reported more frequently (2.7%) in tedizolid phosphate treated subjects than in the linezolid control group (0%), particularly among Asian patients. These findings suggest a higher frequency of infusion related reacti ons (phlebitis) than was observed in previous clinical studies with tedizolid phosphate.

Tabulated list of adverse reactions

The following adverse reactions have been identified in two comparative pivotal Phase 3 studies and one post-authorisation study in adults treated with Sivextro (Table 2). 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); not known (cannot be estimated from the available data).

Table 2. Adverse reactions by body system and frequency reported in clinical trials and/or post-marketing use:

^* Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.

Paediatric population

In studies of paediatric patients from birth to <18 years of age, the safety profile of tedizolid phosphate was generally similar to the profile observed in adults.

The most common adverse reactions occurring in paediatric patients <18 years of age receiving tedizolid phosphate in the ABSSSI clinical trials were nausea (1.1%), vomiting (1.1%), and phlebitis (1.1%).

The safety of tedizolid phosphate in adolescents 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 safety of tedizolid phosphate (intravenously and/or orally) was also evaluated in 2 clinical trials that included multiple dosing of 83 children <12 years of age. These included 44 children 6 to <12 years of age receiving a median 9 days of dosing (range 1-12 days), 16 children 2 to <6 years of age receiving a median 9 days of dosing (range 2-14 days), 15 children 28 days to <2 years of age receiving a median 10 days of dosing (range 6-11 days), and 8 neonates <28 days of age (4 full-term and 4 preterm) receiving median 3 days of dosing (range 3 days).

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. Sivextro is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer’s Injection and Hartmann’s Solution.