Tedizolid

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.

The potential for serotonergic interactions has not been studied in either patients or healthy volunteers.

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.

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.

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.

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.

There are no data from the use of tedizolid phosphate in pregnant women. Studies in mice and rats showed developmental effects. 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. 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.

Tedizolid may have a minor influence on the ability to drive and use machines as it may cause dizziness, fatigue or, uncommonly, somnolence.

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 tedizolid. 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).

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 tedizolid 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).