4.1. Therapeutic indications

Sivextro tablets are indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in:

adults

adolescents and children weighing at least 35 kg.

See sections 4.4 and 5.1.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

Tedizolid phosphate tablets or powder for concentrate for solution for infusion may be used as initial therapy. Patients who commence treatment on the parenteral formulation may be switched to the oral presentation when clinically indicated.

The recommended dosage for adults, as well as adolescents and children weighing at least 35 kg is 200 mg once daily for 6 days.

If a dose is missed, it should be taken as soon as possible anytime up to 8 hours prior to the next scheduled dose. If less than 8 hours remains before the next dose, then the patient should wait until the next scheduled dose. Patients should not take a double dose to compensate for a missed dose.

Special populations

Elderly (≥65 years)

No dosage adjustment is required (see section 5.2). The clinical experience in patients ≥75 years is limited.

Hepatic impairment

No dosage adjustment is required (see section 5.2).

Renal impairment

No dosage adjustment is required (see section 5.2).

Paediatric population

Tedizolid phosphate 200 mg tablets are intended for adolescents and children weighing at least 35 kg. For adolescents and children weighing less than 35 kg, tedizolid phosphate powder for concentrate for solution for infusion is available.

Method of administration

For oral use. The film-coated tablets can be taken with or without food. The time to tedizolid peak concentration with oral administration under fasting conditions is 6 hours faster than when administered with a high-fat, high-calorie meal (see section 5.2). If a rapid antibiotic effect is needed, the intravenous administration should be considered.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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 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).

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 neutropenia (neutrophil counts < 1 000 cells/mm3) or severely immunocompromised patients.

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax 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.

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.

Pharmacodynamic interactions

Monoamine oxidase inhibition

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.

4.6. Fertility, pregnancy and lactation

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 respect to fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

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.

Tabulated list of adverse reactions

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); not known (cannot be estimated from the available data).

Table 1: Adverse reactions by body system and frequency reported in clinical trials and/or post-marketing use

System organ class

Frequency

Adverse reactions

Infections and infestations

Uncommon:

Vulvovaginal mycotic infection, fungal infection, vulvovaginal candidiasis, abscess, Clostridioides difficile colitis, dermatophytosis, oral candidiasis, respiratory tract infection

Blood and lymphatic system disorders

Uncommon:

Lymphadenopathy

Not known*:

Thrombocytopenia*

Immune system disorders

Uncommon:

Drug hypersensitivity

Metabolism and nutrition disorders

Uncommon:

Dehydration, diabetes mellitus inadequate control, hyperkalaemia

Psychiatric disorders

Uncommon:

Insomnia, sleep disorder, anxiety, nightmare

Nervous system disorders

Common:

Headache, dizziness

Uncommon:

Somnolence, dysgeusia, tremor, paraesthesia, hypoaesthesia

Eye disorders

Uncommon:

Vision blurred, vitreous floaters

Cardiac disorders

Uncommon:

Bradycardia

Vascular disorders

Uncommon:

Flushing, hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon:

Cough, nasal dryness, pulmonary congestion

Gastrointestinal disorders

Common:

Nausea, diarrhoea, vomiting

Uncommon:

Abdominal pain, constipation, abdominal discomfort, dry mouth, dyspepsia, abdominal pain upper, flatulence, gastro-oesophageal reflux disease, haematochezia, retching

Skin and subcutaneous tissue disorders

Common:

Pruritus generalised

Uncommon:

Hyperhidrosis, pruritus, rash, urticaria, alopecia, rash erythematous, rash generalised, acne, pruritus allergic, rash maculo-papular, rash papular, rash pruritic

Musculoskeletal and connective tissue disorders

Uncommon:

Arthralgia, muscle spasms, back pain, limb discomfort, neck pain

Renal and urinary disorders

Uncommon:

Urine odour abnormal

Reproductive system and breast disorders

Uncommon:

Vulvovaginal pruritus

General disorders and administration site conditions

Common:

Fatigue

Uncommon:

Chills, irritability, pyrexia, peripheral oedema

Investigations

Uncommon:

Grip strength decreased, transaminases increased, white blood cell count decreased

* 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of overdose, Sivextro should be discontinued and general supportive treatment given. Haemodialysis does not result in meaningful removal of tedizolid from systemic circulation. The highest single dose administered in clinical studies was 1 200 mg. All adverse reactions at this dose level were mild or moderate in severity.