Tedizolid Phosphate

Registered South African indications:

• Acute bacterial skin and skin structure infections (ABSSSI), caused by susceptible isolates of the following gram-positive microorganisms:
  Staphylococcus aureus, including
  - Methicillin-resistant (MRSA) and
  - Methicillin-susceptible (MSSA) isolates
  Streptococcus pyogenes
  Streptococcus agalactiae
  Streptococcus anginosus group, including
  - Streptococcus anginosus
  - Streptococcus intermedius
  - Streptococcus constellatus
  Enterococcus faecalis

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To reduce the development of drug-resistant bacteria and maintain the effectiveness of tedizolid phosphate prescribers should adhere to the principles of antibiotic stewardship.

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredient or to any of its excipients

Cautions

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding

Patients with neutropenia

• The efficacy and safety of tedizolid phosphate in patients with neutropenia (neutrophil counts <1 000 cells/mm³) have not been established
• In animal infection models, tedizolid's antibacterial effectiveness was diminished without granulocytes
• The relevance of this to human treatment is unclear, but alternative therapies should be considered for neutropenic patients with acute bacterial skin and skin structure infections (ABSSSI)

Mitochondrial dysfunction

• Tedizolid inhibits mitochondrial protein synthesis, which may lead to adverse reactions such as lactic acidosis, anaemia, and neuropathy (including optic and peripheral)
• Similar adverse effects have been observed with other members of the oxazolidinone class when used for durations exceeding those recommended for tedizolid phosphate

Myelosuppression

• Observations of thrombocytopenia, reduced haemoglobin, and decreased neutrophil counts have occurred during treatment with tedizolid phosphate
• Extended treatment durations beyond the recommended period have commonly been associated with these conditions
• Myelosuppression risks such as anaemia, leukopenia, and pancytopenia are known from other oxazolidinone class drugs and are linked to treatment length
• Regular monitoring and reassessment of the benefit-risk ratio are advised for patients who develop myelosuppression

Peripheral neuropathy and optic nerve disorders

• Cases of peripheral and optic neuropathy leading to vision loss have been reported with prolonged use of other oxazolidinone class drugs, 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
• Patients should immediately report symptoms such as visual changes or impairments. Prompt ophthalmologic evaluation is advised

Lactic acidosis

• Lactic acidosis instances have been reported with prolonged use of other drugs in the oxazolidinone class but not with tedizolid phosphate when used as recommended for 6 days

Hypersensitivity reactions

• Use tedizolid phosphate cautiously in patients with known hypersensitivity to oxazolidinones, due to potential cross-reactivity

Clostridioides difficile associated diarrhoea (CDAD)

• CDAD has been reported with tedizolid phosphate use, which can range from mild diarrhoea to fatal colitis
• Consider CDAD in all patients presenting with severe diarrhoea after antibiotic use. Discontinue tedizolid phosphate if CDAD is suspected or confirmed, and initiate appropriate treatment

Monoamine oxidase inhibition

• Tedizolid acts as a reversible, non-selective monoamine oxidase inhibitor in vitro

Serotonin syndrome

• Risk of serotonin syndrome when tedizolid is co-administered with serotonergic agents such as SSRIs, SNRIs, tricyclic antidepressants, MAO inhibitors, triptans, and other medicines with potential adrenergic or serotonergic activity
• No extensive Phase 3 clinical data on the co-administration of tedizolid with serotonergic drugs; caution is advised

Non-susceptible microorganisms

• Avoid prescribing tedizolid phosphate without confirmed or strongly suspected bacterial infection to prevent the development of drug-resistant bacteria
• Tedizolid is generally inactive against gram-negative bacteria

Additional recommendations in other jurisdictions

Limitations of clinical data

• Safety and efficacy of tedizolid phosphate for treatment durations exceeding 6 days have not been established
• Clinical trials for ABSSSI (acute bacterial skin and skin structure infections) only included cellulitis/erysipelas, major cutaneous abscesses, and wound infections; other skin infections have not been studied
• Limited experience in treating patients with concurrent ABSSSI and secondary bacteraemia; no experience in managing ABSSSI with severe sepsis or septic shock
• Controlled studies did not include patients with neutropenia (neutrophil counts <1 000 cells/mm³) or those who are severely immunocompromised

Sodium content (IV)

• This medicinal product contains less than 1 mmol sodium (23mg) per vial, effectively making it 'sodium-free' (IV)

Forms avail. in SA and covered in this monograph: fct, inj

South African registered indications and dosages

Acute bacterial skin and skin structure infections (ABSSSI) also known as complicated skin and soft tissue infections (cSSTI) or complicated skin and skin structure infections (cSSSI), caused by susceptible isolates of the following gram-positive microorganisms:
Staphylococcus aureus, including
- Methicillin-resistant (MRSA) and
- Methicillin-susceptible (MSSA) isolates
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group, including
- Streptococcus anginosus
- Streptococcus intermedius
- Streptococcus constellatus
Enterococcus faecalis

• IV: 200mg, once daily as an infusion over 60min; Treatment duration: 6 days
• Oral (tab): 200mg, once daily; Treatment duration: 6 days

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May be taken with or without food or drink

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Intravenous and oral formulations may be used interchangeably and no dose adjustment is necessary

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Missed doses: If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose

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For administration directions of tedizolid phosphate powder for solution for infusion, see Additional Prescribing Points

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• No adequate, well-controlled studies in pregnant women with tedizolid phosphate
• Embryo-foetal development studies in mice and rats showed no teratogenic effects at exposures 4-fold and 6-fold higher than human exposure levels
• Foetal developmental toxicities observed in both mice and rats included reduced foetal weights and skeletal abnormalities at high doses
• No observed adverse effect levels (NOAELs) for foetal toxicity in mice and for both maternal and foetal toxicity in rats were identified at lower doses, comparable to human therapeutic exposure
• No adverse maternal or offspring effects in rats treated with tedizolid phosphate during pregnancy and lactation at doses with plasma exposures equivalent to the human clinical dose

Recommendations in other jurisdictions

• Caution; not recommended
• 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

Breastfeeding

South African recommendations

• Caution; not recommended
• Mothers should not use tedizolid phosphate while breastfeeding their babies
• Tedizolid is excreted in the breast milk of rats. A risk to the breastfed infant cannot be excluded

Recommendations in other jurisdictions

• Caution
• 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 breastfeeding infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from tedizolid phosphate therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• 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

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended
  The clinical experience in patients ≥75 years is limited

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
• Upper abdominal pain
• Flatulence
• Gastroesophageal reflux disease
• Haematochezia
• Retching

Skin and Subcutaneous Tissue Disorders

Common

• Generalised pruritus

Uncommon

• Hyperhidrosis
• Pruritus
• Rash
• Urticaria
• Alopecia
• Erythematous rash
• Generalised rash
• Acne
• Allergic pruritus
• Maculo-papular rash
• Papular rash ​​​​​​​
• Pruritic rash ​​​​​​​

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Arthralgia
• Muscle spasms
• Back pain
• Limb discomfort
• Neck pain

Renal and Urinary Disorders

Uncommon

• Abnormal urine odour

Reproductive System and Breast Disorders

Uncommon

• Vulvovaginal pruritus

General Disorders and Administration Site Conditions

Common

• Fatigue
• Infusion site reactions (phlebitis)

Uncommon

• Chills
• Irritability
• Pyrexia
• Peripheral oedema
• Infusion site pain
• Infusion-related reaction

Investigations

Uncommon

• Grip strength decreased
• Increased transaminases
• Decreased white blood cell count

• Breast cancer resistant protein (BCRP) substrate
• Imatinib
• Lapatinib
• Methotrexate
• Pitavastatin
• Rosuvastatin
• Sulfasalazine
• Topotecan

• Baseline complete blood count (CBC) with differential

Administration of tedizolid phosphate powder for solution for infusion

• Administer as an intravenous infusion only
• Do not administer as an intravenous push or bolus. Do not mix tedizolid phosphate with other drugs when administering
• It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration
• The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration
• Discard if visible particles are observed
• The resulting solution is clear and colourless to pale-yellow in colour
• After reconstitution and dilution, tedizolid phosphate is to be administered via intravenous infusion using a total time of 1 hour
• The total time from reconstitution to administration should not exceed 24 hours at room temperature or under refrigeration at 2°C to 8°C

Tedizolid phosphate is an oxazolidinone phosphate prodrug. The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis. Tedizolid is primarily active against Gram-positive bacteria.

Spectrum of activity: Bacteriostatic against enterococci, staphylococci, and streptococci in vitro