4.1. Therapeutic indications

Tenkasi is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults and paediatric patients aged 3 months and older (see sections 4.2, 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

Adults

1 200 mg administered as a single dose by intravenous infusion over 3 hours.

Paediatric patients aged 3 months to < 18 years

15 mg/kg administered as a single dose by intravenous infusion over 3 hours (maximum 1 200 mg).

Please refer to Table 1 for relevant example, and to section 6.6 for further details.

Table 1: 15 mg/kg Body Weight Dose of Oritavancin: 3-Hour Infusion (Concentration of 1.2 mg/ml)

Patient's Weight (kg)

Calculated Oritavancin Dose (mg)

Total Infusion Volume

(ml)

Volume of Reconstituted Oritavancin (ml)

Volume of D5W to add to IV Bag (ml)

5

75

62.5

7.5

55

10

150

125

15

110

15

225

187.5

22.5

165

20

300

250

30

220

25

375

312.5

37.5

275

30

450

375

45

330

35

525

437.5

52.5

385

40

600

500

60

440

Special populations

Elderly (≥ 65 years)

No dose adjustment is required for patients ≥ 65 years of age (see section 5.2).

Renal impairment

No dose adjustment is needed in patients with mild or moderate renal impairment . Very limited data are available in patients with severe renal impairment. Renal impairment had no clinically relevant effect on the exposure of oritavancin (see section 5.2), however caution should be exercised when prescribing oritavancin in patients with severe renal impairment. Oritavancin is not removed from blood by haemodialysis procedures.

Hepatic impairment

No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). The pharmacokinetics of oritavancin in patients with severe hepatic impairment (Child-Pugh Class C) has not been evaluated, however based on pharmacokinetic parameters, severe hepatic impairment is not expected to have an impact on oritavancin exposure. Therefore no dose adjustment is required, even if caution should be exercised when prescribing oritavancin to patients with severe hepatic impairment (Child-Pugh Class C).

Paediatric population

The safety and efficacy of oritavancin in paediatric patients < 3 months of age have not yet been established.

Method of administration

Intravenous use.

There are two oritavancin medicinal products (Tenkasi 400 mg and Tenkasi 1 200 mg) that:

• Are supplied in different dose strengths of oritavancin.

• Have different recommended duration of infusion.

• Have different preparation instructions, including differences in reconstitution, dilution, and compatible diluents.

Carefully follow the recommended posology (see section 4.2) and the instructions on reconstitution and dilution for Tenkasi 400 mg before administration (see section 6.6).

Each of the three 400 mg vials should first be reconstituted with 40 mL of sterile water for injection (WFI). The reconstituted solutions should be withdrawn and added to a 1 000 mL glucose 5% intravenous bag (D5W) for an intravenous infusion over 3 hours (see section 6.6).

Only D5W should be used for dilution. Sodium chloride solution should not be used for dilution (see section 6.2)

Refer to Tenkasi 1 200 mg for relevant information on the other oritavancin medicinal product.

4.3. Contraindications

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

Use of intravenous unfractionated heparin sodium is contraindicated for 120 hours (5 days) after oritavancin administration, because the activated partial thromboplastin time (aPTT) test results may remain falsely elevated for up to 120 hours after oritavancin administration (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported with the use of oritavancin. If an acute hypersensitivity reaction occurs during oritavancin infusion, oritavancin should be discontinued immediately and appropriate supportive care should be instituted.

No data are available on cross-reactivity between oritavancin and other glycopeptides, including vancomycin. Before using oritavancin, it is important to inquire carefully about previous hypersensitivity reactions to glycopeptides (e.g. vancomycin, telavancin). Due to the possibility of cross-hypersensitivity, there should be careful monitoring of patients with any history of glycopeptide hypersensitivity during and after the infusion.

Infusion related reactions

Oritavancin is given via intravenous infusion over 3 hours, to minimise the risk of infusion-related reactions. Intravenous infusions of oritavancin can cause reactions such as flushing of the upper body, urticaria, pruritus and/or rash. Infusion-associated reactions characterised by chest pain, chest discomfort, chills, tremor, back pain, neck pain, dyspnoea, hypoxia, abdominal pain, and fever have been observed with the use of oritavancin, including after the administration of more than one dose of oritavancin during a single course of therapy. If reactions do occur, stopping or slowing the infusion may result in cessation of these symptoms (see section 4.8).

Need for additional antibacterial agents

Oritavancin is active against Gram-positive bacteria only (see section 5.1). In mixed infections where Gram-negative and/or certain types of anaerobic bacteria are suspected, oritavancin should be co-administered with appropriate antibacterial agent(s).

Concomitant use of warfarin

Oritavancin has been shown to artificially prolong prothrombin time (PT) and international normalised ratio (INR) for up to 12 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 12 hours after an oritavancin dose.

Interference with assay for coagulation tests

Oritavancin has been shown to interfere with certain laboratory coagulation tests (see sections 4.3 and 4.5). Oritavancin concentrations that are found in the blood of patients following administration of a single dose have been shown to artificially prolong:

• aPTT for up to 120 hours,

• PT and INR for up to 12 hours,

• Activated Clotting Time (ACT) for up to 24 hours,

• Silica Clot Time (SCT) for up to 18 hours, and

• Dilute Russell's Viper Venom Test (DRVVT) for up to 72 hours.

These effects result from oritavancin binding to and preventing the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. For patients who require aPTT monitoring within 120 hours of oritavancin dosing, a non-phospholipid-dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.

The Chromogenic Factor Xa Assay, the Thrombin Time (TT) assay and the assays, used for the diagnosis of Heparin Induced Thrombocytopenia (HIT) are not affected by oritavancin. In vitro, oritavancin 46.6 μg/mL did not affect an assay for activated protein C resistance (APCR), suggesting that there is a low likelihood that oritavancin will interfere with this test. However, APCR is a phospholipid-based test and it cannot be ruled out that higher concentrations of oritavancin that may occur during clinical use could interfere with this test.

No effect of oritavancin on the in vivo coagulation system was observed in nonclinical and clinical studies.

Clostridioides difficile-associated diarrhoea

Antibacterial-associated colitis and pseudomembranous colitis have been reported for oritavancin and may range in severity from mild to life threatening diarrhoea. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of oritavancin (see section 4.8). In such a circumstance, the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered.

Superinfection

The use of antibacterial medicinal products may increase the risk of overgrowth of non-susceptible micro-organisms. If superinfection occurs, appropriate measures should be taken.

Osteomyelitis

In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the oritavancin-treated arm than in the vancomycin-treated arm (see section 4.8). Patients should be monitored for signs and symptoms of osteomyelitis after administration of oritavancin. If osteomyelitis is suspected or diagnosed, appropriate alternative antibacterial therapy should be instituted.

Abscess

In the Phase 3 clinical trials, slightly more cases of newly emergent abscesses were reported in the oritavancin-treated arm than in the vancomycin-treated arm (4.6% vs 3.4%, respectively) (see section 4.8). If newly emergent abscesses occur, appropriate measures should be taken.

Limitations of the clinical data

In the two major trials in ABSSSI, the types of infections treated were confined to cellulitis, abscesses, and wound infection only. Other types of infections have not been studied. There is limited experience in clinical studies in patients with bacteraemia, peripheral vascular disease' or neutropenia, in immunocompromised patients, in patients aged > 65 years, in patients with severe renal impairment and in infections due to Streptococcus pyogenes.

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

Substances metabolised by cytochrome P450

A screening drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the concomitant administration of a single 1 200 mg dose of oritavancin with probe substrates for several CYP450 enzymes. Oritavancin was found to be a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or a weak inducer (CYP3A4 and CYP2D6) of several CYP isoforms.

Caution should be used when administering oritavancin concomitantly with medicinal products with a narrow therapeutic window that are predominantly metabolised by one of the affected CYP450 enzymes (e.g., warfarin), as co-administration may increase (e.g., for CYP2C9 substrates) or decrease (e.g., for CYP2D6 substrates) concentrations of the narrow therapeutic range medicinal product. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given oritavancin while on a potentially affected compound (e.g. patients should be monitored for bleeding, if concomitantly receiving oritavancin and warfarin) (see section 4.4). A study to assess the drug-drug interaction effect of a single 1 200 mg dose of oritavancin on the pharmacokinetics of S-warfarin following a single dose was conducted in 36 healthy subjects. S-warfarin pharmacokinetics were evaluated following a single dose of warfarin 25 mg given alone, or administered at the start, 24 or 72 hours after a single 1 200 mg dose of oritavancin. The results showed no effect of oritavancin on S-warfarin AUC and Cmax.

Drug-laboratory test interactions (see sections 4.3 and 4.4)

Oritavancin binds to and prevents the action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. Oritavancin concentrations achieved in the blood after 1 200 mg doses may produce falsely elevated results from certain laboratory tests (see Table 2).

Table 2: Coagulation tests affected by oritavancin

Assay

Duration of interference

Prothrombin time (PT)

Up to 12 hours

International normalized ratio (INR)

Up to 12 hours

Activated partial thromboplastin time (aPTT)

Up to 120 hours

Activated clotting time (ACT)

Up to 24 hours

Silica clot time (SCT)

Up to 18 hours

Dilute Russell's viper venom time (DRVVT)

Up to 72 hours

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of oritavancin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Tenkasi during pregnancy unless the clinical condition of the woman requires treatment with oritavancin.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of oritavancin in milk (for details see section 5.3). It is unknown whether oritavancin/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Tenkasi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies have revealed no evidence of impaired fertility due to oritavancin at the highest concentrations administered.However, there are no data on the effects of oritavancin on human fertility.

4.7. Effects on ability to drive and use machines

Tenkasi has a minor influence on the ability to drive and use machines. Dizziness may occur and this may have an effect on driving and use of machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions (≥5%) were: nausea, hypersensitivity reactions, infusion site reactions, and headache. The most commonly reported serious adverse reaction was cellulitis (1.1%). The most common reported reasons for discontinuation were cellulitis (0.4%) and osteomyelitis (0.3%). Female patients had a higher reporting rate for adverse reactions than male patients.

Tabulated list of adverse reactions

Adverse reactions for oritavancin from the pooled Phase 3 ABSSSI clinical trials with single- dose oritavancin are listed by system organ class in the following table.

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 <1/1000); very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Frequency of adverse reactions by system organ class

System organ class

Frequency

Adverse Reactions

Infections and infestations

Common

Cellulitis, abscess (limb and subcutaneous)

Uncommon

Osteomyelitis

Blood and lymphatic system disorders

Common

Anaemia

Uncommon

Eosinophilia, thrombocytopenia

Immune system disorders

Uncommon

Hypersensitivity (see sections 4.3 and 4.4), anaphylactic reaction

Unknown

Anaphylactic shock

Metabolism and nutrition disorders

Uncommon

Hypoglycaemia, hyperuricaemia

Nervous system disorders

Common

Headache, dizziness

Rare

Tremor*

Cardiac disorders

Common

Tachycardia

Respiratory, thoracic and mediastinal disorders

Uncommon

Bronchospasm, wheezing, dyspnoea*

Rare

Hypoxia*

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhoea, constipation

Uncommon

Abdominal pain*

Hepatobiliary disorders

Common

Liver function test abnormal (Alanine aminotransferase increased, Aspartate aminotransferase increased)

Uncommon

Blood bilirubin increased

Skin and subcutaneous tissue disorders

Common

Urticaria, rash, pruritus

Uncommon

Leucocytoclastic vasculitis, angioedema, erythema multiforme, flushing

Musculoskeletal and connective tissue disorders

Common

Myalgia

Uncommon

Tenosynovitis

Rare

Back pain*, neck pain*

General disorders and administration site conditions

Common

Infusion site reactions**

Uncommon

Chest pain*, pyrexia*

Rare

Chest discomfort*, chills*

*These reactions may be infusion-related (see section 4.4)

** Infusion site reactions includes: infusion site phlebitis, infusion site erythema, extravasation, induration, pruritus, rash, oedema peripheral.

Paediatric population

The safety assessment in paediatric patients is based on data from one trial in which 38 patients aged from 3 months to 18 years with suspected or confirmed Gram-positive bacterial infection received Tenkasi. Overall, the safety profile in these 38 patients was similar to that observed in the adult population. The following ADRs not reported in Table 3 for adult patients have been observed in no more than 1 paediatric patient: irritability, electrocardiogram QT prolonged (transient, asymptomatic and not associated to other ECG abnormalities), Clostridioides difficile colitis (see Section 4.4).

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

4.9. Overdose

In the clinical programme of 3017 oritavancin-treated subjects, there was no incidence of accidental overdose of oritavancin.

Oritavancin is not removed from blood by haemodialysis procedures. In the event of overdose, supportive measures should be taken.