SIVEXTRO 200mg powder for concentrate infusion solution medication leaflet

Sivextro 200 mg powder for concentrate for solution for infusion

Each vial contains disodium tedizolid phosphate corresponding to 200 mg tedizolid phosphate.

After reconstitution each mL contains 50 mg tedizolid phosphate.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white powder.

Sivextro is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) inadults and adolescents 12 years of age and older (see sections 4.4 and 5.1).

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

Tedizolid phosphate film-coated tablets or powder for concentrate for solution for infusion may beused as initial therapy. Patients who commence treatment on the parenteral formulation may beswitched to the oral presentation when clinically indicated.

Recommended dose and duration

The recommended dosage for adults and adolescents 12 years of age and older is 200 mg once dailyfor 6 days.

The safety and efficacy of tedizolid phosphate when administered for periods longer than 6 days havenot been established (see section 4.4).

If a dose is missed it should be given to the patient as soon as possible anytime up to 8 hours prior tothe next scheduled dose. If less than 8 hours remains before the next dose, then the physician shouldwait until the next scheduled dose. A double dose should not be given to compensate for a misseddose.

Elderly (≥65 years)

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

No dosage adjustment is required (see section 5.2).

No dosage adjustment is required (see section 5.2).

The safety and efficacy of tedizolid phosphate in children below 12 years of age have not yet beenestablished. Currently available data are described in section 5.2, but no recommendation on aposology for children below 12 years of age can be made.

Sivextro must be administered by intravenous infusion over a 60-minute period.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6

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

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 antibacterialactivity of tedizolid was reduced in the absence of granulocytes. The clinical relevance of this findingis unknown. Alternative therapies should be considered when treating patients with neutropenia and

ABSSSI (see section 5.1).

Tedizolid inhibits mitochondrial protein synthesis. Adverse reactions such as lactic acidosis, anaemiaand neuropathy (optic and peripheral) may occur as a result of this inhibition. These events have beenobserved with another member of the oxazolidinone class when administered over a durationexceeding that recommended for tedizolid phosphate.

Thrombocytopenia, decreased haemoglobin and decreased neutrophils have been observed duringtreatment with tedizolid phosphate. Anaemia, leucopenia and pancytopenia have been reported inpatients treated with another member of the oxazolidinone class and the risk of these effects appearedto be related to the duration of treatment.

Most cases of thrombocytopenia occurred with treatment lasting longer than the recommendedduration. 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 managementstrategies should be implemented.

Peripheral neuropathy and optic nerve disorders

Peripheral neuropathy, as well as optic neuropathy sometimes progressing to loss of vision, have beenreported in patients treated with another member of the oxazolidinone class with treatment durationsexceeding that recommended for tedizolid phosphate. Neuropathy (optic and peripheral) has not beenreported 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 visualacuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluationis 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. Lacticacidosis has not been reported in patients treated with tedizolid phosphate at the recommendedtreatment duration of 6 days.

Tedizolid phosphate should be administered with caution in patients known to be hypersensitive toother oxazolidinones since cross-hypersensitivity may occur.

Clostridioides difficile associated diarrhoea

Clostridioides difficile associated diarrhoea (CDAD) has been reported for tedizolid phosphate (seesection 4.8). CDAD may range in severity from mild diarrhoea to fatal colitis. Treatment withantibacterial 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 theadministration of antibacterial agents.

If CDAD is suspected or confirmed, tedizolid phosphate and, if possible, other antibacterial agents notdirected against C. difficile should be discontinued and adequate therapeutic measures should beinitiated immediately. Appropriate supportive measures, antibiotic treatment of C. difficile, andsurgical evaluation should be considered. Medicinal products inhibiting peristalsis are contraindicatedin this situation.

Monoamine oxidase inhibition

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

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with the co-administration of another memberof the oxazolidinone class together with serotonergic agents have been reported (see section 4.5).

There is no Phase 3 clinical experience in patients with co-administration of tedizolid phosphate withserotonergic agents such as selective serotonin re-uptake inhibitors [SSRI], serotonin norepinephrinereuptake inhibitors (SNRI), tricyclic antidepressants, MAO inhibitors, triptans, and other medicineswith potential adrenergic or serotonergic activity.

Non-susceptible microorganisms

Prescribing tedizolid phosphate in the absence of a proven or strongly suspected bacterial infectionincreases the risk of the development of drug-resistant bacteria.

Tedizolid is generally not active against Gram-negative bacteria.

Limitations of the clinical data

The safety and efficacy of tedizolid phosphate when administered for periods longer than 6 days havenot been established.

In ABSSSI, the types of infections treated were confined to cellulitis/erysipelas or major cutaneousabscesses, 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 concomitantacute bacterial skin and skin structure infections and secondary bacteraemia and no experience in thetreatment 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.

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

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-daily200 mg oral dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%,respectively, when coadministered with tedizolid phosphate. Therefore, orally administered tedizolidphosphate 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 oftreatment with oral tedizolid phosphate.

Monoamine oxidase inhibitors

Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro; however, no interaction isanticipated when comparing the IC50 for MAO-A inhibition and the anticipated plasma exposures inman. Drug interaction studies to determine effects of 200 mg oral tedizolid phosphate at steady stateon pseudoephedrine and tyramine pressor effects were conducted in healthy volunteers. Nomeaningful changes in blood pressure or heart rate with pseudoephedrine were observed in the healthyvolunteers, 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 section 5.2).

There are no data from the use of tedizolid phosphate in pregnant women. Studies in mice and ratsshowed developmental effects (see section 5.3). As a precautionary measure, it is preferable to avoidthe use of tedizolid phosphate during pregnancy.

It is unknown whether tedizolid phosphate or its metabolites are excreted in human milk. Tedizolid isexcreted in the breast milk of rats (see section 5.3). A risk to the breast-feeding infant cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom tedizolid phosphate therapy taking into account the benefit of breast-feeding for the child and thebenefit of therapy for the woman.

The effects of tedizolid phosphate on fertility in humans have not been studied. Animal studies withtedizolid phosphate do not indicate harmful effects with respect to fertility (see section 5.3).

Sivextro may have a minor influence on the ability to drive and use machines as it may causedizziness, fatigue or, uncommonly, somnolence (see section 4.8).

The most frequently reported adverse reactions occurring in patients receiving tedizolid phosphate inthe pooled controlled Phase 3 clinical studies (tedizolid phosphate 200 mg once daily for 6 days) werenausea (6.9%), headache (3.5%), diarrhoea (3.2%) and vomiting (2.3%), and were generally mild tomoderate in severity.

The safety profile was similar when comparing patients receiving intravenous tedizolid phosphatealone to patients who received oral administration alone, except for a higher reported rate ofgastrointestinal 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 withtedizolid phosphate 200 mg administered IV and/or oral once daily for 6 days, and 297 patients treatedwith linezolid 600 mg administered IV and/or oral every 12 hours for 10 days for ABSSSI. The safetyprofile 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 thelinezolid control group (0%), particularly among Asian patients. These findings suggest a higherfrequency of infusion related reactions (phlebitis) than was observed in previous clinical studies withtedizolid phosphate.

The safety of tedizolid phosphate was evaluated in one Phase 3 clinical trial, which included91 paediatric patients (12 to <18 years of age) with ABSSSI treated with IV and/or oral Sivextro200 mg for 6 days and 29 patients treated with comparator agents for 10 days.

The following adverse reactions have been identified in two comparative pivotal Phase 3 studies andone post-authorisation study in adults treated with Sivextro (Table 1). Increased ALT, increased ASTand 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/orpost-marketing use

System organ class Frequency Adverse reactions

Infections and infestations Uncommon: Vulvovaginal mycotic infection, fungal infection,vulvovaginal candidiasis, abscess, Clostridioidesdifficile colitis, dermatophytosis, oral candidiasis,respiratory tract infection

Blood and lymphatic system Uncommon: Lymphadenopathydisorders Not known*: Thrombocytopenia*

Immune system disorders Uncommon: Drug hypersensitivity

Metabolism and nutrition Uncommon: Dehydration, diabetes mellitus inadequate control,disorders 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 Uncommon: Cough, nasal dryness, pulmonary congestionmediastinal disorders

Gastrointestinal disorders Common: Nausea, diarrhoea, vomiting

Uncommon: Abdominal pain, constipation, abdominal discomfort,dry mouth, dyspepsia, abdominal pain upper,flatulence, gastrooesophageal reflux disease,haematochezia, retching

Skin and subcutaneous tissue Common: Pruritus generaliseddisorders Uncommon: Hyperhidrosis, pruritus, rash, urticaria, alopecia, rasherythematous, rash generalised, acne, pruritusallergic, rash maculo-papular, rash papular, rashpruritic

Musculoskeletal and Uncommon: Arthralgia, muscle spasms, back pain, limbconnective tissue disorders discomfort, neck pain

Renal and urinary disorders Uncommon: Urine odour abnormal

Reproductive system and Uncommon: Vulvovaginal pruritusbreast disorders

General disorders and Common: Fatigue, infusion site reactions (phlebitis)administration site conditions Uncommon: Chills, infusion site pain, irritability, pyrexia,infusion related reaction, 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 apopulation of uncertain size, it is not possible to reliably estimate their frequency which istherefore categorised as not known.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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. Thehighest single dose administered in clinical studies was 1,200 mg. All adverse reactions at this doselevel were mild or moderate in severity.

Pharmacotherapeutic group: Antibacterials for systemic use, other antibacterials, ATC code: J01XX11

Tedizolid phosphate is an oxazolidinone phosphate prodrug. The antibacterial activity of tedizolid ismediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of proteinsynthesis.

Tedizolid is primarily active against Gram-positive bacteria.

Tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci in vitro.

The most commonly observed mutations in staphylococci and enterococci that result in oxazolidinoneresistance are in one or more copies of the 23S rRNA genes (G2576U and T2500A). Organismsresistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomalproteins (L3 and L4) are generally cross-resistant to tedizolid.

A second resistance mechanism is encoded by a plasmid-borne and transposon associatedchloramphenicol-florfenicol resistance (cfr) gene, conferring resistance in staphylococci andenterococci to oxazolidinones, phenicols, lincosamides, pleuromutilins, streptogramin A and 16-membered macrolides. Due to a hydroxymethyl group in the C5 position, tedizolid retains activityagainst strains of Staphylococcus aureus that express the cfr gene in the absence of chromosomalmutations.

The mechanism of action is different from that of non-oxazolidinone class antibacterial medicinalproducts; therefore, cross-resistance between tedizolid and other classes of antibacterial medicinalproducts is unlikely.

Antibacterial activity in combination with other antibacterial and antifungal agents

In vitro drug combination studies with tedizolid and amphotericin B, aztreonam, ceftazidime,ceftriaxone, ciprofloxacin, clindamycin, colistin, daptomycin, gentamicin, imipenem, ketoconazole,minocycline, piperacillin, rifampicin, terbinafine, trimethoprim/sulfamethoxazole, and vancomycinindicate that neither synergy nor antagonism have been demonstrated.

Susceptibility testing breakpoints

Minimum inhibitory concentration (MIC) breakpoints determined by the European Committee on

Antimicrobial Susceptibility Testing (EUCAST) are:

Minimum Inhibitory Concentrations

Organisms (mg/L)

Susceptible (≤S) Resistant (R>)

Staphylococcus spp. 0.5 0.5

Beta haemolytic Streptococci of Groups A,B,C,G 0.5 0.5

Viridans group streptococci (Streptococcus anginosus0.25 0.25group only)

The AUC/MIC ratio was the pharmacodynamic parameter shown to best correlate with efficacy inmouse thigh and lung S. aureus infection models.

In a mouse thigh infection model of S. aureus, the antibacterial activity of tedizolid was reduced in theabsence of granulocytes. The AUC/MIC ratio to achieve bacteriostasis in neutropenic mice was atleast 16 times that in immunocompetent animals (see section 4.4).

Clinical efficacy against specific pathogens

Efficacy has been demonstrated in clinical studies against the pathogens listed under each indicationthat were susceptible to tedizolid in vitro.

Acute bacterial skin and skin structure infections

* Staphylococcus aureus

* Streptococcus pyogenes

* Streptococcus agalactiae

* Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus)

Antibacterial activity against other relevant pathogens

Clinical efficacy has not been established against the following pathogens although in vitro studiessuggest that they would be susceptible to tedizolid in the absence of acquired mechanisms ofresistance:

* Staphylococcus lugdunensis

The European Medicines Agency has deferred the obligation to submit the results of studies with

Sivextro in one or more subsets of the paediatric population in the treatment of acute bacterial skin andskin structure infections (see section 4.2 for information on paediatric use).

Oral and intravenous tedizolid phosphate is a prodrug that is rapidly converted by phosphatases totedizolid, the microbiologically active moiety. Only the pharmacokinetic profile of tedizolid isdiscussed in this section. Pharmacokinetic studies were conducted in healthy volunteers andpopulation pharmacokinetic analyses were conducted in patients from Phase 3 studies.

At steady state, tedizolid mean (SD) Cmax values of 2.2 (0.6) and 3.0 (0.7) mcg/mL and AUC values of25.6 (8.5) and 29.2 (6.2) mcg·h/mL were similar with oral and IV administration of tedizolidphosphate, respectively. The absolute bioavailability of tedizolid is above 90%. Peak plasma tedizolidconcentrations are achieved within approximately 3 hours after dosing after oral administration oftedizolid phosphate under fasted conditions.

Peak concentrations (Cmax) of tedizolid are reduced by approximately 26% and delayed by 6 hourswhen tedizolid phosphate is administered after a high-fat meal relative to fasted, while total exposure(AUC0-∞) is unchanged between fasted and fed conditions.

The average binding of tedizolid to human plasma proteins is approximately 70-90%.

The mean steady state volume of distribution of tedizolid in healthy adults (n=8) following a singleintravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L.

Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to themicrobiologically active moiety, tedizolid. Other than tedizolid, which accounts for approximately95% of the total radiocarbon AUC in plasma, there are no other significant circulating metabolites.

When incubated with pooled human liver microsomes, tedizolid was stable suggesting that tedizolid isnot a substrate for hepatic CYP450 enzymes. Multiple sulfotransferase (SULT) enzymes (SULT1A1,

SULT1A2, and SULT2A1) are involved in the biotransformation of tedizolid, to form an inactive andnon-circulating sulphate conjugate found in the excreta.

Tedizolid is eliminated in excreta, primarily as a non-circulating sulphate conjugate. Following singleoral administration of 14C-labeled tedizolid phosphate under fasted conditions, the majority ofelimination occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% inurine, with most of the elimination (>85%) occurring within 96 hours. Less than 3% of tedizolidphosphate administered dose is excreted as active tedizolid. The elimination half-life of tedizolid isapproximately 12 hours and the intravenous clearance is 6-7 L/h.

Tedizolid demonstrated linear pharmacokinetics with regard to dose and time. The Cmax and AUC oftedizolid increased approximately dose proportionally within the single oral dose range of 200 mg to1,200 mg and across the intravenous dose range of 100 mg to 400 mg. Steady-state concentrations areachieved within 3 days and indicate modest active substance accumulation of approximately 30%following multiple once-daily oral or intravenous administration as predicted by a half-life ofapproximately 12 hours.

Following administration of a single 200 mg IV dose of tedizolid phosphate to 8 subjects with severerenal impairment defined as eGFR <30 mL/min, the Cmax was basically unchanged and AUC0-∞ waschanged by less than 10% compared to 8 matched healthy subject controls. Haemodialysis does notresult in meaningful removal of tedizolid from systemic circulation, as assessed in subjects withend-stage renal disease (eGFR <15 mL/min). The eGFR was calculated using the MDRD4 equation.

Following administration of a single 200 mg oral dose of tedizolid phosphate, the pharmacokinetics oftedizolid are not altered in patients with moderate (n=8) or severe (n=8) hepatic impairment(Child-Pugh Class B and C).

Elderly population (≥ 65 years)

The pharmacokinetics of tedizolid in elderly healthy volunteers (age 65 years and older, with at least5 subjects at least 75 years old; n=14) was comparable to younger control subjects (25 to 45 years old;n=14) following administration of a single oral dose of tedizolid phosphate 200 mg.

The pharmacokinetics of tedizolid were evaluated in adolescents (12 to 17 years; n=20) followingadministration of a single oral or IV dose of tedizolid phosphate 200 mg and in adolescents (12 to<18 years; n=91) receiving tedizolid phosphate 200 mg IV or oral every 24 hours for 6 days. Theestimated mean Cmax and AUC0-24h at steady state for tedizolid in adolescents were 3.37 µg/mL and30.8 µg·h/mL which were similar to adults.

The impact of gender on the pharmacokinetics of tedizolid phosphate was evaluated in healthy malesand females in clinical studies and in a population pharmacokinetics analysis. The pharmacokinetics oftedizolid were similar in males and females.

Effects of other medicines on Sivextro

In vitro studies have shown that drug interactions between tedizolid and inhibitors or inducers ofcytochrome P450 (CYP) isoenzymes are unanticipated.

Multiple sulfotransferase (SULT) isoforms (SULT1A1, SULT1A2, and SULT2A1) were identified invitro that are capable of conjugating tedizolid which suggests that no single isozyme is critical to theclearance of tedizolid.

Effects of Sivextro on other medicines

Drug metabolising enzymes

In vitro studies in human liver microsomes indicate that tedizolid phosphate and tedizolid do notsignificantly inhibit metabolism mediated by any of the following CYP isoenzymes (CYP1A2,

CYP2C19, CYP2A6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4). Tedizolid did not alter activity ofselected CYP isoenzymes, but induction of CYP3A4 mRNA was observed in vitro in hepatocytes.

A clinical study comparing the single dose (2 mg) pharmacokinetics of midazolam (CYP3A4substrate) alone or in combination with tedizolid phosphate (once-daily 200 mg oral dose for 10 days),demonstrated no clinically meaningful difference in midazolam Cmax or AUC. No dose adjustment isnecessary for co-administered CYP3A4 substrates during treatment with Sivextro.

Membrane transporters

The potential for tedizolid or tedizolid phosphate to inhibit transport of probe substrates of importantdrug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gpand BCRP) was tested in vitro. No clinically relevant interactions are expected to occur with thesetransporters, with the administration of the parenteral formulation.

In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (BCRPsubstrate) alone or in combination with the oral administration of tedizolid phosphate 200 mg,rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, whencoadministered with Sivextro. Therefore, orally administered Sivextro can result in inhibition of

BCRP at the intestinal level.

Monoamine oxidase inhibition

Tedizolid is a reversible inhibitor of MAO in vitro; however, no interaction is anticipated whencomparing the IC50 and the anticipated plasma exposures in man. No evidence of MAO-A inhibitionwas observed in Phase 1 studies specifically designed to investigate the potential for this interaction.

Adrenergic agents

Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oraltedizolid phosphate at steady state to enhance pressor responses to pseudoephedrine and tyramine inhealthy individuals. No meaningful changes in blood pressure or heart rate were seen withpseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressureof ≥30 mmHg from pre-dose baseline was 325 mg with tedizolid phosphate compared to 425 mg withplacebo. Administration of Sivextro with tyramine-rich foods (i.e., containing tyramine levels ofapproximately 100 mg) would not be expected to elicit a pressor response.

Serotonergic agents

Serotonergic effects at doses of tedizolid phosphate up to 30-fold above the human equivalent dose didnot differ from vehicle control in a mouse model that predicts brain serotonergic activity. There arelimited data in patients on the interaction between serotonergic agents and tedizolid phosphate. In

Phase 3 studies, subjects taking serotonergic agents including antidepressants such as selectiveserotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine(5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.

Long-term carcinogenicity studies have not been conducted with tedizolid phosphate.

Repeated oral and intravenous dosing of tedizolid phosphate in rats in 1-month and 3-monthtoxicology studies produced dose- and time-dependent bone marrow hypocellularity (myeloid,erythroid, and megakaryocyte), with associated reduction in circulating RBCs, WBCs, and platelets.

These effects showed evidence of reversibility and occurred at plasma tedizolid exposure levels(AUC) ≥6-fold greater than the plasma exposure associated with the human therapeutic dose. In a1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown tosignificantly reduce splenic B cells and T cells and reduce plasma IgG titres. These effects occurred atplasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposureassociated with the therapeutic dose.

A special neuropathology study was conducted in pigmented Long Evans rats administered tedizolidphosphate daily for up to 9 months. This study used sensitive morphologic evaluation ofperfusion-fixed peripheral and central nervous system tissue. No evidence of neurotoxicity, includingneurobehavioral changes or optic or peripheral neuropathy, was associated with tedizolid after 1, 3, 6or 9 months of oral administration up to doses with plasma exposure levels (AUC) up to 8-fold greaterthan the expected human plasma exposure at the oral therapeutic dose.

Tedizolid phosphate was negative for genotoxicity in all in vitro assays (bacterial reverse mutation[Ames], Chinese hamster lung [CHL] cell chromosomal aberration) and in all in vivo tests (mousebone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolidphosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolidwas positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity inother in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrowmicronucleus assay.

Tedizolid phosphate had no adverse effects on the fertility or reproductive performance of male rats,including spermatogenesis, at oral doses up to the maximum tested dose of 50 mg/kg/day, or adultfemale rats at oral doses up to the maximum tested dose of 15 mg/kg/day. These dose levels equate toexposure margins of ≥ 5.3-fold for males and ≥ 4.2-fold for females relative to tedizolid plasma

AUC0-24 levels at the human oral therapeutic dose.

Embryo-foetal development studies in mice and rats showed no evidence of a teratogenic effect atexposure levels 4-fold and 6-fold, respectively, those expected in humans. In embryo-foetal studies,tedizolid phosphate was shown to produce foetal developmental toxicities in mice and rats. Foetaldevelopmental effects occurring in mice in the absence of maternal toxicity included reduced foetalweights and an increased incidence of costal cartilage fusion (an exacerbation of the normal geneticpredisposition to sternal variations in the CD-1 strain of mice) at the high dose of 25 mg/kg/day(4-fold the estimated human exposure level based on AUCs). In rats, decreased foetal weights andincreased skeletal variations including reduced ossification of the sternabrae, vertebrae, and skull wereobserved at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) andwere associated with maternal toxicity (reduced maternal body weights). The no observed adverseeffect levels (NOAELs) for foetal toxicity in mice (5 mg/kg/day) as well as maternal and foetaltoxicity in rats (2.5 mg/kg/day) were associated with tedizolid plasma area under the curve (AUC)values approximately equivalent to the tedizolid AUC value associated with the oral humantherapeutic dose.

Tedizolid is excreted into the milk of lactating rats and the concentrations observed similar to those inmaternal plasma.

Mannitol

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

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

3 years.

The combined storage time (from reconstitution to dilution to administration) must not exceed24 hours when stored at either room temperature or in a refrigerator (2°C - 8°C).

This medicinal product does not require any special storage conditions. For storage conditions afterreconstitution and dilution of the medicinal product, see section 6.3.

Type I (10 mL) clear borosilicate tubing glass vial with a siliconised grey chlorobutyl rubber stopper.

Available in packs of 1 vial and 6 vials.

Not all pack sizes may be marketed.

Sivextro vials are intended for single use only.

It must be administered as an intravenous infusion only. It must not be administered as an intravenousbolus.

Aseptic technique must be followed in preparing the infusion solution. The contents of the vial shouldbe reconstituted with 4 mL of water for injections, and be swirled gently until the powder hasdissolved entirely. Shaking or rapid movement should be avoided as it may cause foaming.

For administration, the reconstituted solution must be further diluted in 250 mL of sodium chloride0.9% solution for injection. The bag should not be shaken. The resulting solution is a clear colourlessor light-yellow solution and should be administered over approximately 1 hour.

Only limited data are available on the compatibility of Sivextro with other intravenous substances,therefore additives or other medicinal products should not be added to Sivextro single use vials orinfused simultaneously. If the same intravenous line is used for sequential infusion of several differentmedicinal products, the line should be flushed before and after infusion with 0.9% sodium chloride.

The reconstituted solution should be inspected visually for particulate matter prior to administration.

Reconstituted solutions containing visible particles should be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/15/991/002

EU/1/15/991/003

Date of first authorisation: 23 March 2015

Date of latest renewal: 09 January 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.