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ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
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This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Sivextro 200 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 200 mg tedizolid phosphate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Oval (13.8 mm long by 7.4 mm wide) yellow film-coated tablet debossed with “TZD” on the obverse
side and “200” on the reverse side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Sivextro is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in
adults (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 film-coated 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.
Recommended dose and duration
The recommended dosage is 200 mg once daily for 6 days.
The safety and efficacy of tedizolid phosphate when administered for periods longer than 6 days have
not been established in patients (see section 4.4).
Missed dose
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.
Elderly (≥65 years)
No dosage adjustment is required (see section 5.2). The clinical experience in patients ≥75 years is
limited.
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Hepatic impairment
No dosage adjustment is required (see section 5.2).
Renal impairment
No dosage adjustment is required (see section 5.2).
Paediatric population
The safety and efficacy of tedizolid phosphate in children and adolescents below 18 years of age have
not yet been established. Currently available data are described in section 5.2, but no recommendation
on a posology can be made.
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 phosphate 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 Sivextro.
Myelosuppression
Decreased platelets, decreased haemoglobin and decreased neutrophils have been observed in a few
subjects during treatment with tedizolid phosphate. In cases where tedizolid was discontinued, the
affected haematological parameters have returned back to pre-treatment levels. Myelosuppression
(including anaemia, leucopenia, pancytopenia and thrombocytopenia) has 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.
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 Sivextro. 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
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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.
Clostridium difficile associated diarrhoea
Clostridium 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 another member
of 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 Sivextro with
serotonergic agents such as selective serotonin re-uptake inhibitors [SSRI], serotonin norepinephrine
reuptake inhibitors (SNRI), tricyclic antidepressants, MAO inhibitors, triptans, and other medications
with potential adrenergic or serotonergic activity.
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 phosphate 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 have
not been established.
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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 bacteremia 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 Sivextro (once-daily 200 mg oral
dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when
coadministered with Sivextro. Therefore, orally administered Sivextro 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 six days of treatment with oral Sivextro.
In a clinical study comparing the single dose (2 mg) pharmacokinetics of midazolam (CYP3A4
substrate) alone or in combination with Sivextro (once-daily 200 mg oral dose for 10 days),
midazolam AUC and Cmax when co-administered with Sivextro 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 Sivextro 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 Sivextro 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 section 5.2).
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 Sivextro therapy taking into account the benefit of breast-feeding for the child and the benefit of
therapy for the woman.
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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
No studies on the effects on the ability to drive and use machines have been performed. 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
The safety of tedizolid phosphate has been evaluated in a total of 1,485 subjects receiving at least one
dose of tedizolid phosphate administered either orally or intravenously. The primary safety database is
the Phase 3 clinical studies in which 662 subjects received 200 mg tedizolid phosphate orally and or
intravenously (331/662 patients) for a maximum of 6 days.
Approximately 22.4% of patients treated with Sivextro in Phase 3 clinical studies (n= 662)
experienced at least one treatment-emergent adverse reaction. The most frequently reported adverse
reactions occurring in patients receiving tedizolid phosphate in the pooled controlled Phase 3 clinical
studies (tedizolid 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.
Tabulated list of adverse reactions
The following adverse reactions have been identified in two comparative pivotal Phase 3 studies with
Sivextro (Table 1). The safety profile was similar when comparing patients receiving intravenous
Sivextro alone to patients who received oral administration alone, except for a higher reported rate of
gastrointestinal disorders associated with oral administration. 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).
Table 1 Frequency of adverse reactions by System Organ Class in pooled Phase 3
comparative clinical studies
System Organ Class Common Uncommon
Infections and infestations Vulvovaginal mycotic infection
Fungal infection
Vulvovaginal candidiasis
Abscess
Clostridium difficile colitis
Dermatophytosis
Oral candidiasis
Respiratory tract infection
Blood and lymphatic system
disorders
Lymphadenopathy
Immune system disorders Drug hypersensitivity
Metabolism and nutrition disorders Dehydration
Diabetes mellitus inadequate
control
Hyperkalaemia
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System Organ Class Common Uncommon
Psychiatric disorders Insomnia
Sleep disorder
Anxiety
Nightmare
Nervous system disorders Headache Somnolence
Dizziness Dysgeusia
Tremor
Paraesthesia
Hypoaesthesia
Eye disorders Vision blurred
Vitreous floaters
Cardiac disorders Bradycardia
Vascular disorders Flushing
Hot flush
Respiratory, thoracic and
mediastinal disorders
Cough
Nasal dryness
Pulmonary congestion
Gastrointestinal disorders Nausea Abdominal pain
Diarrhoea Constipation
Vomiting Abdominal discomfort
Dry mouth
Dyspepsia
Abdominal pain upper
Flatulence
Gastrooesophageal reflux
disease
Haematochezia
Retching
Skin And subcutaneous tissue
disorders
Pruritus
Generalised
Hyperhidrosis
Pruritus
Rash
Urticaria
Alopecia
Rash erythematous
Rash generalised
Acne
Pruritus allergic
Rash maculo-papular
Rash papular
Rash pruritic
Musculoskeletal and connective
tissue disorders
Arthralgia
Muscle spasms
Back pain
Limb discomfort
Neck pain
Renal and urinary disorders Urine odor abnormal
Reproductive and breast disorders Vulvovaginal pruritus
General disorders and
administration site conditions
Fatigue Chills
Irritability
Pyrexia
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System Organ Class Common Uncommon
Peripheral oedema
Investigations Grip strength decreased
Transaminases increased
White blood cell count decreased
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 national reporting system
listed in Appendix V.
4.9 Overdose
In the event of overdose, Sivextro should be discontinued and general supportive treatment given.
Hemodialysis 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code:
J01XX11
Mechanism of action
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.
Tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci in vitro.
Resistance
The most commonly observed mutations in staphylococci and enterococci that result in oxazolidinone
resistance are in one or more copies of the 23S rRNA genes (G2576U and T2500A). Organisms
resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal
proteins (L3 and L4) are generally cross-resistant to tedizolid.
A second resistance mechanism is encoded by a plasmid-borne and transposon associated
chloramphenicol-florfenicol resistance (cfr) gene, conferring resistance in staphylococci and
enterococci to oxazolidinones, phenicols, lincosamides, pleuromutilins, streptogramin A and
16-membered macrolides. Due to a hydroxymethyl group in the C5 position, tedizolid retains activity
against strains of Staphylococcus aureus that express the cfr gene in the absence of chromosomal
mutations.
The mechanism of action is different from that of non-oxazolidinone class antibacterial medicinal
products; therefore, cross-resistance between tedizolid and other classes of antibacterial medicinal
products is unlikely.
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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 vancomycin
indicate 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:
Organisms
Minimum Inhibitory Concentrations
(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 anginosus
group only) 0.25 0.25
Pharmacokinetic/pharmacodynamic relationship
The AUC/MIC ratio was the pharmacodynamic parameter shown to best correlate with efficacy in
mouse thigh and lung S. aureus infection models.
In a mouse thigh infection model of S. aureus, the antibacterial activity of tedizolid was reduced in the
absence of granulocytes. The AUC/MIC ratio to achieve bacteriostasis in neutropenic mice was at
least 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 indication
that 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 studies
suggest that they would be susceptible to tedizolid in the absence of acquired mechanisms of
resistance:
• Staphylococcus lugdunensis
Paediatric population
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 and
skin structure infections (see section 4.2 for information on paediatric use).
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5.2 Pharmacokinetic properties
Oral and intravenous tedizolid phosphate is a prodrug that is rapidly converted by phosphatases to
tedizolid, the microbiologically active moiety. Only the pharmacokinetic profile of tedizolid is
discussed in this section. Pharmacokinetic studies were conducted in healthy volunteers and
population pharmacokinetic analyses were conducted in patients from Phase 3 studies.
Absorption
At steady state, tedizolid mean (SD) Cmax values of 2.2 (0.6) and 3.0 (0.7) mcg/mL and AUC values of
25.6 (8.5) and 29.2 (6.2) mcg·h/mL were similar with oral and IV administration of tedizolid
phosphate, respectively. The absolute bioavailability of tedizolid is above 90%. Peak plasma tedizolid
concentrations are achieved within approximately 3 hours after dosing after oral administration of
Sivextro under fasted conditions.
Peak concentrations (Cmax) of tedizolid are reduced by approximately 26% and delayed by 6 hours
when tedizolid phosphate is administered after a high-fat meal relative to fasted, while total exposure
(AUC0-∞) is unchanged between fasted and fed conditions.
Distribution
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 single
intravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L.
Biotransformation
Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to the
microbiologically active moiety, tedizolid. Other than tedizolid, which accounts for approximately
95% 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 is
not 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 and
non-circulating sulphate conjugate found in the excreta.
Elimination
Tedizolid is eliminated in excreta, primarily as a non-circulating sulfate conjugate. Following single
oral administration of 14C-labeled Sivextro under fasted conditions, the majority of elimination
occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% in urine, with
most of the elimination (>85%) occurring within 96 hours. Less than 3% of Sivextro administered
dose is excreted as active tedizolid. The elimination half-life of tedizolid is approximately 12 hours
and the intravenous clearance is 6-7 L/h.
Linearity/non-linearity
Tedizolid demonstrated linear pharmacokinetics with regard to dose and time. The Cmax and AUC of
tedizolid increased approximately dose proportionally within the single oral dose range of 200 mg to
1,200 mg and across the intravenous dose range of 100 mg to 400 mg. Steady-state concentrations are
achieved 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 of
approximately 12 hours.
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Special populations
Renal impairment
Following administration of a single 200 mg IV dose of Sivextro to 8 subjects with severe renal
impairment defined as eGFR <30 mL/min, the Cmax was basically unchanged and AUC0-∞ was changed
by less than 10% compared to 8 matched healthy subject controls. Hemodialysis does not result in
meaningful removal of tedizolid from systemic circulation, as assessed in subjects with end-stage renal
disease (eGFR <15 mL/min). The eGFR was calculated using the MDRD4 equation.
Hepatic impairment
Following administration of a single 200 mg oral dose of Sivextro, the pharmacokinetics of tedizolid
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 least
5 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 Sivextro 200 mg.
Paediatric population
The pharmacokinetics of tedizolid were evaluated in adolescent subjects (12 to 17 years; n=20)
following administration of a single oral or IV dose of Sivextro 200 mg. The mean Cmax and AUC0-∞
for oral or IV administration of tedizolid 200 mg were similar in adolescent and in healthy adult
subjects.
Gender
The impact of gender on the pharmacokinetics of Sivextro was evaluated in healthy males and females
in clinical studies and in a population pharmacokinetics analysis. The pharmacokinetics of tedizolid
were similar in males and females.
Drug interaction studies
Effects of Other Medicines on Sivextro
In vitro studies have shown that drug interactions between tedizolid and inhibitors or inducers of
cytochrome P450 (CYP) isoenzymes are unanticipated.
Multiple sulfotransferase (SULT) isoforms (SULT1A1, SULT1A2, and SULT2A1) were identified in
vitro that are capable of conjugating tedizolid which suggests that no single isozyme is critical to the
clearance of tedizolid.
Effects of Sivextro on Other Medicines
Drug metabolizing enzymes
In vitro studies in human liver microsomes indicate that tedizolid phosphate and tedizolid do not
significantly inhibit metabolism mediated by any of the following CYP isoenzymes (CYP1A2,
CYP2C19, CYP2A6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4). Tedizolid did not alter activity of
selected 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 (CYP3A4
substrate) alone or in combination with Sivextro (once-daily 200 mg oral dose for 10 days),
demonstrated no clinically meaningful difference in midazolam Cmax or AUC. No dose adjustment is
necessary 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 important
drug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gp
and BCRP) was tested in vitro. No clinically relevant interactions are expected to occur with these
transporters, with the exception of BCRP.
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In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (BCRP
substrate) alone or in combination with the oral administration of Sivextro film-coated tablets,
rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when
coadministered with Sivextro (see section 4.5).
Monoamine oxidase inhibition
Tedizolid is a reversible inhibitor of MAO in vitro; however, no interaction is anticipated when
comparing the IC50 and the anticipated plasma exposures in man. No evidence of MAO-A inhibition
was 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 oral
tedizolid phosphate at steady state to enhance pressor responses to pseudoephedrine and tyramine in
healthy individuals. No meaningful changes in blood pressure or heart rate were seen with
pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure
of ≥30 mmHg from pre-dose baseline was 325 mg with Sivextro compared to 425 mg with placebo.
Administration of Sivextro with tyramine-rich foods (i.e., containing tyramine levels of approximately
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 did
not differ from vehicle control in a mouse model that predicts brain serotonergic activity. There are
limited data in patients on the interaction between serotonergic agents and tedizolid phosphate. In
Phase 3 studies, subjects taking serotonergic agents including antidepressants such as selective
serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine
(5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.
5.3 Preclinical safety data
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-month
toxicology 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 a
1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to
significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at
plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure
associated with the therapeutic dose.
A special neuropathology study was conducted in pigmented Long Evans rats administered tedizolid
phosphate daily for up to 9 months. This study used sensitive morphologic evaluation of
perfusion-fixed peripheral and central nervous system tissue. No evidence of neurotoxicity, including
neurobehavioral changes or optic or peripheral neuropathy, was associated with tedizolid after 1, 3, 6
or 9 months of oral administration up to doses with plasma exposure levels (AUC) up to 8-fold greater
than 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 (mouse
bone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolid
phosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolid
was positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity in
other in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrow
micronucleus assay.
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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 adult
female rats at oral doses up to the maximum tested dose of 15 mg/kg/day. These dose levels equate to
exposure 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 at
exposure 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. Foetal
developmental effects occurring in mice in the absence of maternal toxicity included reduced foetal
weights and an increased incidence of costal cartilage fusion (an exacerbation of the normal genetic
predisposition 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 and
increased skeletal variations including reduced ossification of the sternabrae, vertebrae, and skull were
observed at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) and
were associated with maternal toxicity (reduced maternal body weights). The no observed adverse
effect levels (NOAELs) for foetal toxicity in mice (5 mg/kg/day) as well as maternal and foetal
toxicity 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 human
therapeutic dose.
Tedizolid is excreted into the milk of lactating rats and the concentrations observed were similar to
those in maternal plasma.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Mannitol
Povidone
Crospovidone
Magnesium stearate
Film coat
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol
Talc
Yellow iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
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6.5 Nature and contents of container
6 × 1 tablets in aluminum/Polyethylene Terephthalate (PET)/Paper foil and polyvinyl chloride
(PVC)/polyvinylidene chloride (PVdC) clear film perforated child-resistant unit-dose blisters.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/15/991/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23 March 2015
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
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This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Sivextro 200 mg powder for concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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.
3. PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion (powder for concentrate).
White to off-white powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Sivextro is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in
adults (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 film-coated 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 one when clinically indicated.
Recommended dose and duration
The recommended dosage is 200 mg once daily for 6 days.
The safety and efficacy of tedizolid phosphate when administered for periods longer than 6 days have
not been established in patients (see section 4.4).
Missed dose
If a dose is missed it should be given to the patient 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 physician should
wait until the next scheduled dose. A double dose should not be given to compensate for a missed
dose.
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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
The safety and efficacy of tedizolid phosphate in children and adolescents below 18 years of age have
not yet been established. Currently available data are described in section 5.2, but no recommendation
on a posology can be made.
Method of administration
Sivextro must be administered by intravenous infusion over a 60-minute period.
For instructions on reconstitution and dilution of the medicinal product before administration, see
section 6.6
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 phosphate 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 Sivextro.
Myelosuppression
Decreased platelets, decreased haemoglobin and decreased neutrophils have been observed in a few
subjects during treatment with tedizolid phosphate. In cases where tedizolid was discontinued, the
affected haematological parameters have returned back to pre-treatment levels. Myelosuppression
(including anaemia, leucopenia, pancytopenia and thrombocytopenia) has 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.
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 Sivextro. Neuropathy (optic and peripheral) has not been reported in
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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.
Clostridium difficile associated diarrhoea
Clostridium 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 another member
of 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 Sivextro with
serotonergic agents such as selective serotonin re-uptake inhibitors [SSRI], serotonin norepinephrine
reuptake inhibitors (SNRI), tricyclic antidepressants, MAO inhibitors, triptans, and other medications
with potential adrenergic or serotonergic activity.
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 phosphate is generally not active against Gram-negative bacteria.
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Limitations of the clinical data
The safety and efficacy of tedizolid phosphate when administered for periods longer than 6 days have
not been established.
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 bacteremia 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 Sivextro (once-daily 200 mg oral
dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when
coadministered with Sivextro. Therefore, orally administered Sivextro 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 six days of treatment with oral Sivextro.
Pharmacodynamic interactions
Monoamine oxidase inhibitors
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 Sivextro 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 section 5.2).
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 Sivextro therapy taking into account the benefit of breast-feeding for the child and the benefit of
therapy for the woman.
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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
No studies on the effects on the ability to drive and use machines have been performed. 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
The safety of tedizolid phosphate has been evaluated in a total of 1,485 subjects receiving at least one
dose of tedizolid phosphate administered either orally or intravenously. The primary safety database is
the Phase 3 clinical studies in which 662 subjects received 200 mg tedizolid phosphate orally and/or
intravenously (331/662 patients) for a maximum of 6 days.
Approximately 22.4% of patients treated with Sivextro in Phase 3 clinical studies (n=662) experienced
at least one treatment-emergent adverse reaction. The most frequently reported adverse reactions
occurring in patients receiving tedizolid phosphate in the pooled controlled Phase 3 clinical studies
(tedizolid 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.
Safety was additionally evaluated in a randomized, double-blind, multicenter study conducted in
China, the Philippines, Taiwan, and the US, which included a total 292 adult patients treated with
tedizolid 200 mg administered 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 treated subjects than in the linezolid
control group (0%), particularly among Asian patients. These findings suggest a higher frequency of
infusion related reactions (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 with Sivextro (Table 1). The safety profile was similar when comparing
patients receiving intravenous Sivextro alone to patients who received oral administration alone,
except for a higher reported rate of gastrointestinal disorders associated with oral administration.
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).
Table 1 Frequency of adverse reactions by System Organ Class in comparative clinical
studies
System Organ Class Common Uncommon
Infections and infestations Vulvovaginal mycotic infection
Fungal infection
Vulvovaginal candidiasis
Abscess
Clostridium difficile colitis
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System Organ Class Common Uncommon
Dermatophytosis
Oral candidiasis
Respiratory tract infection
Blood and lymphatic system
disorders
Lymphadenopathy
Immune system disorders Drug hypersensitivity
Metabolism and nutrition disorders Dehydration
Diabetes mellitus inadequate
control
Hyperkalaemia
Psychiatric disorders Insomnia
Sleep disorder
Anxiety
Nightmare
Nervous system disorders Headache Somnolence
Dizziness Dysgeusia
Tremor
Paraesthesia
Hypoaesthesia
Eye disorders Vision blurred
Vitreous floaters
Cardiac disorders Bradycardia
Vascular disorders Flushing
Hot flush
Respiratory, thoracic and
mediastinal disorders
Cough
Nasal dryness
Pulmonary congestion
Gastrointestinal disorders Nausea Abdominal pain
Diarrhoea Constipation
Vomiting Abdominal discomfort
Dry mouth
Dyspepsia
Abdominal pain upper
Flatulence
Gastrooesophageal reflux
disease
Haematochezia
Retching
Skin and subcutaneous tissue
disorders
Pruritus
Generalised
Hyperhidrosis
Pruritus
Rash
Urticaria
Alopecia
Rash erythematous
Rash generalised
Acne
Pruritus allergic
Rash maculo-papular
Rash papular
Rash pruritic
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System Organ Class Common Uncommon
Musculoskeletal and connective
tissue disorders
Arthralgia
Muscle spasms
Back pain
Limb discomfort
Neck pain
Renal and urinary disorders Urine odor abnormal
Reproductive and breast disorders Vulvovaginal pruritus
General disorders and
administration site conditions
Fatigue Chills
Infusion site
reactions
(phlebitis)
Infusion site pain
Irritability
Pyrexia
Infusion related reaction
Peripheral oedema
Investigations Grip strength decreased
Transaminases increased
White blood cell count decreased
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 national reporting system
listed in Appendix V.
4.9 Overdose
In the event of overdose, Sivextro should be discontinued and general supportive treatment given.
Hemodialysis 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:Antibacterials for systemic use, Other antibacterials, ATC code:
J01XX11
Mechanism of action
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.
Tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci in vitro.
Resistance
The most commonly observed mutations in staphylococci and enterococci that result in oxazolidinone
resistance are in one or more copies of the 23S rRNA genes (G2576U and T2500A).
Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or
ribosomal proteins (L3 and L4) are generally cross-resistant to tedizolid.
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A second resistance mechanism is encoded by a plasmid-borne and transposon associated
chloramphenicol-florfenicol resistance (cfr) gene, conferring resistance in staphylococci and
enterococci to oxazolidinones, phenicols, lincosamides, pleuromutilins, streptogramin A and 16-
membered macrolides. Due to a hydroxymethyl group in the C5 position, tedizolid retains activity
against strains of Staphylococcus aureus that express the cfr gene in the absence of chromosomal
mutations.
The mechanism of action is different from that of non-oxazolidinone class antibacterial medicinal
products; therefore, cross-resistance between tedizolid and other classes of antibacterial medicinal
products 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 vancomycin
indicate 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:
Organisms
Minimum Inhibitory Concentrations
(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 anginosus
group only) 0.25 0.25
Pharmacokinetic/pharmacodynamic relationship
The AUC/MIC ratio was the pharmacodynamic parameter shown to best correlate with efficacy in
mouse thigh and lung S. aureus infection models.
In a mouse thigh infection model of S. aureus, the antibacterial activity of tedizolid was reduced in the
absence of granulocytes. The AUC/MIC ratio to achieve bacteriostasis in neutropenic mice was at
least 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 indication
that 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)
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Antibacterial activity against other relevant pathogens
Clinical efficacy has not been established against the following pathogens although in vitro studies
suggest that they would be susceptible to tedizolid in the absence of acquired mechanisms of
resistance:
• Staphylococcus lugdunensis
Paediatric population
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 and
skin structure infections (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Oral and intravenous tedizolid phosphate is a prodrug that is rapidly converted by phosphatases to
tedizolid, the microbiologically active moiety. Only the pharmacokinetic profile of tedizolid is
discussed in this section. Pharmacokinetic studies were conducted in healthy volunteers and
population pharmacokinetic analyses were conducted in patients from Phase 3 studies.
Absorption
At steady state, tedizolid mean (SD) Cmax values of 2.2 (0.6) and 3.0 (0.7) mcg/mL and AUC values of
25.6 (8.5) and 29.2 (6.2) mcg·h/mL were similar with oral and IV administration of tedizolid
phosphate, respectively. The absolute bioavailability of tedizolid is above 90%. Peak plasma tedizolid
concentrations are achieved within approximately 3 hours after dosing after oral administration of
Sivextro under fasted conditions.
Peak concentrations (Cmax) of tedizolid are reduced by approximately 26% and delayed by 6 hours
when tedizolid phosphate is administered after a high-fat meal relative to fasted, while total exposure
(AUC0-∞) is unchanged between fasted and fed conditions.
Distribution
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 single
intravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L.
Biotransformation
Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to the
microbiologically active moiety, tedizolid. Other than tedizolid, which accounts for approximately
95% 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 is
not 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 and
non-circulating sulphate conjugate found in the excreta.
Elimination
Tedizolid is eliminated in excreta, primarily as a non-circulating sulfate conjugate. Following single
oral administration of 14C-labeled Sivextro under fasted conditions, the majority of elimination
occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% in urine, with
most of the elimination (>85%) occurring within 96 hours. Less than 3% of Sivextro administered
dose is excreted as active tedizolid. The elimination half-life of tedizolid is approximately 12 hours
and the intravenous clearance is 6-7 L/h.
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Linearity/non-linearity
Tedizolid demonstrated linear pharmacokinetics with regard to dose and time. The Cmax and AUC of
tedizolid increased approximately dose proportionally within the single oral dose range of 200 mg to
1,200 mg and across the intravenous dose range of 100 mg to 400 mg. Steady-state concentrations are
achieved 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 of
approximately 12 hours.
Special populations
Renal impairment
Following administration of a single 200 mg IV dose of Sivextro to 8 subjects with severe renal
impairment defined as eGFR <30 mL/min, the Cmax was basically unchanged and AUC0-∞ was changed
by less than 10% compared to 8 matched healthy subject controls. Hemodialysis does not result in
meaningful removal of tedizolid from systemic circulation, as assessed in subjects with end-stage renal
disease (eGFR <15 mL/min). The eGFR was calculated using the MDRD4 equation.
Hepatic impairment
Following administration of a single 200 mg oral dose of Sivextro, the pharmacokinetics of tedizolid
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 least
5 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 Sivextro 200 mg.
Paediatric population
The pharmacokinetics of tedizolid were evaluated in adolescent subjects (12 to 17 years; n=20)
following administration of a single oral or IV dose of Sivextro 200 mg. The mean Cmax and AUC0-∞
for oral or IV administration of tedizolid 200 mg were similar in adolescent and in healthy adult
subjects.
Gender
The impact of gender on the pharmacokinetics of Sivextro was evaluated in healthy males and females
in clinical studies and in a population pharmacokinetics analysis. The pharmacokinetics of tedizolid
were similar in males and females.
Drug interaction studies
Effects of Other Medicines on Sivextro
In vitro studies have shown that drug interactions between tedizolid and inhibitors or inducers of
cytochrome P450 (CYP) isoenzymes are unanticipated.
Multiple sulfotransferase (SULT) isoforms (SULT1A1, SULT1A2, and SULT2A1) were identified in
vitro that are capable of conjugating tedizolid which suggests that no single isozyme is critical to the
clearance of tedizolid.
Effects of Sivextro on Other Medicines
Drug metabolizing enzymes
In vitro studies in human liver microsomes indicate that tedizolid phosphate and tedizolid do not
significantly inhibit metabolism mediated by any of the following CYP isoenzymes (CYP1A2,
CYP2C19, CYP2A6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4). Tedizolid did not alter activity of
selected CYP isoenzymes, but induction of CYP3A4 mRNA was observed in vitro in hepatocytes.
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A clinical study comparing the single dose (2 mg) pharmacokinetics of midazolam (CYP3A4
substrate) alone or in combination with Sivextro (once-daily 200 mg oral dose for 10 days),
demonstrated no clinically meaningful difference in midazolam Cmax or AUC. No dose adjustment is
necessary 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 important
drug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gp
and BCRP) was tested in vitro. No clinically relevant interactions are expected to occur with these
transporters, with the administration of the parenteral formulation.
In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (BCRP
substrate) alone or in combination with the oral administration of Sivextro film-coated tablets,
rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when
coadministered 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 when
comparing the IC50 and the anticipated plasma exposures in man. No evidence of MAO-A inhibition
was 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 oral
tedizolid phosphate at steady state to enhance pressor responses to pseudoephedrine and tyramine in
healthy individuals. No meaningful changes in blood pressure or heart rate were seen with
pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure
of ≥30 mmHg from pre-dose baseline was 325 mg with Sivextro compared to 425 mg with placebo.
Administration of Sivextro with tyramine-rich foods (i.e., containing tyramine levels of approximately
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 did
not differ from vehicle control in a mouse model that predicts brain serotonergic activity. There are
limited data in patients on the interaction between serotonergic agents and tedizolid phosphate. In
Phase 3 studies, subjects taking serotonergic agents including antidepressants such as selective
serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine
(5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.
5.3 Preclinical safety data
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-month
toxicology 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 a
1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to
significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at
plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure
associated with the therapeutic dose.
A special neuropathology study was conducted in pigmented Long Evans rats administered tedizolid
phosphate daily for up to 9 months. This study used sensitive morphologic evaluation of
perfusion-fixed peripheral and central nervous system tissue. No evidence of neurotoxicity, including
neurobehavioral changes or optic or peripheral neuropathy, was associated with tedizolid after 1, 3, 6
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or 9 months of oral administration up to doses with plasma exposure levels (AUC) up to 8-fold greater
than 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 (mouse
bone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolid
phosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolid
was positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity in
other in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrow
micronucleus 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 adult
female rats at oral doses up to the maximum tested dose of 15 mg/kg/day. These dose levels equate to
exposure 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 at
exposure 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. Foetal
developmental effects occurring in mice in the absence of maternal toxicity included reduced foetal
weights and an increased incidence of costal cartilage fusion (an exacerbation of the normal genetic
predisposition 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 and
increased skeletal variations including reduced ossification of the sternabrae, vertebrae, and skull were
observed at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) and
were associated with maternal toxicity (reduced maternal body weights). The no observed adverse
effect levels (NOAELs) for foetal toxicity in mice (5 mg/kg/day) as well as maternal and foetal
toxicity 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 human
therapeutic dose.
Tedizolid is excreted into the milk of lactating rats and the concentrations observed similar to those in
maternal plasma.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6. Sivextro is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+),
including Lactated Ringer’s Injection and Hartmann's Solution.
6.3 Shelf life
3 years.
After reconstitution and dilution, it should be used within 4 hours at room temperature or 24 hours
when stored at 2°C to 8°C.
27
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. For storage conditions after
reconstitution and dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
Sivextro vials are intended for single use only.
It must be administered as an intravenous infusion only. It must not be administered as an intravenous
bolus.
Aseptic technique must be followed in preparing the infusion solution. The contents of the vial should
be reconstituted with 4 mL of water for injections, and be swirled gently until the powder has
dissolved 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 chloride
0.9% solution for injection. The bag should not be shaken. The resulting solution is a clear colourless
or 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 or
infused simultaneously. If the same intravenous line is used for sequential infusion of several different
medicinal 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 local
requirements.
7. MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/15/991/002
EU/1/15/991/003
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23 March 2015
28
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
29
ANNEX II
A. MANUFACTURERS RESPONSIBLE FOR BATCH
RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY
AND USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE
MARKETING AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
PRODUCT
30
A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturers responsible for batch release
MSD Italia S.r.l.
Via Fontana del Ceraso 7
03012 - Anagni (FR)
Italy
Laboratoires Merck Sharp & Dohme-Chibret
Route de Marsat, Riom
63963, Clermont-Ferrand Cedex 9
France
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
Medicinal product subject to medical prescription.
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION
Periodic safety update reports
The requirements for submission of periodic safety update reports for this medicinal product are set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines web-portal.
The marketing authorisation holder shall submit the first periodic safety update report for this product
within 6 months following authorisation.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent
updates of the RMP.
An updated RMP should be submitted:
At the request of the European Medicines Agency;
Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of
an important (pharmacovigilance or risk minimisation) milestone being reached.
31
ANNEX III
LABELLING AND PACKAGE LEAFLET
32
A. LABELLING
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1. NAME OF THE MEDICINAL PRODUCT
Sivextro 200 mg film-coated tablets
tedizolid phosphate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 200 mg tedizolid phosphate.
3. LIST OF EXCIPIENTS
4. PHARMACEUTICAL FORM AND CONTENTS
Film-coated tablet
6 x 1 film-coated tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
34
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/15/991/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Sivextro
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA
PC:
SN:
NN:
35
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1. NAME OF THE MEDICINAL PRODUCT
Sivextro 200 mg tablets
tedizolid phosphate
2. NAME OF THE MARKETING AUTHORISATION HOLDER
MSD
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. OTHER
Peel, then push
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (VIAL)
1. NAME OF THE MEDICINAL PRODUCT
Sivextro 200 mg powder for concentrate for solution for infusion
tedizolid phosphate
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains disodium tedizolid phosphate corresponding to 200 mg tedizolid phosphate.
After reconstitution each ml contains 50 mg tedizolid phosphate.
3. LIST OF EXCIPIENTS
mannitol, sodium hydroxide, hydrochloric acid
4. PHARMACEUTICAL FORM AND CONTENTS
Powder for concentrate for solution for infusion
1 vial
6 vials
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use after reconstitution and dilution
For single use only
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
9. SPECIAL STORAGE CONDITIONS
37
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/15/991/002 1 vial
EU/1/15/991/003 6 vials
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
17. UNIQUE IDENTIFIER – 2D BARCODE
2D barcode carrying the unique identifier included.
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA
PC:
SN:
NN:
38
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
Sivextro 200 mg powder for concentrate
tedizolid phosphate
IV
2. METHOD OF ADMINISTRATION
Read the package leaflet before use.
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
200 mg
6. OTHER
39
B. PACKAGE LEAFLET
40
Package leaflet: Information for the patient
Sivextro 200 mg film-coated tablets
tedizolid phosphate
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Sivextro is and what it is used for
2. What you need to know before you take Sivextro
3. How to take Sivextro
4. Possible side effects
5. How to store Sivextro
6. Contents of the pack and other information
1. What Sivextro is and what it is used for
Sivextro is an antibiotic that contains the active substance tedizolid phosphate. It belongs to a group of
medicines called “oxazolidinones.”
It is used to treat adults with infections of the skin and tissues below the skin.
It works by stopping the growth of certain bacteria which can cause serious infections.
2. What you need to know before you take Sivextro
Do not take Sivextro
if you are allergic to tedizolid phosphate or any of the other ingredients of this medicine (listed
in section 6).
Warnings and precautions
Your doctor will have decided if Sivextro is suitable to treat your infection.
Talk to your doctor or nurse before taking Sivextro if any of the following apply to you:
- are suffering from diarrhoea, or have suffered from diarrhoea whilst (or up to 2 months after)
taking antibiotics in the past.
- are allergic to other medicines belonging to the group “oxazolidinones” (e.g., linezolid,
cycloserine).
- are taking certain medicines known as tricyclics or SSRIs (selective serotonin reuptake
inhibitors) to treat depression, for example,
- amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine,
imipramine, lofepramine, paroxetine, and sertraline.
41
- are taking certain medicines used to treat migraine known as “triptans,” such as sumatriptan and
zolmitriptan.
- are taking certain medicines known as MAOIs to treat depression, for example,
- phenelzine, isocarboxazid, selegiline, and moclobemide.
Ask your doctor or pharmacist if you are not sure whether you are taking any of these medicines.
Diarrhoea
Contact your doctor straight away if you suffer from diarrhoea during or after your treatment. Do not
take any medicine to treat your diarrhoea without first checking with your doctor.
Resistance to antibiotics
Bacteria can become resistant to treatment with antibiotics over time. This is when antibiotics cannot
stop the growth of bacteria and treat your infection. Your doctor will decide if you should be given
Sivextro to treat your infection.
Certain side effects have been observed with another member of the oxazolidinone class when
administered over a duration exceeding that recommended for Sivextro. Tell your doctor straight away
if you suffer from any of the following while taking Sivextro:
a low white blood cell count
anaemia (low red blood cells)
bleeding or bruising easily
loss of sensitivity in your hands or feet (such as numbness, prickling/tingling, or sharp pains)
any problems with your eyesight such as blurred vision, changes in colour vision, difficulty in
seeing detail or if your field of vision becomes restricted.
Children and adolescents
This medicine should not be used in children and adolescents as it has not been studied enough in
these populations.
Other medicines and Sivextro
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines. It is especially important that you tell your doctor if you are also taking:
imatinib, lapatinib (used to treat cancer)
methotrexate (used to treat cancer or rheumatoid arthritis)
sulfasalazine (used to treat inflammatory bowel diseases)
topotecan (used to treat cancer)
statins such as pitavastatin, rosuvastatin (used to lower blood cholesterol)
Sivextro can interfere with the effects of these medicines. Your doctor will explain more.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or pharmacist for advice before taking this medicine.
It is not known if Sivextro passes into breast milk in humans. Ask your doctor for advice before
breast-feeding your baby.
If you are a woman who could become pregnant you must use reliable contraception while you are
taking Sivextro. Contact your doctor straight away if you become pregnant while you are taking
Sivextro.
Driving and using machines
Do not drive or use machines if you feel dizzy or tired after taking this medicine.
42
3. How to take Sivextro
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor
or pharmacist if you are not sure.
The recommended dose is one 200 mg tablet once a day for 6 days. The tablets are swallowed whole
and can be taken with or without food or drink.
Talk to a doctor if you do not feel better, or if you feel worse after 6 days.
If you take more Sivextro than you should
Contact your doctor, pharmacist or nearest hospital casualty department as soon as possible if you
have taken more tablets than you should, and take your medicine with you.
If you forget to take Sivextro
If you forget to take your medicine, take the dose 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 wait until the next
scheduled dose. Do not take a double dose to make up for a forgotten dose. If in any doubt, contact
your pharmacist for advice.
You should take all 6 tablets to complete your course of treatment, even if you have missed a dose.
If you stop taking Sivextro
If you stop taking Sivextro without the advice of your doctor, your symptoms may get worse. Talk to
your doctor or pharmacist before you stop taking your medicine.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor straight away if you suffer from diarrhoea during or after your treatment.
Other side effects may include:
Common side effects (may affect up to 1 in 10 people)
Nausea
Vomiting
Headache
Itching all over the body
Tiredness
Dizziness
Uncommon side effects (may affect up to 1 in 100 people)
Fungal infections of skin , mouth and vagina (oral / vaginal thrush)
Itching (including itching due to allergic reaction), hair loss, acne, red and/or itchy rash or hives,
excessive sweating
Decrease or loss of skin sensitivity, tingling/prickling skin sensation
Hot flush or blushing/redness in the face, neck or upper chest
Abscess (swollen, pus-filled lump)
Vaginal infection, inflammation or itching
Anxiety, irritability, shaking or trembling
Respiratory tract (sinuses, throat and chest) infection
Dryness in the nose, congestion in the chest, cough
Sleepiness, abnormal sleep pattern, difficulty sleeping, nightmares (unpleasant/disturbing
dreams)
43
Dry mouth, constipation, indigestion, pain/discomfort in the belly (abdomen), retching, dry
heaving, bright red blood in the stool
Acid reflux disease (heartburn, pain or difficulty swallowing), flatulence/passing wind
Joint pain, muscle spasms, back pain, neck pain, pain/discomfort in limbs, decrease of grip
strength
Blurred vision, ‘floaters’ (small shapes seen floating in the field of vision)
Swollen or enlarged lymph nodes
Allergic reaction
Dehydration
Poor control of diabetes
Abnormal sense of taste
Slow heartbeat
Fever
Swelling in ankles and/or feet
Abnormal smelling urine, abnormal blood tests
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V. By reporting side effects you can help provide more information on the safety of
this medicine.
5. How to store Sivextro
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton or blister label after
“EXP”. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Sivextro contains
The active substance is tedizolid phosphate. Each film-coated tablet contains 200 mg of
tedizolid phosphate.
The other ingredients are microcrystalline cellulose, mannitol, povidone, crospovidone and
magnesium stearate within the tablet core. The film coat of the tablet contains polyvinyl
alcohol, titanium dioxide (E171), macrogol, talc and yellow iron oxide (E172).
What Sivextro looks like and contents of the pack
Sivextro is an oval, yellow film-coated tablet imprinted with ‘TZD’ on one side and ‘200’ on the other
side.
It is available in 6 × 1 tablets in perforated unit-dose blisters.
Marketing Authorisation Holder
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
44
Manufacturer
MSD Italia S.r.l.
Via Fontana del Ceraso 7
03012 - Anagni (FR)
Italy
Laboratoires Merck Sharp & Dohme-Chibret
Route de Marsat, Riom
63963, Clermont-Ferrand Cedex 9
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: 0800 38 693 (+32(0)27766211)
[email protected]
Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
[email protected]
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
[email protected]
Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
[email protected]
Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
[email protected]
Magyarország
MSD Pharma Hungary Kft.
Tel.: +361 888 53 00
[email protected]
Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
[email protected]
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
[email protected]
Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
[email protected]
Nederland
Merck Sharp & Dohme BV
Tel: 0800 9999000 (+31 23 5153153)
[email protected]
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
[email protected]
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@ msd.no
Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
[email protected]
Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
[email protected]
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
[email protected]
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
[email protected]
45
France
MSD France
Tél: + 33 (0) 1 80 46 40 40
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
[email protected]
Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
[email protected]
România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
[email protected]
Ireland
Merck Sharp & Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 299 8700
[email protected]
Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: + 386 1 5204 201
[email protected]
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
[email protected]
Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
[email protected]
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
[email protected]
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 800 00 673 (+357 22866700)
[email protected]
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
[email protected]
Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364224
[email protected].
United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
[email protected]
This leaflet was last revised in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
46
Package leaflet: Information for the patient
Sivextro 200 mg powder for concentrate for solution for infusion
tedizolid phosphate
This medicine is subject to additional monitoring. This will allow quick identification of new
safety information. You can help by reporting any side effects you may get. See the end of section 4
for how to report side effects.
Read all of this leaflet carefully before you start receiving this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or nurse.
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects
not listed in this leaflet. See section 4.
What is in this leaflet
1. What Sivextro is and what it is used for
2. What you need to know before you are given Sivextro
3. How you will be given Sivextro
4. Possible side effects
5. How to store Sivextro
6. Contents of the pack and other information
1. What Sivextro is and what it is used for
Sivextro is an antibiotic that contains the active substance tedizolid phosphate. It belongs to a group of
medicines called “oxazolidinones.”
It is used to treat adults with infections of the skin and tissues below the skin.
It works by stopping the growth of certain bacteria which can cause serious infections.
2. What you need to know before you are given Sivextro
Do not use Sivextro:
if you are allergic to tedizolid phosphate or any of the other ingredients of this medicine (listed
in section 6).
Warnings and precautions
Your doctor will have decided if Sivextro is suitable to treat your infection.
Talk to your doctor or nurse before being given Sivextro if any of the following apply to you:
- are suffering from diarrhoea, or have suffered from diarrhoea whilst (or up to 2 months after)
being treated with antibiotics in the past.
- are allergic to other medicines belonging to the group “oxazolidinones” (e.g., linezolid,
cycloserine).
- are taking certain medicines known as tricyclics or SSRIs (selective serotonin reuptake
inhibitors) to treat depression, for example,
- amitriptyline, citalopram, clomipramine, dosulepin, doxepin, fluoxetine, fluvoxamine,
imipramine, lofepramine, paroxetine, and sertraline.
- are taking certain medicines used to treat migraine known as “triptans,” such as sumatriptan and
zolmitriptan.
- are taking certain medicines known as MAOIs to treat depression, for example,
47
- phenelzine, isocarboxazid, selegiline, and moclobemide.
Ask your doctor or pharmacist if you are not sure whether you are taking any of these medicines.
Diarrhoea
Contact your doctor straight away if you suffer from diarrhoea during or after your treatment. Do not
take any medicine to treat your diarrhoea without first checking with your doctor.
Resistance to antibiotics
Bacteria can become resistant to treatment with antibiotics over time. This is when antibiotics cannot
stop the growth of bacteria and treat your infection. Your doctor will decide if you should be given
Sivextro to treat your infection.
Certain side effects have been observed with another member of the oxazolidinone class when
administered over a duration exceeding that recommended for Sivextro. Tell your doctor straight
away if you suffer from any of the following while taking Sivextro:
a low white blood cell count
anaemia (low red blood cells)
bleeding or bruising easily
loss of sensitivity in your hands or feet (such as numbness, prickling/tingling, or sharp pains)
any problems with your eyesight such as blurred vision, changes in colour vision, difficulty in
seeing detail or if your field of vision becomes restricted.
Children and adolescents
This medicine should not be used in children and adolescents as it has not been studied enough in
these populations.
Other medicines and Sivextro
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor or nurse for advice before using this medicine.
It is not known if Sivextro passes into breast milk in humans. Ask your doctor for advice before
breast-feeding your baby.
If you are a woman who could become pregnant, you must use reliable contraception while you are
taking Sivextro. Contact your doctor straight away if you become pregnant while you are taking
Sivextro.
Driving and using machines
Do not drive or use machines if you feel dizzy or tired after taking this medicine.
Sivextro contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodiumfree.”
3. How you will be given Sivextro
Sivextro will be given to you by a nurse or doctor.
It will be given to you through a drip directly into a vein (intravenously) over approximately 1 hour.
You will be given one 200 mg infusion of Sivextro once a day for 6 days.
Talk to a doctor if you do not feel better, or if you feel worse after 6 days.
48
If you are given more Sivextro than you should
Tell your doctor or nurse immediately if you are concerned that you may have been given too much
Sivextro.
If you miss a dose of Sivextro
Tell your doctor or nurse immediately if you are concerned that you may have missed a dose.
If you have any further questions on the use of this medicine, ask your doctor or nurse.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor straight away if you suffer from diarrhoea during or after your treatment.
Other side effects may include:
Common side effects (may affect up to 1 in 10 people)
Nausea
Vomiting
Headache
Itching all over the body
Tiredness
Dizziness
Infusion site pain or swelling.
Uncommon side effects (may affect up to 1 in 100 people)
Fungal infections of skin , mouth and vagina (oral / vaginal thrush)
Itching (including itching due to allergic reaction), hair loss, acne, red and/or itchy rash or hives,
excessive sweating
Decrease or loss of skin sensitivity, tingling/prickling skin sensation
Hot flush or blushing/redness in the face, neck or upper chest
Abscess (swollen, pus-filled lump)
Vaginal infection, inflammation or itching
Anxiety, irritability, shaking or trembling
Respiratory tract (sinuses, throat and chest) infection
Dryness in the nose, congestion in the chest, cough
Sleepiness, abnormal sleep pattern, difficulty sleeping, nightmares (unpleasant/disturbing
dreams)
Dry mouth, constipation, indigestion, pain/discomfort in the belly (abdomen), retching, dry
heaving, bright red blood in the stool
Acid reflux disease (heartburn, pain or difficulty swallowing), flatulence/passing wind
Joint pain, muscle spasms, back pain, neck pain, pain/discomfort in limbs, decrease of grip
strength
Blurred vision, ‘floaters’ (small shapes seen floating in the field of vision)
Swollen or enlarged lymph nodes
Allergic reaction
Dehydration
Poor control of diabetes
Abnormal sense of taste
Slow heartbeat
Fever
Swelling in ankles and/or feet
49
Abnormal smelling urine, abnormal blood tests
Infusion reactions (chills, shaking or shivering with fever, muscle pain, swelling of the face,
weakness, fainting, shortness of breath, chest tightness and angina pectoris).
Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not
listed in this leaflet. You can also report side effects directly via the national reporting system listed in
Appendix V. By reporting side effects you can help provide more information on the safety of this
medicine.
5. How to store Sivextro
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the vial label after “EXP”. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not use this medicine if you notice any particles or the solution is cloudy.
Once opened this medicine must be used immediately. If not, the reconstituted solution should be
stored at room temperature for up to 4 hours or in a refrigerator at 2°C to 8°C, for up to 24 hours.
Any unused medicine or waste material, including materials used for reconstitution, dilution and
administration, should be disposed of in accordance with local requirements.
6. Contents of the pack and other information
What Sivextro contains
The active substance is tedizolid phosphate. Each vial of powder contains disodium tedizolid
phosphate which is equal to 200 mg of tedizolid phosphate.
The other ingredients are mannitol, sodium hydroxide (for pH adjustment) and hydrochloric
acid (for pH adjustment).
What Sivextro looks like and contents of the pack
Sivextro is a white to off-white powder for concentrate for solution for infusion in a glass vial. The
powder will be reconstituted in the vial with 4 mL of water for injections. The reconstituted solution
will be withdrawn from the vial and added to an infusion bag of 0.9% sodium chloride in the hospital.
It is available in packs containing 1 or 6 vials.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
Manufacturer
MSD Italia S.r.l.
Via Fontana del Ceraso 7
03012 - Anagni (FR)
50
Italy
Laboratoires Merck Sharp & Dohme-Chibret
Route de Marsat, Riom
63963, Clermont-Ferrand Cedex 9
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel: 0800 38 693 (+32(0)27766211)
[email protected]
Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
[email protected]
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
[email protected]
Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
[email protected]
Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
[email protected]
Magyarország
MSD Pharma Hungary Kft.
Tel.: +361 888 53 00
[email protected]
Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
[email protected]
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
[email protected]
Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
[email protected]
Nederland
Merck Sharp & Dohme BV
Tel: 0800 9999000 (+31 23 5153153)
[email protected]
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
[email protected]
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@ msd.no
Ελλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
[email protected]
Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
[email protected]
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
[email protected]
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
[email protected]
France
MSD France
Tél: + 33 (0) 1 80 46 40 40
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
[email protected]
51
Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
[email protected]
România
Merck Sharp & Dohme Romania S.R.L.
Tel: +40 21 529 29 00
[email protected]
Ireland
Merck Sharp & Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 299 8700
[email protected]
Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: + 386 1 5204 201
[email protected]
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
[email protected]
Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
[email protected]
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
[email protected]
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 800 00 673 (+357 22866700)
[email protected]
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
[email protected]
Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364224
[email protected].
United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
[email protected]
This leaflet was last revised in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for healthcare professionals only:
Important: Please refer to the Summary of Product Characteristics (SmPC) before prescribing.
Patients who commence treatment on the parenteral formulation may be switched to the oral
presentation when clinically indicated.
Sivextro must be reconstituted with water for injections and subsequently diluted in 250 mL of 0.9%
sodium chloride for infusion.
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 or
infused simultaneously. If the same intravenous line is used for sequential infusion of several different
medicinal products, the line should be flushed before and after infusion with 0.9% sodium chloride.
Do not use Lactated Ringer’s Injection or Hartmann’s Solution.
Reconstitution
Aseptic technique must be followed when preparing the infusion solution. Reconstitute the contents of
the vial with 4 mL water for injections, and swirl gently until the powder has dissolved entirely. Avoid
shaking or rapid movement as it may cause foaming.
52
Dilution
For administration, the reconstituted solution must be further diluted in 250 mL 0.9% sodium chloride.
Do not shake the bag. The resulting solution is a clear colourless or light-yellow solution.
Infusion
The reconstituted solution should be inspected visually for particulate matter prior to administration.
Reconstituted solutions containing visible particles should be discarded.
Sivextro is administered intravenously over approximately 1 hour.
The reconstituted solution must be administered as an intravenous infusion only. It must not be
administered as an intravenous bolus. Sivextro must not be mixed with other medicinal products.
Each vial is for single use only.
