Sievextro - instructions for use, dose, side effects, contraindications

Active substanceTedisolideTedisolide

Similar drugsTo uncover

Sivekstro

lyophilizate d / infusion

Bayer Pharma AG Germany

Sivekstro

pills inwards

Bayer Pharma AG Germany

Dosage form: & nbspTfilm-covered abeys.

Composition:

One tablet, coated, 200 mg contains:

Active substance: Tedisolide phosphate 200 mg.

Excipients: cellulose microcrystalline 78.0 mg; Mannitol 78.0 mg, Povidone 16.0 mg; crospovidone (Kollidon® CL) 24.0 mg; magnesium stearate 4.0 mg;

film sheath: fall off II Yellow 85F92127 14.0 mg (polyvinyl alcohol, titanium dioxide, macrogol, talc, iron oxide, yellow oxide).

Description:

Oval tablets covered with a film shell, yellow, with an engraving "TZD"on one side and" 200 "on the other.

Pharmacotherapeutic group:antibiotic-oxazolidinone

ATX: & nbsp

Tedisolide

Pharmacodynamics:

Mechanism of action

Tedisolide (an active metabolite of tadizolide phosphate) is an antibiotic of the class of oxazolidinones with activity predominantly against gram-positive microorganisms. In studies in vitro The bacteriostatic effect of tadizolide against such microorganisms as Enterococcus spp., Staphylococcus spp. and Streptococcus spp. The antibacterial effect of tedizolide is due to binding to the subunit 50S bacterial ribosome, which leads to inhibition of protein synthesis. Tedisolide inhibits bacterial protein synthesis through an action mechanism different from that for antibiotics not belonging to the class of oxazolidinones, hence cross-resistance between tadizolide and other classes of antibacterial drugs (penicillins, cephalosporins, aminoglycosides, glycopeptides, lipopeptides, streptogramins, quinolones, macrolides and tetracyclines) is unlikely.

The mechanism of resistance

Organisms resistant to oxazolidinones due to mutations of chromosome genes encoding 23S rRNA or ribosomal proteins (L3 and L4), usually have cross-resistance to tedizolide. It is also known that the appearance of the chloramphenicol-florphenicol resistance gene (cfr-gene) forms the resistance of staphylococci and enterococci to oxazolidinones, fenicolam, lincosamides, pleuromutilins, streptogramin A, 16-member macrolides. In a limited number of strains tested Staphylococcus aureus Availability cfr-gen did not lead to resistance to tedizolide in the absence of chromosomal mutations. This is due to the presence of a hydroxyl group in the tadizolide molecule at position C5.

Spontaneous mutations, which cause a decreased sensitivity to tedizolide, arise in vitro with a frequency of approximately 10^-10.

Spectrum of antibacterial activity

The following are pathogenic microorganisms sensitive to tedizolide in vitro, in relation to which the clinical efficacy of tedizolide has been shown in clinical studies:

Aerobic and facultative gram positive bacteria

- Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-sensitive [MSSA] strains),

- Streptococcus pyogenes (group A beta-hemolytic streptococci),

- Streptococcus agalactiae (group B beta-hemolytic streptococci),

- Group Streptococcus anginosus, including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus,

- Enterococcus faecalis.

The clinical efficacy of tedizolide against the pathogenic microorganisms listed below has not been established, but the results of the studies in vitro suggest that they are sensitive to tedizolide in the absence of acquired resistance mechanisms:

Aerobic and facultative anaerobic Gram-positive bacteria

- Staphylococcus epidermidis (including methicillin-resistant and methicillin-sensitive strains),

- Staphylococcus haemolyticus,

- Staphylococcus lugdunensis,

- Enterococcus faecium.

Tedisolide, as a rule, is not active against gram-negative microorganisms.

Sensitivity limit

The minimum inhibitory concentration was determined by the European Committee for the Determination of Sensitivity to Antibiotics (EUCAST) and is given in the table:

Microorganisms	The minimum inhibitory concentration (mg / l)
Microorganisms	Sensitive	Resistant
Staphylococcus spp.	≤0,5	>0,5
beta-hemolytic streptococci (A,B,C,G group)	≤0,5	>0,5
Group Streptococcus anginosus	≤0,25	>0,25

Relationship pharmacokinetics and pharmacodynamics

On the model of infection in animals, it was shown that the ratio of the area under the pharmacokinetic curve "concentration-time" (AUC) to the minimal inhibitory concentration (MIC) correlates with the activity of tedizolide.

Pharmacokinetics:

Tedisolide phosphate is the starting material, which, with the help of phosphatases after oral administration, is converted into tvedisolide, a microbiologically active substance. Further, only the pharmacokinetic profile of tadizolide is considered, since after oral administration the systemic effect of tadizolide phosphate is negligible. After repeated oral administration, once a day, equilibrium concentrations are reached for about 3 days with the accumulation of approximately 30% of tedizolide (half-life of tadizolide approximately 12 hours).Pharmacokinetic parameters of tedizolide after oral administration of 200 mg of tadizolide phosphate once a day are presented in the table:

Pharmacokinetic parameters of tedizolide *	Single Reception	The equilibrium state
FROM_mOh (μg / ml)	2,0 (0,7)	2,2 (0,6)
T_mOh (h)^†	2,5 (1,0-8,0)	3,5 (1,0-6,0)
AUC (μg_xh / ml)^‡	23,8 (6,8)	25,6 (8,4)
CL or CL/F (l / h)	6,9 (1,7)	8,4 (2,1)

* FROM_mOh, maximum concentration; T_mOh, time to reach C_mOh; AUC, area under the pharmacokinetic concentration-time curve; CL, system clearance; CL/F, apparent overall clearance

^† median (range)

‡ AUC represents AUC_0-∞ (AUC from moment 0 to infinity) for a single application and AUC₀_-24(AUC from moment 0 to 24 hours) for multiple reception

Suction

The maximum concentration of tadizolide in the blood plasma is reached about 3 hours after oral administration of tadizolide phosphate on an empty stomach. Absolute bioavailability is approximately 91%.

Tedisolide phosphate in the form of film-coated tablets can be taken regardless of food intake, since the total systemic exposure (AUC_0-∞) does not change in conditions of hunger or satiety (food with a high content of fat, calories).

Distribution

Communication with blood proteins is approximately 70% to 90%.

Tedisolide penetrates the intercellular fluid of adipose tissue and skeletal muscles, and its effect is similar to that of a free drug in the blood plasma.

Metabolism

Tedisolide phosphate is converted into a microbiologically active substance, tvedisolide, with the help of endogenous plasma and tissue phosphatases. There are no other significant circulating metabolites in humans except tadizolide, which accounts for approximately 95% of the total AUC radioactive carbon in the plasma after a single oral administration of tidizolide labeled with a radioactive isotope of carbon C14.

There was no decay of tedizolide in human liver microsomes, indicating that tvedisolide with a low probability is a substrate for hepatic isoenzymes of cytochrome CYP₄₅₀. Several sulfotransferases (SULT: SULT1A1, SULT1A2 and SULT2A1) are involved in the biotransformation of tedizolide.

Excretion

After a single oral administration of tadizolide phosphate on an empty stomach, excretion was mainly performed through the liver, with 82% of the dose being excreted through the intestine and 18% by the kidneys, mainly as a non-circulating and microbiologically inactive conjugate with sulfate. Most of the tedizolide (more than 85%) is excreted within 96 hours.Less than 3% of the administered dose of tadizolide phosphate is excreted by the kidneys and through the intestine in the form of unchanged tadizolide.

Pharmacokinetics in different patient groups

Based on the population pharmacokinetic analysis, there are no clinically relevant demographic or clinical factors (including age, sex, race, ethnicity, body weight, body mass index and renal or hepatic function assessment) that affect the pharmacokinetics of tadizolide.

Patients with impaired hepatic function

After a single oral intake of 200 mg of tadizolide, there were no clinically significant changes in the mean C_mOh and AUC_0-∞ for tedizolide in patients with moderate (n= 8) or heavy (n= 8) hepatic insufficiency (class B and C according to the Child-Pugh classification) in comparison with 8 healthy subjects from the control group. In patients with hepatic insufficiency, dose adjustment is not required.

Patients with impaired renal function

After a single intravenous injection of 200 mg of tedizolide 8 in patients with severe renal failure at a calculated rate of kFiltration (rSCF) less than 30 ml / min / 1.73 m², FROMmOh did not change significantly, a AUC_0-∞decreased by less than 10% in comparison with 8 healthy subjects from the control group. Hemodialysis does not lead to a significant removal of tedizolide from the systemic blood flow, as has been estimated in patients with end-stage renal failure (with rSKF less than 15 mL / min / 1.73 m²). In patients with renal insufficiency or on hemodialysis, dose adjustment is not required.

Elderly patients

The pharmacokinetics of tedizolide was evaluated in a phase I clinical study conducted in healthy elderly volunteers (age 65 and older, with at least 5 volunteers at the age of 75; n= 14) in comparison with younger healthy volunteers from the control group (from 25 to 45 years; n= 14) after a single oral administration of tidizolide 200 mg. There were no clinically significant differences in C_mOh and AUC_0-∞ for tedizolide in elderly participants in the study compared with the younger of the control group. In elderly patients, dose adjustment of tadizolide is not required.

Floor

The effect of sex on the pharmacokinetics of tedizolide was evaluated in clinical studies involving healthy men and women, as well as in population pharmacokinetic analysis.The pharmacokinetics of tadizolide were similar in men and women. No dosage adjustment of tadizolide is required depending on sex.

Children

Safety and efficacy in children under the age of 18 years is not established.

Since there are no available data on the use of Sivextro in children, the drug is contraindicated in patients under 18 (see "Contraindications").

Indications:

Complicated skin and soft tissue infections caused by sensitive microorganisms:

- Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-sensitive [MSSA] strains),

- Streptococcus pyogenes (group A beta-hemolytic streptococci),

- Streptococcus agalactiae (group B beta-hemolytic streptococci),

- Group Streptococcus anginosus, including Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus,

- Enterococcus faecalis.

It is necessary to take into account the current official guidelines on the rules for the use of antibacterial agents.

Contraindications:

Age under 18 years (safety and efficacy in this age group are not established).

Hypersensitivity to tedizolide or excipients of the drug.

Carefully:Hypersensitivity to other oxazolidinones in the anamnesis.

Pregnancy and lactation:

Pregnancy

Data on the use of the drug Sievextro in pregnant women are absent. Studies on models of rats and mice have shown an effect on fetal development. For the sake of precaution, it is preferable to exclude the use of Sievextro during pregnancy.

Breastfeeding period

There is no data on the use of the drug Sievextro in the period of breastfeeding. Pre-clinical studies have shown that tvedisolide excreted in breast milk of rats. The decision to stop breastfeeding or to abolish and / or abstain from taking the drug should be taken in consideration of the risk-benefit ratio.

Fertility

The effect of tadizolide phosphate on human fertility has not been studied. Studies of tadizolide phosphate on animals have not revealed a negative effect on fertility.

Dosing and Administration:

Recommended dosing regimen in patients aged 18 years and older: with complicated infections of the skin and soft tissues 200 mg (1 tablet, coated film shell) once a day for 6 days.

When switching from an intravenous to an oral application preparation of Sivextro dosage adjustment is not required.

Tedisolide phosphate in the form of film-coated tablets can be taken regardless of food intake.

If the patient misses the drug, then the missed tablet should be taken as soon as possible at any time, but no later than 8 hours before the next scheduled intake of the drug. If there is less than 8 hours left until the next scheduled appointment, the missed tablet should not be taken.

Special patient groups

Patients with impaired hepatic function

In patients with hepatic insufficiency, dose adjustment is not required.

Patients with impaired renal function

In patients with renal insufficiency or on hemodialysis, dose adjustment is not required.

Children

The safety and efficacy of Sivextro in children under 18 years of age have not been established.

Elderly patients

In elderly patients, dose adjustment of tadizolide is not required. Clinical studies using Sievextro did not include a sufficient number of patients aged 75 years and older to determine if their response to treatment differs from that of younger patients. In general, there was no difference in the pharmacokinetics between elderly and younger patients (see Fig.also see "Pharmacological properties").

Side effects:

The most frequent adverse reactions that developed in patients treated with Sievexto in the form of film-coated tablets and with stepwise therapy (intravenous administration followed by oral administration) in the combined analysis of phase III clinical trials were nausea, headache, diarrhea, and vomiting.

The adverse events presented below are listed according to organ systems and according to frequency of occurrence.

Frequency of occurrence is defined as follows: very often (≥ 1/10 or ≥10%), often (> 1/100 <1/10 or ≥ 1% and <10%), infrequently (≥ 1/1 000 and <1 / 100 or ≥ 0.1% and <1%), rarely (≥ 1/10 000 and <1/1000 or ≥ 0.01% and <0.1%), very rarely (<1/10 000 or <0 , 01%). Frequency categories were formed on the basis of data obtained in clinical trials of the drug.

Infectious and parasitic diseases

Infrequently: vulvovaginal fungal infection, fungal infections, vulvovaginal candidiasis, abscess, colitis (caused by Clostridium difficile), dermatophytosis, candidiasis of the oral mucosa, respiratory tract infections.

Violations of the blood and lymphatic system

Infrequent: lymphadenopathy.

Immune system disorders

Infrequent: hypersensitivity.

Disorders from the metabolism and nutrition

Infrequently: dehydration, inadequate control of diabetes mellitus, hyperkalemia.

Disorders of the psyche

Infrequently: insomnia, sleep disturbances, anxiety, nightmares.

Disturbances from the nervous system

Often: headache, dizziness.

Infrequent: drowsiness, a taste disorder (dysgeusia), tremor, paresthesia, hypoesthesia.

Disturbances on the part of the organ of sight

Infrequent: blurred vision, floating opacities of the vitreous.

Heart Disease

Infrequent: bradycardia.

Vascular disorders

Infrequently: congestion, "hot flashes".

Disturbances from the respiratory system, chest and mediastinal organs

Infrequent: cough, dry mucous membrane of the nasal cavity, stagnation of blood in the lungs.

Disturbances from the gastrointestinal tract (GIT)

Often: nausea, diarrhea, vomiting.

Infrequent: abdominal pain, constipation, abdominal discomfort, dryness of the oral mucosa, indigestion, upper abdominal pain, flatulence, gastroesophageal reflux disease, haemathece, urge to vomit.

Disturbances from the skin and subcutaneous tissues

Often: generalized itching.

Infrequent: hyperhidrosis, itching, rash, urticaria, alopecia, erythematous rash, generalized rash, acne, itching of allergic genesis, maculopapular rash, papular rash, itching rash.

Disturbances from musculoskeletal and connective tissue

Infrequently: arthralgia, muscle spasms, back pain, discomfort in the limbs, pain in the neck.

Disorders from the kidneys and urinary tract

Infrequent: a change in the smell of urine.

Violations of the genitals and mammary glands

Infrequent: vulvovaginal itching.

General disorders and disorders at the site of administration

Often: general malaise.

Infrequent: chills, pain at the injection site, phlebitis at the injection site, irritability, fever, reaction to infusion, peripheral edema.

Laboratory and instrumental data

Infrequent: a decrease in the compression force of the hand, increased activity of transaminases, a decrease in the number of leukocytes.

Overdose:

Symptoms

In clinical studies, the maximum single dose of 1200 mg was used. All adverse reactions in this case were mild or moderate in severity.

Treatment

In case of an overdose, stop taking the drug and start general maintenance therapy.

Hemodialysis does not lead to a significant elimination of tedizolide from the systemic blood flow.

Interaction:

Interaction with other antimicrobial agents

In studies in vitro the combination of tidizolide with the following antimicrobial agents: amphotericin B, aztreonam, ceftazidime, ceftriaxone, ciprofloxacin, clindamycin, colistin, daptomycin, gentamicin, imipenem, ketoconazole, minocycline, piperacillin, rifampicin, terbinafine, trimethoprim / sulfamethoxazole, vancomycin.

Pharmacokinetic interactions

Enzymes that metabolize drugs

By the results of the study in vitro there is a risk of enzymatic induction caused by tedizolide phosphate, which can lead to a decrease in the effectiveness of co-administered drugs with a narrow therapeutic index, which are substrates CYP3A4 (such as midazolam, triazolam, alfentanil, ciclosporin, fentanyl, pimozide, quinidine and tacrolimus), CYP2B6 (efavirenz), CYP2C9 (warfarin) and P-gp (digoxin).

Induction of enzymes caused by tadizolide by phosphate may also decrease the effectiveness of oral hormonal contraceptives.

Membrane carriers

According to research in vitro, Tedisolide phosphate can inhibit carriers of organic anions (OATP1B1). The validity of this data in vivo is not proved. Inhibition of OATP1B1 can lead to increased exposure to drugs such as statins (atorvastatin, fluvastatin, Pitavastatin and lovastatin), repaglinide, bosentan, valsartan, olmesartan and glyburide. If possible, the concomitant medications from this group should be temporarily discontinued during treatment with tadizolide with phosphate.

Inhibitors of monoamine oxidase

Tedisolide is a reversible inhibitor of monoamine oxidase (MAO) in vitro. Interaction with MAO inhibitors could not be evaluated in phase II and III clinical trials because patients who took such drugs were not included in the studies.

Adrenergic substances

Two placebo-controlled cross-sectional clinical trials were conducted to evaluate the drug's potentialSievextro (in a dose of 200 mg when taken orally) in an equilibrium state to strengthen the pressor response to pseudoephedrine and tyramine in healthy individuals. When using pseudoephedrine, no significant changes in blood pressure or heart rate were observed. The median dose of tyramine required to increase systolic blood pressure by ≥ 30 mmHg. from baseline to admission, was 325 mg when administered with the drug Sivextro versus 425 mg when applied with placebo. The rapid heartbeat was reported in 21/29 (72.4%) of patients receiving the drug Sivextro compared with 13/28 (46.4%) receiving placebo in a study with provocation of tyramine.

Serotonergic substances

Serotonergic effects at doses of tadizolide phosphate, up to 30 times higher than the equivalent dose for humans, did not differ from the control in a model in mice that predicted serotonergic activity. In phase III clinical trials, patients taking serotonergic substances, including antidepressants, such as selective serotonin reuptake inhibitors, tricyclic antidepressants and serotonin-5-hydroxytryptamine (5-HT1) receptor (tryptane) receptor agonists, meperidine or buspirone, were not included.

Special instructions:

Patients with neutropenia

There is insufficient data to adequately assess the safety and efficacy of tedizolide in neutropenic patients (neutrophil count <1000 cells / mm³). In the model of infection in animals, the antibacterial activity of the drug Sievextro was reduced in the absence of granulocytes. An alternative method of treating patients with neutropenia and a complicated infection of the skin and soft tissues should be considered (see section "Pharmacological properties").

Mitochondrial dysfunction

Tedisolide inhibits the synthesis of mitochondrial proteins. As a result of this process, undesirable phenomena such as lactic acidosis, anemia and neuropathy (of the optic nerve and peripheral) may appear.

Similar cases were observed in another preparation of the class of oxazolidinones when applied for a longer period than recommended for the drug Sievextro.

Myelosuppression

During the treatment of tadizolide with phosphate in several patients, a low content of platelets, hemoglobin and neutrophils was observed. When the drug was discontinued, the hematologic parameters were reversed to the initial level (before treatment).Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) was observed in patients treated with another drug of the oxazolidinone class, and the risk of these events depended on the duration of treatment.

Peripheral neuropathy and optic nerve neuropathy

Peripheral neuropathy, as well as neuropathy of the optic nerve, sometimes progresses to loss of vision, which was documented in patients undergoing therapy with another oxazolidinone class with a treatment duration exceeding that recommended for the drug Sievextro. Neuropathy (peripheral and optic nerve) has not been documented in patients undergoing tidizolide phosphate therapy during the recommended 6-day treatment period. All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity / blurred vision, change in color perception, visual field defect. In such cases, an immediate assessment of the condition is recommended and, if necessary, an appeal to the ophthalmologist.

Lactate Acidosis

Lactatacidosis was reported in another class of oxazolidinone.Lactatacidosis in patients treated with tadizolide phosphate during the recommended 6-day period was not reported.

Electrophysiology of the heart

In a randomized, cross-sectional clinical trial with positive control and placebo control with a detailed study of the interval QTc 48 patients received tvedisolide once inside at a therapeutic dose of 200 mg, tvedisolide in a super therapeutic dose of 1200 mg, placebo and positive control; no significant effect of tedizolide on the heart rate, the morphology of the electrocardiogram, PR, QRS or interval QT. Consequently, tvedisolide does not affect cardiac repolarization.

Diarrhea associated with Clostridium difficile

About diarrhea associated with Clostridium difficile, reported mailand for all systemic antibacterial drugs, including the drug Sievextro, while its severity ranged from mild diarrhea to fatal colitis. Treatment with antibacterial drugs can disrupt the normal microflora of the colon and, thus, provoke excessive growth Clostridium difficile.

In all patients with diarrhea after antibiotic use, the likelihood of diarrhea associated with Clostridium difficile. It is necessary to carefully collect the anamnesis, as it was reported on the development of diarrhea in 2 and more months after the use of antibacterial drugs.

If you suspect or confirm diarrhea associated with Clostridium difficile, it is necessary to cancel, if possible, the administration of tadizolide phosphate and other antibacterial drugs not directed against Clostridium difficile. In this case, immediate therapy should be prescribed. Drugs that inhibit the intestinal peristalsis are contraindicated.

Development of resistance

The use of the drug Sivextro in the absence of a proven or suspected bacterial infection or its use for prophylactic purposes is unlikely to benefit the patient, and at the same time increase the risk of developing drug-resistant bacteria.

Features of contraception in women with childbearing potential

Women with childbearing potential should use reliable contraceptives when taking tadizolide phosphate. At present, it is not known whether tvedisolide phosphate to lower the effectiveness of hormonal contraceptives, therefore, women taking hormonal contraceptives should use additional methods of contraception.

Limitation of clinical data

The safety and efficacy of tadizolide phosphate for longer than 6 days is not established.

Complicated infections of the skin and soft tissues were limited only to cellulitis / erysipelatous inflammation, an extensive cutaneous abscess and wound infection. Other types of skin infections have not been studied.

There is limited experience with the use of tadizolide phosphate in the treatment of patients with concomitant complicated infections of the skin and soft tissues and secondary bacteremia. Experience in the treatment of patients with complicated infections of the skin and soft tissue with acute sepsis or septic shock is absent. Controlled clinical trials do not include patients with neutropenia (neutrophil count <1000 cells / mm³) or patients with significantly weakened immunity.

Effect on the ability to drive transp. cf. and fur:

The drug Sivextro can cause dizziness, nausea and, in rare cases, drowsiness, so it can affect the ability to drive vehicles and mechanisms.

Form release / dosage:

Tablets, film-coated, 200 mg.

Packaging:

For 6 tablets in an aluminum / polyvinyl chloride / polyvinylidene chloride foil blister,1 blister with instructions for use is placed in a cardboard box.

Storage conditions:

At a temperature of 15 to 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003761

Date of registration:29.07.2016

Expiration Date:29.07.2021

The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp21.08.2016

Illustrated instructions

Instructions

Sivekstro (Sivextro)