Tygacil - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Tigecycline

Tygacil 50 mg powder for solution for infusion

Why is Tygacil used? What is it for?

Tygacil is an antibiotic from the glycylcycline group that works by stopping the growth of bacteria that cause infections.

Your doctor has prescribed Tygacil for you because you or your child who is at least 8 years old has one of the following types of serious infection:

  • Complicated skin (skin) and soft tissue (tissue under the skin) infection, excluding diabetic foot infections.
  • Complicated infection of the abdomen

Tygacil is only used when your doctor thinks that other antibiotics are not suitable.

Contraindications When Tygacil should not be used

Do not use Tygacil

  • If you are allergic (hypersensitive) to tigecycline, the active substance in Tygacil. If you are allergic to the tetracyclin class of antibiotics (e.g. minocycline, doxycycline, etc.), you may also be allergic to tigecycline.

Precautions for use What you need to know before you take Tygacil

Talk to your doctor or nurse before using Tygacil:

  • if you develop poor or slow wound healing.
  • if you are suffering from diarrhea before Tygacil treatment. If you get diarrhea during or after treatment with Tygacil, tell your doctor immediately. Do not take diarrhea medications without first checking with your doctor.
  • if you have or have previously had any side effects due to antibiotics belonging to the tetracyclines class (for example skin sensitization due to sunlight, stains in growing teeth, inflammation of the pancreas and changes in some laboratory values ​​carried out to evaluate the blood clotting ability).
  • if you are taking certain medicines (called anticoagulants) used to prevent excessive blood clotting (see also "Other medicines and Tygacil" in this leaflet).
  • if you are taking birth control pills as you may need to use additional contraception during treatment with Tygacil (see also "Other medicines and Tygacil" in this leaflet).
  • if you have or have previously had liver problems. Depending on the condition of your liver, your doctor may reduce the dose to avoid side effects.

During treatment with Tygacil:

  • Tell your doctor right away if you develop symptoms of an allergic reaction.
  • Tell your doctor immediately if you develop severe abdominal pain, nausea and vomiting; because they could be symptoms of acute pancreatitis (i.e. inflamed pancreas, which can lead to severe abdominal pain, nausea and vomiting).
  • For certain severe infections, your doctor may decide to use Tygacil in combination with other antibiotics.
  • Your doctor will monitor you closely for the development of any other bacterial infections. In this case, he or she may prescribe a different antibiotic, specific to the type of infection.
  • Although antibiotics such as Tygacil fight some bacteria, other bacteria and fungi can continue to grow; this phenomenon is called overgrowth. Your doctor will closely monitor you for any possible infection and treat you if necessary.

Children and adolescents

Tygacil should not be used in children less than 8 years of age due to a lack of data on safety and efficacy in this age group and because it can induce permanent tooth defects such as stains in developing teeth.

Interactions Which drugs or foods can change the effect of Tygacil

Always tell your doctor if you are taking or have recently taken any other medicines.

Tygacil can extend some tests that measure how well your blood clots. It is important that you tell your doctor if you are taking any medications to avoid excessive blood clotting. In this case, your doctor will closely monitor you.

Tygacil can interfere with the birth control pill (birth control pill). Talk to your doctor about the need for additional contraception during treatment with Tygacil.

Warnings It is important to know that:

Pregnancy and breastfeeding

Tygacil can cause fetal harm. If you are pregnant, or planning to become pregnant, consult your doctor before taking Tygacil.

It is not known whether Tygacil is excreted in human milk. Ask your doctor for advice before breastfeeding your baby.

Driving and using machines

Tygacil can cause side effects such as dizziness. This may affect the ability to drive or use machines.

Dose, Method and Time of Administration How to use Tygacil: Posology

Tygacil will be given to you by a doctor or nurse.

The recommended dose in adults is 100 mg initially, followed by a dose of 50 mg every 12 hours. This dose is given intravenously (directly into your blood) over a period of 30 to 60 minutes.

The recommended dose in children 8 to <12 years of age is 1.2 mg / kg administered intravenously every 12 hours up to a maximum dose of 50 mg every 12 hours.

The recommended dose in adolescents 12 to <18 years of age is 50 mg given every 12 hours

. A course of treatment usually lasts from 5 to 14 days. Your doctor will decide how long you need to be treated for.

Overdose What to do if you have taken too much Tygacil

If you use more Tygacil than you should

If you are concerned because you think you have received too much Tygacil, speak to your doctor or nurse immediately.

If you miss a dose of Tygacil

If you are concerned because you think you have forgotten a dose, talk to your doctor or nurse immediately.

Side Effects What are the side effects of Tygacil

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequency of possible side effects listed below is defined using the following convention

: Very common (may affect more than 1 in 10 people)

Common (may affect up to 1 in 10 people)

Uncommon (may affect up to 1 in 100 people)

Rare (may affect up to 1 in 1,000 people)

Very rare (may affect up to 1 in 10,000 people)

Not known (frequency cannot be estimated from the available data)

Very common side effects are:

  • Nausea, vomiting and diarrhea.

Common side effects are:

  • Abscess (collection of pus), infections;
  • Laboratory tests attesting to decreased coagulation capacity;
  • Dizziness
  • Vein irritation due to injection including pain, inflammation, swelling and clotting:
  • abdominal pain, dyspepsia (stomach pain and indigestion), anorexia (loss of appetite);
  • Increased liver enzymes, hyperbilirubinaemia (excess bile pigments in the blood)
  • Itching, skin rash;
  • Poor or slow wound healing
  • Headache
  • Increase in amylase, an enzyme found in the salivary glands and pancreas, increase in urea nitrogen (BUN);
  • Pneumonia;
  • Low blood sugar levels
  • Sepsis (severe infection in the body and blood) / septic shock (serious medical condition that can lead to multiple organ damage and death as a result of sepsis);
  • Reactions at the injection site (pain, redness, inflammation);
  • Low levels of protein in the blood

Uncommon side effects are:

  • Acute pancreatitis (inflammation of the pancreas which can manifest itself as severe abdominal pain, nausea and vomiting);
  • Jaundice (yellowing of the skin), inflammation of the liver;
  • Low levels of platelets in the blood (which could lead to an "increased tendency to bleed and bruising / hematoma).

Unknown side effects are:

  • Anaphylactic / anaphylactoid reaction (which can be mild to severe, including a "sudden and generalized allergic reaction which can lead to life-threatening shock [eg difficulty in breathing, rapid drop in blood pressure, rapid pulse];
  • Liver failure; (liver)
  • Skin reaction, which can result in severe blistering and cracking of the skin (Stevens-Johnson Syndrome).

Pseudomembranous colitis can occur with most antibiotics including Tygacil. It consists of severe, persistent diarrhea or bloody diarrhea associated with abdominal pain or fever, which may be a sign of severe "bowel inflammation" which may occur during or after your treatment

Reporting of side effects

If you get any side effects, talk to your doctor. 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.

Expiry and Retention

Keep out of the sight and reach of children

Tygacil should be stored below 25 C.

Do not use Tygacil after the expiry date printed on the vial.

The expiry date refers to the last day of the month

Preservation after preparation

Once the powder has been dissolved in a solution and diluted for use, it should be given to you immediately.

The Tygacil solution after dissolution must be yellow to orange in color; if this is not the case, the solution must be discarded.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Tygacil contains

The active ingredient is tigecycline. Each vial contains 50 mg of tigecycline.

The other ingredients are lactose monohydrate, hydrochloric acid, and sodium hydroxide.

What Tygacil looks like and contents of the pack

Tygacil is supplied as a powder for solution for infusion in a vial and has the appearance of an orange powder or tablet before being diluted. These vials are distributed to hospitals in a pack of ten vials. The powder must be mixed in the vial with one. small amount of solution. The vial should be shaken gently until the drug dissolves. Thereafter, the solution should be withdrawn immediately from the vial and added to a 100 ml intravenous infusion bag or other suitable container for infusion into hospital.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Tygacil can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TYGACIL

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml vial of Tygacil contains 50 mg of tigecycline. After reconstitution, 1 ml contains 10 mg of tigecycline.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Powder for solution for infusion.

Orange colored lyophilized powder or tablet.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Tygacil is indicated for the treatment of the following infections (see sections 4.4 and 5.1):

• complicated skin and soft tissue infections, excluding diabetic foot infections (see section 4.4)

• complicated intra-abdominal infections

Refer to the official guidelines on the appropriate use of antibiotics.


04.2 Posology and method of administration

Dosage

The recommended dose for adults is a starting dose of 100 mg followed by 50 mg every 12 hours for 5-14 days.

The duration of therapy should be guided by the severity, site of infection and the patient's clinical response.

Hepatic insufficiency

No dosage adjustment is required in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B).

In patients with severe hepatic impairment (Child Pugh C), the Tygacil dose should be reduced to 25 mg every 12 hours following a 100 mg loading dose. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for response to treatment (see sections 4.4 and 5.2).

Kidney failure

No dosage adjustment is required in patients with renal insufficiency or in patients undergoing hemodialysis (see section 5.2).

Elderly patients

No dosage adjustment is necessary in elderly patients (see section 5.2).

Pediatric patients

Tygacil is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy (see sections 5.2 and 4.4).

Method of administration

Tygacil is administered by intravenous infusion only, over a period of 30 to 60 minutes (see section 6.6).


04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to tigecycline.


04.4 Special warnings and appropriate precautions for use

Anaphylactic / anaphylactoid reactions, potentially life-threatening, have been reported with tigecycline (see sections 4.3 and 4.8).

Cases of hepatic injury with predominantly cholestatic characteristics have been reported in patients receiving tigecycline, including some cases of hepatic failure with fatal outcomes. Although hepatic failure may occur in patients treated with tigecycline due to latent co-morbidity or concomitant treatments, a possible contribution of tigecycline should be considered (see section 4.8).

Antibiotics of the glycylcycline class are structurally similar to the tetracyclines class of antibiotics. Tigecycline can cause similar adverse reactions to antibiotics of the tetracycline class. Such reactions may include photosensitivity, pseudotumor cerebri, pancreatitis and an anti-anabolic action leading to increased urea nitrogen (BUN), BUN, acidosis and hyperphosphataemia (see section 4.8).

Acute pancreatitis, which can be severe, has occurred (frequency: uncommon) in association with tigecycline treatment (see section 4.8). The diagnosis of acute pancreatitis should be made in patients taking tigecycline who develop clinical symptoms, signs or laboratory abnormalities related to acute pancreatitis. The majority of reported cases developed after at least one week of treatment. Cases have been reported in patients with no known risk factors for pancreatitis. Patients generally improve after stopping tigecycline. Discontinuation of tigecycline treatment should be considered in cases where there is a suspicion that you have developed pancreatitis.

There is "limited experience" of the use of tigecycline in the treatment of infections in patients with severe underlying conditions.

In clinical trials of complicated skin and soft tissue infections, the most common type of infection in patients treated with tigecycline was cellulitis (59%), followed by major abscesses (27.5%). Patients with severe Concomitant conditions, such as immunocompromised ones, patients with pressure ulcer infections, or patients with infections requiring treatment longer than 14 days (for example: necrotizing fasciitis) were not enrolled. co-morbidities such as diabetes (20%), peripheral vascular disease (7%), intravenous drug abuse (2%) and HIV infections (1%). There was also a "limited experience in treating patients with concomitant bacteraemia (3%). Therefore, caution is advised when treating these patients. The results of a large study in patients with diabetic foot infections showed that tigecycline was less effective than the therefore, tigecycline is not recommended in these patients. (see paragraph 4.1)

In clinical trials of complicated intra-abdominal infections, the most common type of infection in patients treated with tigecycline was complicated appendicitis (51%), followed by other less commonly reported diagnoses, such as complicated cholecystitis (14%). , intra-abdominal abscesses (10%), bowel perforation (10%) and gastric or duodenal ulcers that have been perforated for less than 24 hours (5%). Of these patients, 76% had associated diffuse peritonitis (surgically evident peritonitis ). C "there were a limited number of patients with concomitant serious illnesses such as immunocompromised patients, patients with an APACHE II score> 15 (4%) or with multiple surgically detected intra-abdominal abscesses (10%). There was "limited" experience in the treatment of patients with concomitant bacteraemia (6%). Therefore caution is advised when treating these patients.

The use of combination antibacterial therapy should be considered when tigecycline is administered to severe patients with complicated intra-abdominal infections (cIAI) secondary to clinically evident intestinal perforation or patients with incipient sepsis or septic shock (see section 4.8).

The effect of cholestasis on tigecycline pharmacokinetics has not been adequately established.

Biliary excretion accounts for approximately 50% of total tigecycline excretion. Therefore patients with cholestasis should be monitored closely.

If tigecycline is administered with anticoagulants, prothrombin time or other suitable coagulation tests should be performed to monitor patients (see section 4.5).

Pseudomembranous colitis has been reported with almost all antibacterials and the severity can range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or following the administration of any antibacterial (see section 4.8).

The use of tigecycline may lead to overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. Should superinfection occur, appropriate measures should be used (see section 4.8).

The results of studies in rats treated with tigecycline showed bone discoloration. Tigecycline may be associated with permanent tooth discoloration in humans if used during teething (see section 4.8).

Tygacil should not be used in children below 8 years of age due to tooth discoloration, and is not recommended in adolescents below 18 years due to a lack of data on safety and efficacy (see sections 4.2 and 4.8).


04.5 Interactions with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Concomitant administration of tigecycline and warfarin (25 mg in a single dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin of 40% and 23%, respectively, and an increase in AUC of 68%. and 29% respectively. The mechanism of this interaction is not yet clear. Available data do not indicate that this interaction could result in significant changes in the International Normalized Ratio (INR). However, since tigecycline can prolong both prothrombin time (PT) and partially activated thromboplastin time (aPTT), appropriate coagulation tests should be closely monitored when tigecycline is co-administered with anticoagulants (see section 4.4). Warfarin did not affect the pharmacokinetic profile of tigecycline.

Tigecycline is not completely metabolized. Therefore, the clearance of tigecycline is not expected to be affected by active substances that inhibit or induce the activity of these CYP450 isoforms.

In vitro, tigecycline is neither a competitive inhibitor nor an irreversible inhibitor of CYP450 enzymes (see section 5.2).

At recommended dosages, tigecycline did not affect the rate, amount of absorption or clearance of digoxin (0.5 mg followed by 0.25 mg per day) when administered to healthy adults. Digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore no dosage adjustment is necessary when tigecycline is administered with digoxin.

In the studies in vitro, no antagonism was observed between tigecycline and other commonly used classes of antibiotics.

The concomitant use of antibiotics with oral contraceptives can make oral contraceptives less effective.


04.6 Pregnancy and breastfeeding

There are no adequate data on the use of tigecycline in pregnant women. Results from animal studies have shown that tigecycline may cause fetal harm when administered during pregnancy (see section 5.3.). The potential risk to humans. is unknown.As known for the antibiotics of the tetracycline class, tigecycline can also induce permanent dental defects (discoloration and enamel defects) and a delay in ossification processes both in fetuses, exposed in the uterus during the last half of gestation, and in children under eight years of age due to accumulation in tissues with high calcium turnover and the formation of calcium chelate complexes (see section 4.4). Tigecycline should not be used during pregnancy unless is strictly necessary.

It is not known whether this drug is excreted in human milk. In animal studies, tigecycline is secreted in the milk of lactating rats. When treatment with tigecycline is ongoing, caution should be used and consideration should be given to discontinuing breastfeeding as a potential risk to the infant cannot be excluded (see section 5.3).


04.7 Effects on ability to drive and use machines

No studies on the effects of tigecycline on the ability to drive and use machines have been performed. Dizziness may occur and this may have an effect on driving and use of machines (see section 4.8).


04.8 Undesirable effects

The total number of patients treated with tigecycline in phase 3 clinical trials was 1,415. Adverse reactions were reported in approximately 41% of patients treated with tigecycline. In 5% of patients the treatment was stopped due to adverse reactions.

In clinical trials, the most common study drug-related adverse reactions were reversible nausea (20%) and vomiting (14%), which usually occurred early (days 1-2 of treatment) and were generally mild to moderate intensity.

Adverse reactions reported with Tygacil, including those from clinical trials and post marketing experience, are listed below:

The frequency categories are expressed as follows: very common (≥1 / 10); common (≥1 / 100 to

For adverse reactions identified from post-marketing experience with Tygacil resulting from spontaneous reports for which the frequency cannot be estimated, the frequency is categorized as unknown.

Infections and infestations

Common: abscess, infections.

Uncommon: sepsis, septic shock.

In Phase 3 clinical trials, infection-related serious adverse events occurred more frequently in subjects treated with tigecycline (6.7%) than in comparators (4.6%). Significant differences in sepsis / septic shock were observed in patients treated with tigecycline (1.5%) compared to comparators (0.5%).

Disorders of the blood and lymphatic system

Common: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT).

Uncommon: increase in the International Normalized Ratio (INR).

Not known: thrombocytopenia.

Disorders of the immune system

Not known: anaphylactic / anaphylactoid reactions (see sections 4.3 and 4.4).

Metabolism and nutrition disorders

Uncommon: hypoproteinemia.

Nervous system disorders

Common: dizziness.

Vascular pathologies

Common: phlebitis.

Uncommon: thrombophlebitis.

Gastrointestinal disorders

Very common: nausea, vomiting and diarrhea.

Common: abdominal pain, dyspepsia, anorexia.

Uncommon: acute pancreatitis (See section 4.4).

Hepatobiliary disorders

Common: elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), hyperbilirubinaemia.

Abnormalities in AST and ALT values ​​in Tygacil-treated patients were reported more frequently in the post-therapy period than in comparator-treated patients, where these events occurred more often during therapy.

Uncommon: jaundice, liver damage, usually cholestatic.

Not known: hepatic failure (see section 4.4).

Skin and subcutaneous tissue disorders

Common: pruritus, rash.

General disorders and administration site conditions

Common: headache.

Uncommon: injection site reactions, injection site inflammation, injection site pain, injection site edema, injection site phlebitis.

Diagnostic tests

Common: elevated serum amylase levels, increased urea nitrogen (BUN).

In all phase 3 and 4 studies, in complicated skin and soft tissue infections (cSSSI) and complicated intra-abdominal infections (cIAI), deaths occurred in 2.3% (52/2216) of patients who received tigecycline and 1.5% (33/2206) of patients who received comparator drugs.

Class effects of antibiotics

Pseudomembranous colitis which can range from mild to life-threatening (see section 4.4).

Overgrowth of non-susceptible organisms, including fungi (see section 4.4).

Class effects of tetracyclines

The Glycylcycline class of antibiotics is structurally similar to the Tetracyclines class of antibiotics. Tetracycline class adverse reactions may include photosensitivity, pseudo brain tumors, pancreatitis and anti-anabolic actions leading to an increase in BUN, azotaemia, acidosis and hyperphosphataemia (see section 4.4).

Tigecycline may be associated with permanent tooth discoloration if used during tooth development (see section 4.4).


04.9 Overdose

No specific information is available on the treatment of overdose. Intravenous administration of a single 300 mg dose of tigecycline over a period of 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. Tigecycline is not significantly removed by hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: tetracyclines; ATC code: J01AA12

Mechanism of action

Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking the entry of amino-acyl tRNA molecules into site A of the ribosome. This prevents the incorporation of amino acid residues into the elongation chains of the peptides.

In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory concentration (MIC) a 2-log reduction in colony counts was observed with tigecycline per Enterococcus spp., Staphylococcus aureus, and Escherichia coli.

Resistance mechanism

Tigecycline is capable of overcoming the two major mechanisms of resistance to tetracyclines, ribosomal protection and efflux. Cross-resistance has occurred between tigecycline and minocycline-resistant isolates belonging to Enterobacteriaceae due to Multi Drug Resistance (MDR) efflux pumps. There is no target-level cross-resistance between tigecycline and most classes of antibiotics.

Tigecycline is vulnerable to chromosomally encoded MDR efflux pumps Proteeae and of Pseudomonas aeruginosa.

The pathogens of the family Proteeae (Proteus spp., Providencia spp., e Morganella spp.) are generally less sensitive to tigecycline than other members of the Enterobacteriaceae. Decreased sensitivity in both groups was attributed to overexpression of the non-specific AcrAB multi-drug efflux pump. A decreased sensitivity to "Acinetobacter baumannii has been attributed to the overexpression of the AdeABC efflux pump.

Breakpoints

The Minimum Inhibitory Concentrant (MIC) breakpoints established by the European Committee on Antibacterial Sensitivity Tests (EUCAST) are as follows:

Staphylococcus spp S ≤0.5 mg / L and R> 0.5 mg / L

Streptococcus spp. different from S. pneumoniae S ≤0.25 mg / L and R> 0.5 mg / L

Enterococcus spp. S ≤0.25 mg / L and R> 0.5 mg / L

• Enterobacteriaceae S ≤1 (^) mg / L and R> 2 mg / L

(^) Tigecycline has decreased activity in vitro on Proteus, Providencia And Morganella spp.

For anaerobic bacteria there is clinical evidence of efficacy in polymicrobial intra-abdominal infections, but there is no correlation between MIC values, pharmacokinetic and pharmacodynamic data and clinical outcome. Therefore, no breakpoint was assigned for sensitivity. It should be noted that MIC distributions for such organisms Bacteroides And Clostridium they are large and may include values ​​in excess of 2 mg / L of tigecycline.

There is "limited experience" on the clinical efficacy of tigecycline against enterococci. However, intra-abdominal polymicrobial infections have been shown to respond to tigecycline treatment in clinical trials.

Sensitivity

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, when the local prevalence of resistance is such that the utility of the drug in certain types of infections is questionable, an expert should be consulted.

Pathogen Commonly sensitive species Gram-positive aerobes Enterococcus spp. † Staphylococcus aureus * Staphylococcus epidermidis Staphylococcus haemolyticus Streptococcus agalactiae * Streptococcus anginosus group * (including S. anginosus, S. intermedius and S. constellatus) Streptococcus pyogenes * Viridans group streptococci Gram-negative aerobes Citrobacter freundii * Citrobacter koseri Escherichia coli * Klebsiella oxytoca * Anaerobes Clostridium perfringensPeptostreptococcus spp. † Prevotella spp. Species for which acquired stamina could be a problem Gram-negative aerobes Acinetobacter baumannii Burkholderia cepacia Enterobacter aerogenes Enterobacter cloacae * Klebsiella pneumoniae * Morganella morganii Proteus spp. Providencia spp. Serratia marcescens Stenotrophomonas maltophilia Anaerobes Bacteroides fragilis group† Inherently resistant organisms Gram-negative aerobes Pseudomonas aeruginosa

* Denotes the species for which it has been assessed that activity in clinical studies has been satisfactorily demonstrated

† see section 5.1 concerning Breakpoint


05.2 "Pharmacokinetic properties

Absorption

Tigecycline is administered intravenously and therefore has 100% bioavailability.

Distribution

The binding of tigecycline to plasma proteins in vitro, ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg / ml). Pharmacokinetic studies in animals and humans have shown that tigecycline distributes rapidly into tissues .

In rats receiving single or multiple doses of 14C-tigecycline, radioactivity was well distributed in most tissues, with the highest total exposure observed in bone marrow, salivary glands, thyroid, spleen and kidneys. In humans. , the steady-state volume of distribution of tigecycline ranged from 500 to 700 L (7 to 9 L / kg), indicating that tigecycline is extensively distributed beyond plasma volume and concentrates in tissues.

There are no data available regarding the possibility that tigecycline can cross the blood-brain barrier in humans.

In clinical pharmacology studies using the 100 mg therapeutic dosing regimen followed by 50 mg every 12 hours, steady state serum tigecycline Cmax was 866 ± 233 ng / ml for a 30 minute infusion. and 634 ± 97 ng / mL for a 60 minute infusion. The 0-12h AUC at steady state was 2349 ± 850ng · h / ml.

Metabolism

On average, it is estimated that less than 20% of tigecycline is metabolized prior to excretion. In healthy male volunteers who received 14C-tigecycline, unchanged tigecycline was the major 14C-labeled substance found in urine and faeces, where however, a glucuronide, an N-acetyl metabolite and an epimer of tigecycline were also present.

Education in vitro on human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the 6 cytochrome P450 (CYP) isoforms: 1A 2, 2C8, 2C9, 2C19, 2D6 and 3A 4 by competitive inhibition. Furthermore, tigecycline did not show NADPH-dependence in the inhibition of the cytochromes CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of an inhibition at the level of the mechanism of these enzymes.

Elimination

Recovery of total radioactivity in faeces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary / faecal excretion, and 33% is excreted in the urine. In general, the primary route of elimination for tigecycline is biliary excretion of unmodified tigecycline. Glucuronization and urinary excretion of unmodified tigecycline are secondary routes of elimination.

Total clearance of tigecycline is 24 L / h after intravenous infusion. Renal clearance is approximately 13% of the total clearance. Tigecycline exhibits polyexponential elimination from serum with a mean terminal elimination half-life after multiple doses of 42 hours although there is high interindividual variability.

Special populations

Hepatic insufficiency

The single dose pharmacokinetic profile of tigecycline was not changed in patients with mild hepatic impairment. However, the systemic clearance of tigecycline was reduced by 25% and 55% and the half-life of tigecycline was prolonged by 23% and 43% in patients with moderate or severe hepatic impairment, respectively (Child Pugh B and C). , (see section 4.2).

Kidney failure

The single dose pharmacokinetic profile of tigecycline was not changed in patients with renal insufficiency (creatinine clearance

Elderly patients

No overall differences in the pharmacokinetics of healthy elderly versus younger subjects were observed (see section 4.2).

Pediatric patients

The pharmacokinetics of tigecycline in patients less than 18 years of age have not been established (see section 4.2).

Sex

There were no clinically relevant differences in tigecycline clearance between men and women. The AUC was estimated to be 20% higher in women than in men.

Race

There were no differences in the clearance of tigecycline based on race.

Weight

Normalized clearance for weight and AUC were not substantially different between patients with different body weights, including patients weighing ≥125 kg. AUC was 24% lower in patients weighing ≥125 kg. There are no data available for patients weighing 140 kg or more.


05.3 Preclinical safety data

In repeat dose toxicity studies in rats and dogs, lymphoid depletion / atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes and platelets, in association with bone marrow hypocellularity, and adverse events were observed renal and gastrointestinal changes with tigecycline at exposures 8 times and 10 times the human daily dose based on AUC in rats and dogs, respectively. These changes were shown to be reversible after two weeks of treatment.

Non-reversible bone discoloration was observed in rats after two weeks of treatment.

Results from animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. In reproductive toxicity studies, decreased fetal weight in rats and rabbits (with associated ossification delays) and fetal loss in rabbits were observed with tigecycline. Tigecycline was not teratogenic in rats or rabbits.

Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is rapidly excreted via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systematic exposure to tigecycline in pups that are nursed as a result of exposure via breast milk.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline, but short-term genotoxicity studies of tigecycline were negative.

In animal studies, intravenous bolus administration of tigecycline was associated with a histamine response. These effects were observed at exposures of 14 times and 3 times the human daily dose based on AUC in rats and dogs, respectively.

No evidence of photosensitivity was observed in rats following administration of tigecycline.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Lactose monohydrate.

Hydrochloric acid, sodium hydroxide (for pH adjustment).


06.2 Incompatibility

The following active substances must not be administered simultaneously with Tygacil through the same Y-line: amphotericin B, lipid complex of amphotericin B, diazepam, esomeprazole, omeprazole and intravenous solutions which could cause an increase in pH above 7.

Tygacil must not be mixed with other medicinal products for which no compatibility data are available (see section 6.6).


06.3 Period of validity

24 months.

Once reconstituted and diluted in a bag or other suitable infusion container (eg glass bottle), tigecycline should be used immediately.


06.4 Special precautions for storage

Store at or below 25 ° C.

For storage conditions of the reconstituted product see section 6.3.


06.5 Nature of the immediate packaging and contents of the package

Clear glass vials (5 ml, type I glass) closed with gray butyl rubber stoppers and removable aluminum seals. Tygacil is distributed in packs of 10 vials.


06.6 Instructions for use and handling

The lyophilized powder should be reconstituted with 5.3 ml of sodium chloride 9 mg / ml (0.9%) solution for infusion, with 50 mg / ml (5%) dextrose solution for infusion or with lactated Ringer's solution. by infusion to obtain a concentration of 10 mg / ml of tigecycline. The vial should be shaken slowly until the product is dissolved. Thereafter, 5 ml of the reconstituted solution should be immediately withdrawn from the vial and added to a 100 ml intravenous infusion bag or other suitable infusion container (eg glass bottle).

For a 100 mg dose, reconstitute using two vials in a 100 ml intravenous infusion bag or other suitable infusion container (eg glass bottle).

(Note: the vial contains an excess of 6%. Therefore 5 ml of the reconstituted solution is equivalent to 50 mg of the active substance). The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral products should be visually inspected for the presence of corpuscular material and discoloration (eg green or black) prior to administration.

Tygacil can be administered intravenously through a dedicated line or through a Y line. If the same intravenous line is used for sequential infusions of several active substances, the line should be flushed before and after the Tygacil infusion, or with a sodium chloride 9 mg / ml (0.9%) solution for infusion or with a dextrose 50 mg / ml (5%) solution for infusion. Injection via this common line should be performed with a compatible solution for infusion. with tigecycline and any other drug (see section 6.2).

This drug is for single administration only; any unused solution should be discarded.

Compatible intravenous solutions include: sodium chloride 9 mg / ml (0.9%) solution for infusion, dextrose 50 mg / ml (5%) solution for infusion and Lactated Ringer's solution for infusion.

When administered via a Y-line, compatibility of Tygacil diluted in 0.9% sodium chloride solution for infusion has been demonstrated for the following drugs or diluents: amikacin, dobutamine, dopamine hydrochloride, gentamicin, haloperidol, Ringer Lactate , lidocaine hydrochloride, metoclopramide, morphine, noradrenaline, piperacillin / tazobactam (formulation with EDTA), potassium chloride, propofol, ranitidine hydrochloride, theophylline, and tobramycin.

07.0 MARKETING AUTHORIZATION HOLDER

Wyeth Europe Ltd.

Huntercombe Lane South

Taplow, Maidenhead

Berkshire, SL6 OPH

UK

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/06/336/001 - AIC n. 037046012

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 24 April 2006

10.0 DATE OF REVISION OF THE TEXT

July 2010

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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