TYGACIL

Tigecycline is a glycylcycline antibiotic developed and marketed by Wyeth under the brand name Tygacil.

It was developed in response to the growing prevalence of antibiotic resistance in bacteria such as Staphylococcus aureus.

It was granted fast-track approval by the U.S. Food and Drug Administration (FDA) on June 17, 2005.

For the treatment of infections caused by susceptible strains of the designated microorganisms in the following conditions: Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus ), Streptococcus pyogenes and Bacteroides fragilis.

Complicated intra-abdominal infections caused by

Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus ), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Tigecycline is the first clinically-available drug in a new class of antibiotics called the glycylcyclines.

Glycylcyclines are a new class of antibiotics derived from tetracycline.

These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection.

Glycylcycline antibiotics have a similar mechanism of action as tetracycline antibiotics.

Both classes of antibiotics bind to the 30S ribosomal subunit to prevent the amino-acyl tRNA from binding to the A site of the ribosome.

However, the glycylcyclines appear to bind more effectively than the tetracyclines.

16S ribosomal RNA (Enteric bacteria and other eubacteria) Inhibitor Small ribosomal subunit protein uS9 (Escherichia coli (strain K12)) Inhibitor Small ribosomal subunit protein uS12 (Escherichia coli (strain K12)) Inhibitor + 3 more targets.

Tigecycline is not extensively metabolized.

In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites.

A glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) are the primary metabolites.

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Since glycylcyclines are similar to tetracyclines, they share many of the same side effects and contraindications as tetracyclines.

These side effects may include nausea/vomiting, headache, photosensitivity, discoloration of growing teeth, and fetal damage.

Tigecycline for injection is contraindicated for use in patients who have known hypersensitivity to tigecycline or to any of the excipients.

Reactions have included anaphylactic reactions.

Known hypersensitivity to tigecycline.

Initial dose of 100 mg, followed by 50 mg every 12 hours administered intravenously over approximately to 60 minutes.

Severe hepatic impairment (Child Pugh C): Initial dose of 100 mg followed by 25 mg every 12 hours.

Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecyclineetracycline. 2.1 Recommended Adult Dosage The recommended dosage regimen for tigecycline for injection is an initial dose of 100 mg, followed by 50 mg every 12 hours.

Intravenous infusions of tigecycline for injection should be administered over approximately to 60 minutes every 12 hours.

The recommended duration of treatment with tigecycline for injection for complicated skin and skin structure infections or for complicated intra-abdominal infections is to 14 days.

The recommended duration of treatment with tigecycline for injection for community-acquired bacterial pneumonia is to 14 days.

The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress. 2.2 Dosage in Patients With Hepatic Impairment No dosage adjustment is warranted 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 initial dose of tigecycline for injection should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours.

Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response. 2.3 Dosage in Pediatric Patients The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with tigecycline for injection in adult patients.

Avoid use of tigecycline for injection in pediatric patients unless no alternative antibacterial drugs are available.

Under these circumstances, the following doses are suggested: Pediatric patients aged to 11 years should receive 1.2 mg/kg of tigecycline for injection every 12 hours intravenously to a maximum dose of 50 mg of tigecycline for injection every 12 hours.

Pediatric patients aged to 17 years should receive 50 mg of tigecycline for injection every 12 hours.

The proposed pediatric doses of tigecycline for injection were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients.

There are no data to provide dosing recommendations in pediatric patients with hepatic impairment. 2.4 Monitoring of Blood Coagulation Parameters Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecycline for injection. 2.5 Preparation and Administration Each vial of tigecycline for injection should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer’s Injection, USP to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug). The vial should be gently swirled until the drug dissolves.

Reconstituted solution must be transferred and further diluted for intravenous infusion.

Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial).

The maximum concentration in the intravenous bag should be 1 mg/mL.

The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration.

Once reconstituted, tigecycline for injection may be stored at room temperature (not to exceed 25ºC/77ºF) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag).

If the storage conditions exceed 25ºC (77ºF) after reconstitution, tigecycline should be used immediately.

Alternatively, tigecycline for injection mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

Tigecycline for injection may be administered intravenously through a dedicated line or through a Y-site.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of tigecycline for injection with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer’s Injection, USP.

Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line. 2.6 Drug Compatibilities Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer’s Injection, USP.

When administered through a

Y-site, tigecycline for injection is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer’s, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin. 2.7 Drug Incompatibilities The following drugs should not be administered simultaneously through the same Y-site as tigecycline for injection: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole, and omeprazole.

Tigecycline for injection, USP is supplied in a single-dose 5 mL glass vial, each containing 50 mg tigecycline, USP lyophilized powder for reconstitution.

Supplied: 10 single-dose vials in one box.

NDC 60505-6098-1 Prior to reconstitution, tigecycline for injection, USP should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

The reconstituted solution of tigecycline for injection, USP may be stored at room temperature (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag) .

Tigecycline for injection, like other tetracycline class antibacterial drugs, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy.

There are no available data on the risk of major birth defects or miscarriage following the use of tigecycline for injection during pregnancy.

Administration of intravenous tigecycline in pregnant rats and rabbits during the period of organogenesis was associated with reduction in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of and 1 times the human exposure at the recommended clinical dose in rats and rabbits, respectively.

Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

S. general population, the estimated background risk in clinically recognized pregnancies is to 4% and to 20%, respectively.

The use of tetracycline-class antibacterial drugs, that includes tigecycline for injection, during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth.

This adverse reaction is more common during long-term use of tetracyclines but has been observed following repeated short-term courses.

Tigecycline for injection may cause reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy.

A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours.

In embryo-fetal development studies, tigecycline was administered during the period of organogenesis at doses up to 12 mg/kg/day in rats and 4 mg/kg in rabbits or and 1 times the systemic exposure at the recommended clinical dose, respectively.

In the rat study, decreased fetal weight and fetal skeletal variations (reduced ossification of the pubic, ischial, and supraoccipital bones and increased incidences of rudimentary 14 th rib) were observed in the presence of maternal toxicity at 12 mg/kg/day (5 times the recommended clinical dose based on systemic exposure).

In rabbits, decreased fetal weights were observed in the presence of maternal toxicity at 4 mg/kg (equivalent to the human exposure at the recommended clinical dose).

In preclinical safety studies, 14 C-labeled tigecycline crossed the placenta and was found in fetal tissues.

There are no data on the presence of tigecycline in human milk; however, tetracycline-class antibacterial drugs are present in breast milk.

It is not known whether tigecycline has an effect on the breastfed infant or on milk production.

Tigecycline has low oral bioavailability; therefore, infant exposure is expected to be low.

Tigecycline is present in rat milk with little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.

When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tigecycline for injection and any potential adverse effects on the breastfed child from tigecycline for injection or from the underlying maternal condition.

Because of the theoretical risk of dental discoloration and inhibition of bone growth, avoid breastfeeding if taking tigecycline for injection for longer than three weeks.

A lactating woman may also consider interrupting breastfeeding and pumping and discarding breastmilk during administration of tigecycline for injection and for 9 days (approximately 5 half-lives) after the last dose in order to minimize drug exposure to a breastfed infant.

Of the total number of subjects who received tigecycline for injection in Phase 3 clinical studies (n=2,514), 664 were and over, while were 75 and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline.