Tigecycline

Tigecycline is an injectable antibiotic used for the treatment of infections caused by susceptible bacteria. Tigecycline is similar to tetracycline antibiotics and has activity against a large number of bacteria. Tigecycline binds to bacterial ribosomes which produce the cell's proteins. The binding prevents bacterial ribosomes from producing important proteins needed for bacterial growth and multiplication. Tigecycline prevents bacteria from multiplying, but it does not kill bacteria. Tigecycline was approved by the FDA in June 2005.

Tygacil

Single dose vial: 50 mg

The powder should be stored at room temperature between 15 C - 30 C (59 F - 86 F). Once mixed, it may be stored at room temperature for up to 24 hours (up to six hours in the vial and the remaining time in the intravenous bag). It may also be refrigerated at 2 C - 8 C (36 F - 46 F) for up to 48 hours in an intravenous bag after mixing.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Do not share this medicine with another person, even if they have the same symptoms you have.

Tigecycline is injected into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Tigecycline must be given slowly, and the IV infusion can take up to 60 minutes to complete.

Tigecycline is a powder medicine that must be mixed with a liquid (diluent) in an IV bag before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.

Prepare your dose only when you are ready to give yourself an injection. After mixing, the liquid should appear as a yellow or orange color. Do not use the medication if it has changed to green or black, or if it has any particles in it. Call your doctor for a new prescription.

Do not give any of the following drugs through the same IV line used to give your tigecycline injection:

• amphotericin (Amphocin, Fungizone);
• amphotericin B lipid complex (Abelcet);
• diazepam (Valium); or
• esomeprazole (Nexium I.V.).

Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Tigecycline will not treat a viral infection such as the common cold or flu.

Store unmixed powder at room temperature away from moisture and heat.

Mixed medicine in an IV bag must be used within 24 hours if you keep it at room temperature.

Tigecycline mixed in an IV bag with sodium chloride or dextrose solution may be stored in a refrigerator and used within 48 hours.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

The following serious adverse reactions are described elsewhere in the labeling:

• All-Cause Mortality [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
• Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see WARNINGS AND PRECAUTIONS]
• Anaphylaxis [WARNINGS AND PRECAUTIONS]
• Hepatic Adverse Effects [WARNINGS AND PRECAUTIONS]
• Pancreatitis [WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving TYGACIL and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between TYGACIL and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2. Patients with Outcome of Death by Infection Type

Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).

An analysis of mortality in all trials conducted for approved indications -cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) -showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see WARNINGS AND PRECAUTIONS].

The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 - 2 days of therapy. The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intraabdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.

Discontinuation from TYGACIL was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving TYGACIL in clinical studies:

Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis

Cardiovascular System: thrombophlebitis

Digestive System: anorexia, jaundice, abnormal stools

Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia

Special Senses: taste perversion

Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia

Skin and Appendages: pruritus

Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

• anaphylactic reactions
• acute pancreatitis
• hepatic cholestasis, and jaundice
• severe skin reactions, including Stevens-Johnson Syndrome
• symptomatic hypoglycemia in patients with and without diabetes mellitus

Read the entire FDA prescribing information for Tygacil (Tigecycline)

Tigecycline is a prescription medication used to treat serious skin and stomach infections and certain types of pneumonia (lung infection).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• warfarin (Coumadin)
• birth control pills

This is not a complete list of tigecycline drug interactions. Ask your doctor or pharmacist for more information.

All-cause mortality was higher in patients treated with tigecycline than comparators in a meta-analysis of clinical trials. The cause of this mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. Tigecycline should be reserved for use in situations when alternative treatments are not suitable.

Tigecycline is an antibiotic that fights bacteria in the body.

Tigecycline is used to treat many different bacterial infections of the skin or the digestive system, as well as pneumonia.

Tigecycline should be used only for infections that cannot be treated with other medicines.

Tigecycline may also be used for purposes not listed in this medication guide.

Death has occurred more often in people using tigecycline when compared with people using other antibiotics. Deaths were usually caused by complications from the infection or by other medical conditions. It is not known whether tigecycline treatment causes death.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

Avoid exposure to sunlight or tanning beds. Tigecycline can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Not metabolized by and does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, or 3A4.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely with drugs metabolized by or affecting CYP1A2, 2C8, 2C9, 2C19, 2D6, or 3A4.1

Specific Drugs

• It is used to treat bacterial infections.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about tigecycline, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about tigecycline. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using tigecycline.

Review Date: October 4, 2017

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 30 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 5 to 14 days.
The recommended duration of treatment with Tigecycline for injection for community-acquired bacterial pneumonia is 7 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.

 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 [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].

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 in adult patients.   Avoid use of Tigecycline in pediatric patients unless no alternative antibacterial drugs are available.  Under these circumstances, the following doses are suggested:

• Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of Tigecycline every 12 hours intravenously to a maximum dose of 50 mg of Tigecycline every 12 hours.
• Pediatric patients aged 12 to 17 years should receive 50 mg of Tigecycline every 12 hours.

The proposed pediatric doses of Tigecycline were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].

There are no data to provide dosing recommendations in pediatric patients with hepatic impairment.

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 25°C/77°F) 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 25°C (77°F) 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, or 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.

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, Lactated Ringer’s, lidocaine HCl, metoclopramide, morphine, norepinephrine, potassium chloride, propofol (tested with 5% Dextrose Injection, USP only), ranitidine HCl, theophylline, and tobramycin.

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, haloperidol and omeprazole.

• GAR-936

Pneumonia, community-acquired: IV: Initial: 100 mg as a single dose; Maintenance dose: 50 mg every 12 hours for 7 to 14 days

Intra-abdominal infections, complicated (cIAI): IV: Initial: 100 mg as a single dose; Maintenance dose: 50 mg every 12 hours for 5 to 14 days; Note: 2010 IDSA guidelines recommend a treatment duration of 4 to 7 days (provided source controlled) for community-acquired, mild-to-moderate IAI

Skin/skin structure infections, complicated: IV: Initial: 100 mg as a single dose; Maintenance dose: 50 mg every 12 hours for 5 to 14 days

Add 5.3 mL NS, D5W, or LR to each 50 mg vial. Swirl gently to dissolve. Resulting solution is 10 mg/mL. Reconstituted solution must be further diluted to allow IV administration. Transfer to 100 mL IV bag for infusion (final concentration should not exceed 1 mg/mL). Reconstituted solution should be yellow-orange; discard if not this color.

Warfarin: Tigecycline may increase the serum concentration of Warfarin. Monitor therapy

100 mg IV initial dose, followed by 50 mg IV every 12 hours
Duration of therapy: 5 to 14 days

Approved indication: For the treatment of complicated intraabdominal infections due to susceptible isolates of Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus group (includes S anginosus, S intermedius, and S constellatus), Bacteroides fragilis, B thetaiotaomicron, B uniformis, B vulgatus, Clostridium perfringens, and Peptostreptococcus micros

Proposed for community-acquired bacterial pneumonia:
8 to 11 years: 1.2 mg/kg IV every 12 hours
Maximum dose: 50 mg/dose

12 to 17 years: 50 mg IV every 12 hours

Comments:
-Tigecycline should not be used unless no alternative antibacterial agents are available.
-Safety and efficacy of the suggested regimens have not been evaluated due to the increase in mortality observed in tigecycline-treated adult patients.
-Proposed doses based on exposures seen in pharmacokinetic trials (small numbers of pediatric patients included).