Drug Class Description
Not yet assigned

Generic Name
Tigecycline

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

Presentation
Powder for solution for infusion.Lyophilised orange cake or powder.

Indications
Tygacil is indicated for the treatment of the following infections:• Complicated skin and soft tissue infections• Complicated intra-abdominal infections Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Adult Dosage
PosologyThe recommended dose for adults is an initial dose of 100 mg followed by 50 mg every 12 hours for 5 to 14 days.The duration of therapy should be guided by the severity, site of the infection, and the patient's clinical response.Hepatic insufficiencyNo 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 dose of Tygacil should be reduced to 25 mg every 12 hours following the 100 mg loading dose. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response.Renal insufficiencyNo dosage adjustment is necessary in patients with renal impairment or in patients undergoing haemodialysis.Elderly patientsNo dosage adjustment is necessary in elderly patients.Paediatric patientsTygacil is not recommended for use in children and adolescents below 18 years due to the lack of data on safety and efficacy.Method of administration:Tygacil is administered only by intravenous infusion over 30 to 60 minutes.

Child Dosage
Tygacil is not recommended for use in children and adolescents below 18 years due to the lack of data on safety and efficacy (See Special Precautions).

Elderly Dosage
No dosage adjustment is necessary in elderly patients.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients. Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to tigecycline.

Special Precautions
Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with tigecycline.Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Tigecycline may have adverse reactions similar to tetracycline class antibiotics. Such reactions may include photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia.Acute pancreatitis, which can be serious, has occurred (frequency: uncommon) in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Most of the reported cases developed after at least one week of treatment. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis.Experience in the use of tigecycline for treatment of infections in patients with severe underlying diseases is limited.In clinical trials in complicated skin and soft tissue infections, the most common type of infection in tigecycline treated-patients was cellulitis (59 %), followed by major abscesses (27.5 %). Patients with severe underlying disease, such as those that were immunocompromised, patients with decubitus ulcer infections, or patients that had infections requiring longer than 14 days of treatment (for example, necrotizing fasciitis), were not enrolled. Few patients with diabetic foot infections (5%) were enrolled. A limited number of patients were enrolled with co-morbid factors such as diabetes (20 %), peripheral vascular disease (7 %), intravenous drug abuse (2 %), and HIV-positive infection (1 %). Limited experience is also available in treating patients with concurrent bacteraemia (3 %). Therefore, caution is advised when treating such patients.In clinical trials in complicated intra-abdominal infections, the most common type of infection in tigecycline treated-patients was complicated appendicitis (51 %), followed by other diagnoses less commonly reported such as complicated cholecystitis (14 %), intra-abdominal abscess (10 %), perforation of intestine (10 %) and gastric or duodenal ulcer perforation less than 24 hours (5 %). Of these patients, 76 % had associated diffuse peritonitis (surgically-apparent peritonitis). There were a limited number of patients with severe underlying disease such as immunocompromised patients, patients with APACHE II scores > 15 (4 %), or with surgically apparent multiple intra-abdominal abscesses (10 %). Limited experience is also available in treating patients with concurrent bacteraemia (6 %). Therefore, caution is advised when treating such patients.Consideration should be given to the use of combination antibacterial therapy whenever tigecycline is to be administered to severely ill patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation or patients with incipient sepsis or septic shock.The effect of cholestasis in the pharmacokinetics of tigecycline has not been properly established. Biliary excretion accounts for approximately 50 % of the total tigecycline excretion. Therefore, patients presenting with cholestasis should be closely monitored.Prothrombin time or other suitable anticoagulation test should be used to monitor patients if tigecycline is administered with anticoagulants.Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibacterial agent.The use of tigecycline may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If super infection occurs, appropriate measures should be taken.Results of studies in rats with tigecycline have shown bone discolouration. Tigecycline may be associated with permanent tooth discolouration in humans if used during tooth development.Tygacil should not be used in children under 8 years of age because of teeth discolouration, and is not recommended in adolescents below 18 years due to the lack of data on safety and efficacy.

Interactions
Interaction studies have only been performed in adults.Concomitant administration of tigecycline and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40 % and 23 %, and an increase in AUC by 68 % and 29 %, respectively. The mechanism of this interaction is still not elucidated. Available data does not suggest that this interaction may result in significant INR changes. However, since tigecycline may prolong both prothrombin time (PT) and activated partial thromboplastin time (aPTT), the relevant coagulation tests should be closely monitored when tigecycline is co-administered with anticoagulants. Warfarin did not affect the pharmacokinetic profile of tigecycline.Tigecycline is not extensively metabolised. Therefore, clearance of tigecycline is not expected to be affected by active substances that inhibit or induce the activity of the CYP450 isoforms. In vitro, tigecycline is neither a competitive inhibitor nor an irreversible inhibitor of CYP450 enzymes.Tigecycline in recommended dosage did not affect the rate or extent of absorption, or clearance of digoxin (0.5 mg followed by 0.25 mg daily) when administered in healthy adults. Digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment is necessary when tigecycline is administered with digoxin.In in vitro studies, no antagonism has been observed between tigecycline and other commonly used antibiotic classes.Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.

Adverse Reactions
The total number of patients treated with tigecycline in Phase 3 clinical studies was 1415. Adverse reactions were reported in approximately 41 % of patients treated with tigecycline. Treatment was discontinued due to adverse reactions in 5 % of patients.In clinical trials, the most common drug-related treatment emergent adverse reactions were reversible nausea (20 %) and vomiting (14 %), which usually occurred early (on treatment days 1-2) and were generally mild or moderate in severity.Adverse reactions reported with Tygacil, including clinical trials and post-marketing experience, are listed below:Frequency categories are expressed as: Very common ( 1/10); Common ( 1/100 to <1/10); Uncommon ( 1/1,000 to <1/100); Rare ( 1/10,000 to < 1/1,000); Very Rare ( <1/10,000) For adverse reactions identified from post-marketing experience with Tygacil derived from spontaneous reports for which the frequency cannot be estimated, the frequency grouping is categorized as not known.Infections and infestations:Common: Abscess, infectionsUncommon: Sepsis/septic shockIn Phase 3 clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with tigecycline (6.7 %) vs comparators (4.6 %). Significant differences in sepsis/septic shock with tigecycline (1.5 %) vs comparators (0.5 %) were observed. Blood and the lymphatic system disorders:Common: Prolonged activated partial thromboplastin time (aPTT), Prolonged prothrombin time (PT)Uncommon: Increased International Normalised Ratio (INR)Not known: thrombocytopeniaImmune system disorders:Not known: Anaphylaxis/anaphylactoid reactionsMetabolism and nutrition disorders:Uncommon: HypoproteinaemiaNervous system disorders:Common: DizzinessVascular disorders: Common: PhlebitisUncommon: ThrombophlebitisGastrointestinal disorders:Very Common: Nausea, vomiting, diarrhoeaCommon: Abdominal pain, dyspepsia, anorexiaUncommon: Acute pancreatitisHepato-biliary disorders:Common: Elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase (ALT) in serum, hyperbilirubinaemiaAST and ALT abnormalities in Tygacil-treated patients were reported more frequently in the post therapy period than in those in comparator-treated patients, which occurred more often on therapy.Uncommon: Jaundice, liver injury, mostly cholestaticSkin and subcutaneous tissue disorders:Common: Pruritus, rashGeneral disorders and administration site conditions:Common: HeadacheUncommon: Injection site reaction, injection site inflammation, injection site pain, injection site oedema, injection site phlebitisInvestigations:Common: Elevated amylase in serum, increased blood urea nitrogen (BUN)In Phase 3 cSSSI and cIAI studies, death occurred in 2.3 % (32/1383) of patients receiving tigecycline and 1.6 % (22/1375) of patients receiving comparator drugs.Antibiotic Class Effects:Pseudomembranous colitis which may range in severity from mild to life threateningOvergrowth of non-susceptible organisms, including fungiTetracycline Class Effects:Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Tetracycline class adverse reactions may include photosensitivity, pseudotumour cerebri, pancreatitis, and anti-anabolic action which has led to increased BUN, azotaemia, acidosis, and hyperphosphataemia.Tigecycline may be associated with permanent tooth discolouration if used during tooth development.

Manufacturer
Wyeth Pharmaceuticals

Drug Availability
(POM)

Updated
12 August 2009