For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Tigecycline for injection

Injection

Each vial contains:

Tigecycline………….50mg

Excipients ………q.s.

DESCRIPTION

TIGYCURE is yellow to orange lyophilized powder or cake in clear glass vial sealed with rubber stoppers and flip of seal. Each TIGYCURE vial contains 50 mg Tigecycline (Active Ingredient) as lyophilized powder meant for reconstitution for intravenous infusion. The product does not contain preservatives.

Tigecycline is a glycylcycline antibacterial for intravenous infusion. Its empirical formula is C29H39N5O8,  and its molecular weight is 585.65.

INDICATIONS

Treatment

TIGYCURE (Tigecycline for injection) is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below for the patients 18 years of age and older :- Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis ( vancomycin – susceptible isolates only), Staphylococcus aureus ( methicillin – susceptible and resistance isolates), Streptococcus agalactiae , Streptococcus anginosus grp.(includes S.anginosus, S.intermedius, and S.constellatus), Streptococcus pyogenes, Enterobacter  cloacae, Klebsiella pneumonia and Bacteroidesfragilis.

– Complicated intra-abdominal infections caused by Citrobacter freundi, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumonia, Enterococcus faecalis (vancomycin susceptible isolates only), Staphylococcus aureus (methicillin  susceptible and resistant isolates), Streptococcus anginosus grp. (includes S.anginosus, S.intermedius, and S.constellatus), Bacteroides fragillis, Bacteroides thetaiotaomicron, Bacteroides uniformis , Bacteroieds vulgates, Clostridium perfringens, and Peptostreptococcus micros. – community –Acquired Bacterial Pneumonia Community- acquired bacterial pneumonia caused by Streptococcus pneumonia (penicillian- susceptible isolates), including cases with concurrent bacteremia , Haemophilus influenza (beta-lactamase negative isolates) and Legionella pneumophila.

DOSE AND METHOD OF ADMINISTRATION.

The Recommended dosage regimen for TIGYCURE (Tigecycline for injection) is an initial dose of 100 mg,

Followed by 50 mg every 12 hours. Intravenous (IV) infusion of TIGYCURE should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment with TIGYCURE for complicated skin and skin structure infection or for complicated intra-abdominal infection is 5 to 14 days. The recommended duration of treatment with TIGYCURE 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 patients clinical and bacteriological progress. 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 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 PHARMACODYNAMIC AND PHARMACOKINETIC PROPERITES, pharmacokinetic: Special population, Hepatic insufficiency).

Reconstitution and Method of Administration

Each vial of TIGYCURE (Tigecycline for injection) should be reconstituted with 5.3 mL of 0.9% Sodium Chloride injection IP, or 5% Dextrose injection IP, to achieve a concentration 10mg/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. Immediately withdraw 5 mL of the reconstituted solution from the vial and add to a 100mL IV bag for infusion (for a 100 mg dose, reconstitute one vial). The maximum concentration in the IV bag should be 1 mg/mL.  The reconstituted solution should be yellow to orange in colour; if not the solution should be discarded. Parenteral  drug products should be inspected visually for the particulate matter and discoloration (e.g. green or black) prior to administration. Stability and Compatibility prior to reconstitution, TIGYCURE ( Tigecycline for injection) should be stored below 25 C. Reconstituted solution must be immediately transferred further diluted for IV infusion. Tigecycline for the injection may be stored in the IV bag at room temperature for up to 6 hours, or refrigerated at 2 to C 8 C( 36 to 46 F). for up to 24 hours.

Compatible intravenous solutions include 0.9% Sodium Chloride injection IP, and 5% Dextrose injection IP, when administered through a Y-site, tigecycline for injection is compatible with the following drugs of diluents;dobutamine;dopamine HCL, Lactated Ringers, lidocaine HCL, potassium Chloride, ranitidine.

HCL, theophyline.

USE IN SPECIAL POPULATIONS

• Pregnancy

Tigecycline was not teratogenic  in the rat or rabbit. In reported preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with sight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg.hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at matemotoxic  dose in the rabbits with exposure equivalent to human dose. There are no adequate and well controlled studies to tigecycline in pregnant woman. Tigecycline should be used during pregnancy only if the potential risk to the fetus.

• Lactation

Results from reported animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tigecycline is administered to a nursing woman.

• Pediatric

Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended.

• Geriatric

Of the total number of subjects who received tigecycline in phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over, No unexpected overall difference in safety of effectiveness were observed between these 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.

• 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 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.

CONTRAINDICATIONS:

TIGYCURE (Tigecycline for injection) is contraindicated for use in patients who have known hypersensitivity to tigecycline. Patients hypersensitive to tetracycline class antibiotics may be hypersensitive to tigecycline.

WARNINGS & PRECAUTION

All-cause Mortality An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials in Tigecycline-treated patients versus comparator treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tigecycline 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 Tigecycline and comparator treated patients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options Anaphylaxis / anaphylactoid reactions have been reported with nearly all antibacterial agents,

Including tigecycline, and may be life threatening. Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse effects.

Hepatic Effects

Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic failures have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events my occur after the drug has been discontinued. Mortality imbalance and lower cure rates in Ventilator-Associated Pneumonia A trial of patients with hospital acquired pneumonia failed to demonstrate the efficacy of tigecycline . in this trial, patients were randomized to receive Tigecycline (100 mg initially, than 50 mg every 12 hours)or a comparator. In addition, patients were allowed to receive specified adjunctive therapies, The sub-group of patients with ventilator-associated pneumonia who received Tigecycline had lower cure rates (47.9% versus 70.1% for the clinically evaluable population). In this trial, generate mortality was seen in patients with ventilator –associated pneumonia who received Tigecycline (25/131{19.1%}versus 15/122{12.3%}in comparator-treated patients)[See adverse reactions]. Particularly high mortality was seen among Tigecycline treated patients with ventilator associated pneumonia and bacteremia at base line (9/18 {50%}versus 1/13{7.7%} in comparator-treated patients). Pancreatitis Acute pancreatitis, including fatal cases, has occurred in association with Tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients talking Tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. 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. Use during pregnancy Tigecycline may cause fetal harm when administered to a pregnant woman. If the patients becomes pregnant while talking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of reported animal studies indicate that tigecycline crosses the placenta and is found fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline. Tooth development the use of tigecycline during tooth development (last half of pregnancy infancy , and childhood to the age of 8 years)may cause permanent discoloration of the teeth(yellow-gray-brown). Results of studies in rats with tigecycline have shown bone discoloration. Tigecyclin should not be used during development unless other drugs are not likely to be effective or are contraindicated. Tetracycline –class-effects Tigecycline should be administrated with caution in patients with known hypersensitivity to tetracycline class antibiotic. Tigecycline is structurally similar to tetracycline class antibiotic and may have similar adverse effects. Such effects may include photosensitivity, pseudotumor cerebri, and antibiotic action (which has led to increase BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracycline, pancreatitis  has been reported with the use of Tigecycline. Clostridium difficile Associated diarrhea clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline and many range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.difficile. C.difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C.difficile cause increased morbidity and mortality, as this infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history in necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, on going antibiotic use not directed angriest C.diffecile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.difficile, and surgical evolution should be instituted as clinically indicated. Super infection as with other antibacterial drugs, use to 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.

Development of Drug-Resistant Bacteria

Prescribing tigecycline in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patients and increases the risk of the development of drug-resistant bacteria.

PRECAUTIONS

Patients With Intestinal Perforation

Caution should be exercised when considering tigecycline  monotherapy  in patients with complicated intra-abdominal infections(cIAI) secondary to clinically apparent intestinal perforation. In reported phase 3 studies in patients with cIAI(n=1642), 6 patients treated with tigecycline and 2 patients treated with imipenem/ cilastation presented with intestinal perforation and developed sepsis/ septic shock. The 6 patients treated with tigecycline had higher APACHE 11(Acute Physiology and Chronic Health Evaluation) scores (median=13) vs the 2 patients treated with imipenem/ cilastatin  (APACHE 11 scores= 4 and 6). Due to difference in base line APACHE 11 scores between treatment  groups and small overall numbers, the relationship of this outcome to treatment can not be established.

Information for Patients

Patients should be counseled that antibacterial drugs including tigecycline should only be use to treat bacterial infection. They do not treat viral infections (e.g.the common cold). When tigecycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tigecycline or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting  treatment with antibiotic patient can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

DRUG INTERACTIONS

Tigecycline (100 mg followed 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin  by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. There fore no dosage adjustment of either drug in necessary when tigecycline is administered with digoxin. Concomitant administration of tigecycline (100 mg followed by 50 mg every 12 hours) 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%, an increase in Cmax 38% and 43% and increase in AUC by 68% and 29% respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In additional, warfrain did not affect the pharmacokinetic profile of tigecycline. However, since tigecycline may prolong both prothombin time (PT) and activated partial thromboplastin (aPTT) prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin. In vitro studies in human liver microsomes indicated that tidecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450(GYP) isoforms : 1A2,2C8,2C9,2C19,2D6, and 3A4. Therefore tigecycline is not expected to alter the metabolism of drug metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of this CYP450 isoforms , In reported in vitro studies no antagonism has been observed between tigecycline and other commonly used antibiotic classes. Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.

Laboratory Tests

There are no reported drug-laboratory test interactions.

UNDESIRABLE EFFECTS

In reported phase 3 clinical studies, tigecycline was discontinued due to treatment emergent adverse events in 7 % of patients compared to 6% for all comparators. Table below shows the incidence of treatment emergent adverse events through test of cure reported in 2% of patients in this studies regardless of causality.

Post Marketing Experience

The following adverse reactions have been identified during post approval use of tigecycline. Because these reactions are reported voluntarily from the population of uncertain size, it is not always possible to reliable estimate their frequency or establish casual relationship to drug exposure. – Anaphylaxis / anaphylactoid reactions- Acute pancreatitis – Hepatic cholestasis and jaundice.

OVERDOSE

No specific information is available on the treatment of over dosage with tigecycline. Intravenous administration of aigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased of nausea and vomiting. Tigecycline is not removed in significant quantities by hemodialysis. In single-dose IV toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kgin males and 98 mg/kg in females. In rats the estimated LD50 was 106 mg/kg for both sexes.

PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES

Mechanismof action

Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal submit and blocking entry of amino-acyl tRNA molecules in to the A site of the ribosome. This prevents incorporation of amino acid residues in to elongating peptide chains. Tigecycline carries a clycylamido moiety attached to the 9-position of minocycline The substitution pattern is not present in any naturally occurriogor  semisynthetic tetracycline and imparts certain microbiological prosperities to tigecycline. In general, tigecycline  is considered bacteriostatic ; however, Tigecycline has demonstrated bactericidal activity against isolates of S.pneumoniae and L.pneumophila.

Antibacterial Spectrum

In vitro studies have not dernonstarted antagonism between tigecycline and other commonly use antibacterials. Tigecycline has been shown to be active against most of the following bacteria, both in vitro and in clinical infections.

Facultative Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates)

Staphylococcus aureus (mothicilin-suscepitble and resistant isolates)

Staphylococcus agalactiae

Staphylococcus anginosus grp. (includes S.anginosus, S.intermedius and S.constellatus)

Staphylococcus pneumonia (penicillin-susceptible isolates)

Staphylococcus pyogenes

Facultative Gram-negative bacteria

Citrobacterfreundi

Enterobactercioacae

Escherichia coli

Haemophilusinfluenzae (beta-lactamase negative isolates)

Klebsillaoxytoca

Klebsiellapneumoniae

Legionella pneumophila

Anaerobic bacteria

Bacteroidesfragilis

Bacteroidesthetaiotaomicron

Bacteroidesuniformis

Bacteroibesvulgatus

Clostridium perfringens

Peptostreptococcus micros

At least 90% of the following bacteria exhibit in vitro minimum inhibitory concentration (MICs) that are at concentration that are at achievable using the prescribed dosing regimens. However, the clinical significance of this is unknown because the safety and effectiveness of tigecycline in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Facultative Gram-positive bacteria

Enterococcus avium

Enterococcus casseliflavus

Enterococcus faecalis  (vancomycin-resistant isolates)

Enterococcus faecium  (vancomycin-susceptible and resistant isolates)

Enterococcus gallinarum

Listeria monocytogens

Staphylococcus epidermis (methicillin- susceptible and resistant isolates)

Staphylococcus haemolyticus

Facultative Gram-negative bacteria

Acinetobacterbaumanni

Aeromonashydrophila

Citrobacterkoseri

Enterobacteraerogenes

Haemophilusinfluenzae (ampicillin-resistant)

Haemophilusparainnuenzae

Pasteurellamultocida

Serratiamarcescens

Stenotrophomonasmaftophilia

Anaerobic bacteria

Bacteroidesdistasonis

Bacteroidesovatus

Peptostreptococcus spp.

Porphyromonas spp.

Prevotella spp.

Other bacteria

Mycobacterium abscessus

Mycobacterium fortuitum

There have been reported of the development tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attribute to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected blood and other specimens should be obtained and the cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials.

Pharmacokinetics

The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from reported clinical pharmacology studies are summarized in the table below. Intravenous infusion of tigecycline were administered over approximately 30 to 60 minutes.

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