Zutig 50 Injection

Tigecycline Injection IP 50 mg

Each vial contains :

Tigecycline IP 50 mg

Excipients q.s.

Injection 50 mg

4.1 Therapeutic indication

Zutig is indicated in adults and in children from the age of eight years for the treatment of the following infections :

• Skin & skin structure infection
• Intra abdominal infection

Zutig should be used only in situations where other alternative antibiotics are not suitable.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology & method of administration

Adults

The 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.

Children and adolescents (8 to 17 years of age)

Tigecycline is only to be used to treat patients aged 8 years and older after consultation with a physician with appropriate experience in the management of infectious diseases.

Children aged 8 to <12 years: 1.2 mg/kg of tigecycline every 12 hours intravenously to a maximum dose of 50 mg every 12 hours for 5 to 14 days.

Adolescents aged 12 to <18 years : 50 mg of tigecycline every 12 hours for 5 to 14 days.

Elderly

No dosage adjustment is necessary in elderly patients.

Hepatic impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients (including paediatrics) with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced by 50%. Adult dose 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 impairment

No dosage adjustment is necessary in patients with renal impairment or in patients undergoing haemodialysis.

Paediatric population

The safety and efficacy of Zutig in children under 8 years of age have not been established. No data are available. Zutig should not be used in children aged under 8 years because of teeth discolouration.

Method of administration

Zutig 50 mg vial should be reconstituted with 5 ml of 0.9% Sodium Chloride Injection lP or 5% Dextrose lnjection lP or Lactated Ringers injection to achieve a concentration of 10 mg/ml of Tigecycline. The vial should be gently swirled until the drug dissolves. Immediately withdraw entire content of the reconstituted solution from the vial and add to a 100 ml l.V. bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration of the l.V. bag should be 1mg/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 particulate matter and discoloration (e.g., green or black) prior to administration. Zutig may be stored in the lV bag at room temperature for upto 6 hour, or refrigerated at 2°C to 8°C (36 to 46°F) for upto 48 hours. Zutig 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 thoroughly flushed before and after infusion of Zutig.

Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection IP, 5% Dextrose injection IP, and Lactated Ringers injection. When administered through a Y-site, Zutig is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection IP or 5% Dextrose Injection IP, amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol. Lactated Ringers, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin / tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCL, theophylline and tobramycin.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in the formulation.

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

4.4 Warning & precautions

In clinical studies in complicated skin and soft tissue infections (cSSTI), complicated intra-abdominal infections (cIAI), diabetic foot infections, nosocomial pneumonia and studies in resistant pathogens, a numerically higher mortality rate among tigecycline treated patients has been observed as compared to the comparator treatment. The causes of these findings remain unknown, but poorer efficacy and safety than the study comparators cannot be ruled out.

Superinfection

In clinical trials in cIAI patients, impaired healing of the surgical wound has been associated with superinfection. A patient developing impaired healing should be monitored for the detection of superinfection. Patients who develop superinfections, in particular nosocomial pneumonia, appear to be associated with poorer outcomes. Patients should be closely monitored for the development of superinfection. If a focus of infection other than cSSTI or cIAI is identified after initiation of tigecycline therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.

Anaphylaxis

Anaphylaxis/anaphylactoid reactions, potentially life-threatening, have been reported with tigecycline.

Hepatic failure

Cases of liver injury with a predominantly cholestatic pattern have been reported in patients receiving tigecycline treatment, including some cases of hepatic failure with a fatal outcome. Although hepatic failure may occur in patients treated with tigecycline due to the underlying conditions or concomitant medicinal products, a possible contribution of tigecycline should be considered.

Tetracycline class antibiotics

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.

Pancreatitis

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.

Coagulopathy

Tigecycline may prolong both prothrombin time (PT) and activated partial thromboplastin time (aPTT). Additionally, hypofibrinogenaemia has been reported with the use of tigecycline. Therefore, blood coagulation parameters such as PT or other suitable anticoagulation test, including blood fibrinogen, should be monitored prior to treatment initiation with tigecycline and regularly while on treatment. Special care is recommended in seriously ill patients and in patients also using anticoagulants.

Underlying diseases

Experience in the use of tigecycline for treatment of infections in patients with severe underlying diseases is limited. Consideration should be given to the use of combination antibacterial therapy whenever tigecycline is to be administered to severely ill patients with 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. 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. 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.

Paediatric population

Clinical experience in the use of tigecycline for the treatment of infections in paediatric patients aged 8 years and older is very limited. Consequently, use in children should be restricted to those clinical situations where no alternative antibacterial therapy is available. Nausea and vomiting are very common adverse reactions in children and adolescents. Attention should be paid to possible dehydration. Tigecycline should be preferably administered over a 60-minute length of infusion in paediatric patients. Abdominal pain is commonly reported in children as it is in adults. Abdominal pain may be indicative of pancreatitis. If pancreatitis develops, treatment with tigecycline should be discontinued. Liver function tests, coagulation parameters, haematology parameters, amylase and lipase should be monitored prior to treatment initiation with tigecycline and regularly while on treatment. Tigecycline Injection should not be used in children under 8 years of age due to the lack of safety and efficacy data in this age group and because tigecycline may be associated with permanent teeth discolouration.

4.5 Drug 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. Concomitant use of tigecycline and calcineurin inhibitors such as tacrolimus or cyclosporine may lead to an increase in serum trough concentrations of the calcineurin inhibitors. Therefore, serum concentrations of the calcineurin inhibitor should be monitored during treatment with tigecycline to avoid drug toxicity

Based on an in vitro study tigecycline is a P-gp substrate. Co-administration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.

4.6 Special populations

Pregnancy

There are no or limited amount of data from the use of tigecycline in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. As it is known for tetracycline class antibiotics, tigecycline may also induce permanent dental defects (discolouration and enamel defects) and a delay in ossification processes in foetuses, exposed in utero during the last half of gestation, and in children under eight years of age due to the enrichment in tissues with a high calcium turnover and formation of calcium chelate complexes. Tigecycline should not be used during pregnancy unless the clinical condition of the woman requires treatment with tigecycline.

Breast-feeding

It is unknown whether tigecycline / metabolites are excreted in human milk. Available pharmacodynamic / toxicological data in animals have shown excretion of tigecycline / metabolites in milk. A risk to the newborns / infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from tigecycline therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effects of tigecycline on fertility in humans have not been studied. Nonclinical studies conducted with tigecycline in rats do not indicate harmful effects with respect to fertility or reproductive performance. In female rats, there were no compound-related effects on ovaries or oestrus cycles at exposures up to 4.7 times the human daily dose based on AUC.

4.7 Effects on ability to drive and use machines

Dizziness may occur and this may have an effect on driving and use of machines.

4.8 Undesirable effects

In clinical trials, the most common medicinal product-related treatment emergent adverse reactions were reversible nausea and vomiting, which usually occurred early (on treatment days 1-2) and were generally mild or moderate in severity. Adverse reactions reported with tigecycline, including clinical trials and post-marketing experience, are tabulated below. Tabulated list of adverse reactions

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

No specific information is available on the treatment of overdosage. Intravenous administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. Tigecycline is not removed in significant quantities by haemodialysis.

5.1 Mechanism of Action

Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. 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 against Enterococcus spp., Staphylococcus aureus, and Escherichia coli.

5.2 Pharmacodynamic properties

Mechanism of resistance

Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Cross-resistance between tigecycline and minocycline-resistant isolates among the Enterobacteriaceae due to multi-drug resistance (MDR) efflux pumps has been shown. There is no target-based cross-resistance between tigecycline and most classes of antibiotics. Tigecycline is vulnerable to chromosomally-encoded multi-drug efflux pumps of Proteeae and Pseudomonas aeruginosa. Pathogens of the family Proteeae (Proteus spp., Providencia spp., and Morganella spp.) are generally less susceptible to tigecycline than other members of the Enterobacteriaceae. Decreased susceptibility in both groups has been attributed to the overexpression of the non-specific AcrAB multi-drug efflux pump. Decreased susceptibility in Acinetobacter baumannii has been attributed to the overexpression of the AdeABC efflux pump.

Susceptibility

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, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

5.3 Pharmacokinetic proper

Absorption

Tigecycline is administered intravenously and therefore has 100% bioavailability ties

Distribution

The in vitro plasma protein binding of tigecycline ranges from approximately 71 % to 89 % at concentrations observed in clinical studies (0.1 to 1.0 mcg/ml). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. 14 In rats receiving single or multiple doses of C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone marrow, salivary glands, thyroid gland, spleen, and kidney. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and concentrates into tissues. No data are available on whether tigecycline can cross the blood-brain barrier in humans. In clinical pharmacology studies using the therapeutic dosage regimen of 100 mg followed by 50 mg q12h, serum tigecycline steadystate C_max was 866±233 ng/ml for 30-minute infusions and 634±97 ng/ml for 60-minute infusions. The steady-state AUC0-12h was 2349±850 ng•h/ml.

Biotransformation

On average, it is estimated that less than 20 % of tigecycline is metabolised before excretion. In healthy male volunteers, following the 14 14 administration of C-tigecycline, unchanged tigecycline was the primary C-labelled material recovered in urine and faeces, but a glucuronide, an N-acetyl metabolite and a tigecycline epimer were also present. In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 by competitive inhibition. In addition, tigecycline did not show NADPH-dependency in the inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of mechanism-based inhibition of these CYP enzymes.

Elimination

The recovery of the total radioactivity in faeces and urine following administration of C-tigecycline indicates that 59 % of the dose is eliminated by biliary/faecal excretion, and 33 % is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes. The total clearance of tigecycline is 24 L/h after intravenous infusion. Renal clearance is approximately 13 % of total clearance. Tigecycline shows a polyexponential elimination from serum with a mean terminal elimination half-life after multiple doses of 42 hours although high interindividual variability exists.

6.1 Animal Toxicology or Pharmacology

In repeated 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 renal and gastrointestinal effects have been seen with tigecycline at exposures of 8 and 10 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing. Bone discolouring was observed in rats which was not reversible after two weeks of dosing. Results of animal studies indicate that tigecycline crosses the placenta and is found in foetal tissues. In reproduction toxicity studies, decreased foetal weights in rats and rabbits (with associated delays in ossification) have been observed with tigecycline. Tigecycline was not teratogenic in the rat or rabbit. Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or oestrus cycles at exposures up to 4.7 times the human daily dose based on AUC. R 14 esults from animal studies using C-labelled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in the nursing pups as a result of exposure via maternal milk. Lifetime studies in animals to evaluate the carcinogenic potential of tigecycline have not been performed, but short-term genotoxicity studies of tigecycline were negative. Bolus intravenous administration of tigecycline has been associated with a histamine response in animal studies. These effects were observed at exposures of 14 and 3 times the human daily dose based on the AUC in rats and dogs respectively. No evidence of photosensitivity was observed in rats following administration of tigecycline.

Tigecycline for injection, IP is a tetracycline class antibacterial for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12atetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

8.1 Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as Zutig : amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

8.2 Shelf life

Refer on the pack.

8.3 Packaging information

A vial of 50 mg.

8.4 Storage and handling instructions

Store protected from light & moisture, at a temperature not exceeding 30°C.

Keep out of reach of children.

Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell them to contact his or her healthcare provider. Patients should be counseled that antibacterial drugs including tigecycline should only be used to treat bacterial infections. 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.