Consumer medicine information

Tigecycline Juno

Tigecycline

BRAND INFORMATION

Brand name

Tigecycline Juno

Active ingredient

Tigecycline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tigecycline Juno.

What is in this leaflet

This leaflet answers some common questions about TIGECYCLINE JUNO. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TIGECYCLINE JUNO against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What TIGECYCLINE JUNO is used for

TIGECYCLINE JUNO, is an antibiotic of the tetracycline class in the glycylcycline subcategory that works by stopping the growth of bacteria that cause infections.

Your doctor has prescribed TIGECYCLINE JUNO because you have one of the following types of serious infections:

  • Infection of the skin, including those with resistant bacteria
  • Infection in the abdomen.

TIGECYCLINE JUNO is for use in adults aged 18 and over. There is no experience with the use of TIGECYCLINE JUNO in children under 18 years of age.

TIGECYCLINE JUNO, like other tetracyclines, may cause enamel loss and staining in developing teeth.

TIGECYCLINE JUNO will not work against viral infections such as colds or flu.

There is no evidence that TIGECYCLINE JUNO is addictive.

TIGECYCLINE JUNO is available only with a doctor's prescription.

Before you are given TIGECYCLINE JUNO

When you must not be given it

You should not be given TIGECYCLINE JUNO if you have an allergy to:

  • tigecycline
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or troubled breathing.

Do not have TIGECYCLINE JUNO after the expiry date (Exp. Date) printed on the pack has passed.

If you take this medicine after the expiry date it may not work.

Talk to your doctor if you are not sure whether you should be given TIGECYCLINE JUNO.

Before you are given it

You must tell your doctor if:

  • You are allergic to tetracycline antibiotics.
    You may have an increased chance of being allergic to TIGECYCLINE JUNO if you are allergic to tetracyclines.
  • You are pregnant or breastfeeding.
    As with many medicines, TIGECYCLINE JUNO may harm your developing or breastfeeding baby. This may include permanent staining of the child's teeth.
  • You have or have had liver problems.
    Depending on the condition of your liver, your doctor may need to reduce your dose to avoid potential side effects.

If you have not told your doctor or nurse about any of the above, tell them before you are given TIGECYCLINE JUNO.

Your doctor should do blood tests before you start and regularly while you are having treatment with TIGECYCLINE JUNO.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may interfere with TIGECYCLINE JUNO.

These include:

  • Medicines to treat infections that contain ketoconazole or rifampicin
  • Medicines that contain cyclosporin or tacrolimus
  • Warfarin
    If you are taking warfarin, your doctor or nurse will check your blood clotting time.
  • Oral contraceptives (birth control pills)
    TIGECYCLINE JUNO may interfere with birth control pills.

Talk to your doctor about the need for an additional method of contraception while receiving TIGECYCLINE JUNO.

How TIGECYCLINE JUNO is given

How TIGECYCLINE JUNO will be given

TIGECYCLINE JUNO is given as an injection into a vein and administered to you by your doctor or nurse.

How much you will be given

The recommended dosage is 100 mg for the first dose, followed by 50 mg every 12 hours.

How long you will receive TIGECYCLINE JUNO

It is very important that you continue to receive TIGECYCLINE JUNO for as long as your doctor prescribes it.

Your doctor will decide how many days of treatment you need. How long you receive TIGECYCLINE JUNO will depend on how severe your infection is and how quickly you respond to treatment.

If you receive more TIGECYCLINE JUNO than you should (overdose)

Tell your doctor or nurse immediately if you are concerned that you may have been given too much TIGECYCLINE JUNO.

It is unlikely that you will receive an overdose of TIGECYCLINE JUNO because a trained nurse or doctor will give it.

If you miss a dose of TIGECYCLINE JUNO

Talk to your doctor or nurse immediately if you are concerned that you may have missed a dose.

While you are receiving TIGECYCLINE JUNO

Things you must do

If you get severe diarrhoea, tell your doctor or nurse immediately. Do this even if it happens several weeks after treatment with TIGECYCLINE JUNO has been stopped. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care.

Do not take any medicine for diarrhoea without first checking with your doctor.

Tell your doctor immediately if you develop severe abdominal pain, nausea and vomiting. These may be symptoms of inflammation of the pancreas.

Tell your doctor immediately if you realise that you are pregnant while taking TIGECYCLINE JUNO.

Things to be careful of

Tell your doctor if you get thrush (a fungal infection which can affect the mouth and/or vagina) or any other infection while having, or soon after stopping, TIGECYCLINE JUNO. Although antibiotics, including TIGECYCLINE JUNO fight certain bacteria, other bacteria and fungi may continue to grow. Your doctor will check you for any possible infections and, if necessary, will give you treatment.

Protect your skin when you are in the sun, especially between 10 am and 3 pm. If outdoors, wear protective clothing and use a 15+ sunscreen. TIGECYCLINE JUNO may cause your skin to be much more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness, or severe sunburn.

Be careful driving or operating machinery until you know how TIGECYCLINE JUNO affects you. Whilst it is unlikely that you will drive or operate machinery when having TIGECYCLINE JUNO, you need to be aware that TIGECYCLINE JUNO may cause side effects such as dizziness. This may affect your ability to drive or operate machinery.

Side Effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are having TIGECYCLINE JUNO.

TIGECYCLINE JUNO is effective against certain serious infections for most people, but it may have unwanted side effects in some.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Nausea
  • Vomiting
  • Diarrhoea
  • Dizziness
  • Headache
  • Loss of appetite
  • Stomach pain or heartburn
  • Increased bleeding tendency
  • Skin rash and itchiness
  • Low sugar levels in the blood (sweating, weakness, hunger, dizziness, trembling, headache, flushing or paleness, numbness, having a fast, pounding heart beat).

Tell your doctor as soon as possible if you notice any of the following:

  • Increased tendency to bleed or bruise more easily than normal
  • Yellowing of the skin or eyeballs also called jaundice
  • Injection site reaction (pain, redness, inflammation, swelling)
  • Swelling and/or clotting; and redness along a vein which is very tender when touched
  • Abscesses or other infections
  • Abnormal healing

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • Sepsis (rapid heartbeat, rapid breathing and fever)
  • Inflammation of the pancreas (severe upper stomach pain, often with nausea and vomiting)
  • Stevens-Johnson Syndrome (a skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals)
  • Pneumonia (fever, chills, shortness of breath, cough, phlegm and occasionally blood)
  • Bleeding following injury taking longer to clot
  • Sudden onset of signs of allergy such as:
    - rash, itching or hives on the skin
    - swelling of the face, lips, tongue or other parts of the body
    - shortness of breath, wheezing or trouble breathing.

The above list includes very serious side effects. You should need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects (for example, abnormal blood test results including low level of protein/platelet in the blood, high levels of liver enzymes, high levels of enzyme found in the salivary glands/pancreas and increase in blood urea nitrogen) can only be found when your doctor does tests from time to time to check your progress.

After finishing it

Tell your doctor immediately if you notice any of the following side effects, particularly if they occur several weeks after stopping treatment with TIGECYCLINE JUNO.

  • Severe abdominal cramps or stomach cramps
  • Watery and severe diarrhoea, which may also be bloody
  • Fever in combination with one or both of the above.

These are serious side effects. You may have a serious condition affecting your bowel. Therefore, you may need urgent medical attention.

Do not take any medicine for this diarrhoea without first checking with your doctor.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After receiving TIGECYCLINE JUNO

Storage

The hospital will store TIGECYCLINE JUNO under the correct conditions.

TIGECYCLINE JUNO must be kept out of the reach and sight of children. TIGECYCLINE JUNO will be given to you only within the "Exp. Date" date of the product.

Product description

What it looks like

TIGECYCLINE JUNO is an orange to orange-red powder or cake supplied in glass vials. Dissolving the powder in a sterile liquid makes a solution for injection. After mixing, the solution is an orange to orange-red colour.

Ingredients

Each TIGECYCLINE JUNO vial contains 50 mg of tigecycline powder for intravenous infusion.

TIGECYCLINE JUNO also contains L-arginine. It does not contain any preservatives.

Supplier

TIGECYCLINE JUNO is supplied in Australia by:

Juno Pharmaceuticals Pty Ltd
42 Kelso Street
Cremorne
VIC - 3121
Australia

This leaflet was prepared in November 2022.

AUST R 275811

Published by MIMS January 2023

BRAND INFORMATION

Brand name

Tigecycline Juno

Active ingredient

Tigecycline

Schedule

S4

 

1 Name of Medicine

Tigecycline.

2 Qualitative and Quantitative Composition

Each vial contains 50 mg tigecycline.
Each vial contains 50 mg of Arginine. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The reconstituted solution has a pH of 4.5 to 5.5.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tigecycline is an orange to orange-red lyophilised powder or cake. The reconstituted solution is orange to orange-red, essentially free of particulate matter.

4 Clinical Particulars

4.1 Therapeutic Indications

Tigecycline Juno is indicated for the treatment of the following infections in adults:
Complicated skin and skin structure infections, including those with methicillin-resistant Staphylococcus aureus (MRSA), where there is suspected or proven resistance to, intolerance of, or there are co-morbidities preventing the use of, other available agents.
Complicated intra-abdominal infections, where there is suspected or proven resistance to, intolerance of, or there are co-morbidities preventing the use of, other available agents.

4.2 Dose and Method of Administration

Dosage.

The recommended dosage regimen for tigecycline is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
The recommended duration of treatment with tigecycline for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 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 adjustment.

Patients with renal impairment.

No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing haemodialysis (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal insufficiency).

Patients with hepatic impairment.

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Based on the pharmacokinetic profile of tigecycline in patients with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be altered to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic insufficiency).

Use in children.

Safety and effectiveness in patients under 18 years of age have not been established. Therefore, use in patients under 18 years of age is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Use in elderly.

No dosage adjustment is necessary in elderly patients (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Race and gender.

No dosage adjustment is necessary based on race or gender (see Section 5.2 Pharmacokinetic Properties).

Monitoring advice.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.

Mode of administration.

Intravenous infusion.

The lyophilised powder should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Glucose Injection, USP, to achieve a concentration of 10 mg/mL of tigecycline. The vial should be gently swirled until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL IV bag for infusion. For a 100 mg dose, reconstitute using two vials into a 100 mL IV bag. (Note: The vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) 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 discolouration (e.g. green or black) prior to administration whenever solution and container permit. Reconstitution and further dilution of tigecycline must be performed immediately before use. Once reconstituted and diluted in the IV bag, to reduce microbiological hazard, use as soon as practicable after reconstitution/dilution. If storage is necessary, hold at 2°-8°C for not more than 24 hours. Use in one patient on one occasion only. Contains no antimicrobial preservatives.
Tigecycline Juno may be administered intravenously through a dedicated line 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 with either 0.9% Sodium Chloride Injection USP, or 5% Glucose Injection USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line (see Compatibilities; see Section 6.2 Incompatibilities).

Compatibilities.

Compatible intravenous solutions include: sodium chloride 9 mg/mL (0.9%) solution for injection and glucose 50 mg/mL (5%) solution for injection.
Tigecycline Juno is compatible with the following drugs or diluents when administered simultaneously through the same line: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, lactated Ringer's, lignocaine HCl, metoclopramide, morphine, noradrenaline, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline and tobramycin.

4.3 Contraindications

Tigecycline is contraindicated for use in patients who have known hypersensitivity to tigecycline or any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

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 a pooled analysis of 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 resulting in an unadjusted risk difference of 0.9% (95% CI 0.1, 1.8). The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options (see Section 4.8 Adverse Effects (Undesirable Effects)).
The increased risk in all-cause mortality was greater in patients treated for hospital-acquired pneumonia, especially ventilator-associated pneumonia, but was also seen at a lower rate in patients with complicated skin and skin structure infections, complicated intra-abdominal infections and diabetic foot infections. No increased risk in all-cause mortality was observed in patients with community-acquired pneumonia (see Table 2). Tigecycline is not approved for the treatment of hospital-acquired pneumonia (including ventilator-associated pneumonia), community-acquired pneumonia or diabetic foot infections.

Anaphylactic reaction/anaphylactoid reaction.

Anaphylactic reaction/anaphylactoid reaction have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening.

Hypersensitivity to tetracycline-class antibiotics.

Tigecycline is a tetracycline class antibiotic in the glycylcycline subcategory and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action (which has lead to increased plasma urea, azotaemia, acidosis, and hyperphosphataemia). Therefore, tigecycline should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.

Acute pancreatitis.

Acute pancreatitis, which can be fatal, has occurred (frequency: uncommon) in association with tigecycline treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). The diagnosis of acute pancreatitis should be considered in patients taking 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.

Monitoring of blood coagulation parameters.

Monitoring of blood coagulation parameters, including blood fibrinogen, is recommended prior to treatment initiation with tigecycline and regularly while on treatment. (See Section 4.8 Adverse Effects (Undesirable Effects).)

Patients with hospital acquired pneumonia.

The safety and efficacy of tigecycline in patients with hospital acquired pneumonia have not been established. In a study of patients with hospital acquired pneumonia, patients were randomised to receive tigecycline (100 mg initially, then 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) and greater mortality (25/131 [19.1%] versus 15/122 [12.3%]) than the comparator. Of those patients with ventilator-associated pneumonia and bacteraemia at baseline, those who received tigecycline had greater mortality (9/18 [50.0%] versus 1/13 [7.7%]) than the comparator.

Tooth discolouration.

Tigecycline may be associated with permanent tooth discolouration in the teeth in humans during tooth development.

Pseudomembranous colitis.

Pseudomembranous colitis has been reported with nearly all antibiotics. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C. difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.

Superinfection.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection 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 patient and increases the risk of the development of drug-resistant bacteria.

Patients with complicated intra-abdominal infections (cIAI).

Caution should be exercised when considering tigecycline monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation (see Section 4.8 Adverse Effects (Undesirable Effects)). In Phase 3 cIAI studies (n=1642), 6 patients treated with tigecycline and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with tigecycline had higher APACHE II scores (median = 13) vs the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

Histamine response.

Bolus intravenous administration of tigecycline has been associated with a histamine response in animal studies. These effects were observed at exposures of 14.3 and 2.8 times the human daily dose based on the AUC in rats and dogs, respectively.

Use in hepatic impairment.

Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline.
Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic insufficiency).

Use in the elderly.

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 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.

Paediatric use.

Safety and effectiveness in patients under 18 years of age have not been established. Therefore, use in patients under 18 years of age is not recommended.

Effects on laboratory tests.

There are no reported drug-laboratory test interactions.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Digoxin.

Tigecycline (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg every 24 hours) were co-administered 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. Therefore, no dosage adjustment is necessary when tigecycline is administered with digoxin.

Warfarin.

Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.

Cytochrome P450 isoforms.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome CYP450 isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, tigecycline is not expected to alter the metabolism of drugs metabolised by these enzymes. In addition, because tigecycline is not extensively metabolised, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.

*P-glycoprotein inhibitors.

As tigecycline is a substrate of P-glycoprotein (P-gp), coadministration of P-gp inhibitors (e.g. ketoconazole or cyclosporine) or P-gp inducers (e.g. rifampicin) could affect the pharmacokinetics of tigecycline.

Oral contraceptives.

No clinical studies have been conducted on the interaction between tigecycline and oral contraceptives, however, concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective. It is recommended that an additional barrier method of contraception should be used when using tigecycline.

Calcineurin inhibitors.

Concomitant use of tigecycline and calcineurin inhibitors such as tacrolimus or ciclosporin 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Tigecycline did not affect mating or fertility in rats at exposures up to 5 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 5 times the human daily dose based on AUC.
(Category D)
Tigecycline may cause foetal harm when administered to a pregnant woman. In preclinical safety studies, 14C-labelled tigecycline crossed the placenta and was found in foetal tissues, including foetal bony structures.
Tigecycline was not teratogenic in the rat or rabbit. The administration of tigecycline was associated with slight reductions in foetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1.5 times the human daily dose based on AUC in rats and rabbits, respectively. An increased incidence of foetal loss was observed at exposures of 1.5 times the human daily dose based on AUC in rabbits, at dosages producing minimal maternal toxicity.
There are no adequate and well-controlled studies of tigecycline in pregnant women. Tigecycline should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Tigecycline has not been studied for use during labour and delivery.
 Results from animal studies using 14C-labeled 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 the maternal milk.
It is not known whether this drug is excreted in human milk. Because tetracyclines are present in milk of lactating women who are taking a drug in this class, caution should be exercised when tigecycline is administered to a nursing woman.

4.7 Effects on Ability to Drive and Use Machines

Tigecycline can cause dizziness (see Section 4.8 Adverse Effects (Undesirable Effects)), which may impair the ability to drive and/or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Because clinical studies are conducted under varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Phase 3 clinical studies enrolled 1415 patients treated with tigecycline. Adverse reactions (as judged by investigators) to be related to the medicinal product were reported in approximately 40.6% of patients treated with tigecycline. See Table 1.
Expected frequency of adverse reactions is presented in CIOMS frequency categories: very common: ≥ 10%; common: ≥ 1% and < 10%; uncommon: ≥ 0.1% and < 1%; rare: ≥ 0.01% and < 0.1%; very rare: < 0.01%; frequency not known: cannot be estimated from the available data.
For patients who received tigecycline, the following adverse reactions were reported:

Blood and lymphatic system disorders.

Common: Activated partial thromboplastin time prolonged (aPTT), prolonged prothrombin time (PT).
Uncommon: Increased international normalised ratio (INR).

Metabolism and nutrition disorders.

Common: Hypoproteinaemia, decreased appetite.

Nervous system disorders.

Common: Dizziness, headache.

Cardiovascular disorders.

Common: Phlebitis.
Uncommon: Thrombophlebitis.

Gastrointestinal disorders.

Very common: Nausea, vomiting, diarrhoea.
Common: Abdominal pain, dyspepsia.

Skin and subcutaneous tissue disorders.

Common: Pruritus, rash.

General disorders and administration site conditions.

Uncommon: Injection site inflammation, injection site pain, injection site reaction, injection site oedema, injection site phlebitis.

Investigation.

Common: Elevated amylase in serum, blood urea increased (BUN).

Infections and infestations.

Common: Abscess, infections.
Uncommon: Sepsis/septic shock.

Hepato-biliary disorders.

Common: Elevated aspartate aminotransferase (AST) in serum, and elevated alanine aminotransferase (ALT) in serum, hyperbilirubinaemia.
In Phase 3 clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with tigecycline (6.7%) vs. comparator (4.6%). Significant differences in sepsis/septic shock with tigecycline (1.5%) vs. comparators (0.5%) were observed. Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established (see Section 4.4 Special Warnings and Precautions for Use). Other events included nonsignificant differences in abscess (1.8% vs 1.6%) and infections, including wound infections (1.7% vs. 1.1%) for tigecycline vs. comparator, respectively.
AST and ALT abnormalities in tigecycline-treated patients were reported more frequently in the post therapy period than in those in comparator-treated patients, which occurred more often on therapy.
The most common treatment-emergent adverse reactions in patients treated with tigecycline were nausea 26.4% (16.9% mild; 8.1% moderate; 1.3% severe) and vomiting 18.1% (11.0% mild; 6.1% moderate; 1.0% severe). In general, nausea or vomiting occurred early (days 1-2).
Discontinuation from tigecycline was most frequently associated with nausea (1.1%) and vomiting (1.1%).
Treatment was discontinued due to adverse reactions in 5.0% of patients. Discontinuation from tigecycline was most frequently associated with nausea (1.3%) and vomiting (1.0%).

All-cause mortality.

In cSSSI and cIAI trials, death occurred in 2.4% (54/2216) of patients receiving tigecycline and 1.7% (37/2206) of patients receiving comparator drugs.
In a pooled analysis of 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, the risk difference of all cause mortality was 0.9% (95% CI 0.1, 1.8) between tigecycline and comparator treated patients. No significant differences were observed between treatments by infection type (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, or complications of infection or underlying co-morbidities.

Post-marketing experience.

The following adverse reactions have been identified during post marketing use of tigecycline. As 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.
Post-marketing adverse reactions not previously listed in the product information or determined to have a greater frequency in post-marketing use include:

Blood and lymphatic system disorders.

Common: *Thrombocytopenia.
Rare: Hypofibrinogenaemia.

Metabolism and nutrition disorders.

Common: Hypoglycaemia.

Respiratory, thoracic and mediastinal disorders.

Common: Pneumonia.

Gastrointestinal disorders.

Uncommon: Acute pancreatitis.

Skin and subcutaneous tissue disorders.

Frequency not known: Severe skin reactions, including Stevens-Johnson syndrome.

General disorders and administration site conditions.

Common: Healing abnormal, *injection site reaction.

Immune system disorders.

Frequency not known: Anaphylactic reaction/anaphylactoid reaction.

Hepato-biliary disorders.

Uncommon: Jaundice.
Frequency not known: Hepatic cholestasis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

No specific information is available on the treatment of overdosage with tigecycline. 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tigecycline, a tetracycline class antibiotic in the glycylcycline subcategory, 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. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. Tigecycline is not affected by the major tetracycline resistance mechanism of ribosomal protection and is not affected by many efflux systems. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has currently been limited cross-resistance observed between tigecycline and other antibiotics. In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibiotics. In general, tigecycline is considered bacteriostatic.
Tigecycline is not affected by resistance mechanisms such as β-lactamases (including extended spectrum β-lactamases), target site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerase).

Susceptibility tests.

Dilution or Diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method. Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.
A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. See Table 3.

Microbiology.

Tigecycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described, see Section 4.1 Therapeutic Indications.

Gram-positive aerobes.

Enterococcus faecalis (vancomycin-susceptible isolates only); Staphylococcus aureus (methicillin-susceptible and resistant isolates, including isolates that bear molecular and virulence markers commonly associated with community-acquired MRSA including the SCCmec type IV element and the pvl gene); Streptococcus agalactiae; Streptococcus anginosus (includes S. anginosus, S intermedius, S. constellatus); Streptococcus pyogenes; Streptococcus pneumoniae (penicillin-susceptible isolates).

Gram-negative aerobes.

Citrobacter freundii; Enterobacter cloacae; Escherichia coli (including ESBL producing strains); Haemophilus influenzae; Klebsiella oxytoca; Klebsiella pneumoniae (including ESBL producing strains); Legionella pneumophila; Moraxella catarrhalis.

Anaerobic bacteria.

Bacteroides fragilis; Bacteroides thetaiotaomicron; Bacteroides uniformis; Bacteroides vulgatus; Clostridium perfringens; Peptostreptococcus spp.; Peptostreptococcus micros.

Atypical bacteria.

Chlamydia pneumoniae; Mycoplasma pneumoniae.
In vitro data are available for the following organisms, but their clinical significance is unknown. The in vitro minimum inhibitory concentrations (MIC) of 90% or more of these microorganisms were less than or equal to the susceptible breakpoint for tigecycline. However, the safety and effectiveness of tigecycline in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes.

Enterococcus avium; Enterococcus casseliflavus; Enterococcus faecalis (vancomycin-resistant isolates); Enterococcus faecium (vancomycin-susceptible and resistant isolates); Enterococcus gallinarum; Listeria monocytogenes; Staphylococcus epidermidis (methicillin-susceptible and resistant isolates); Staphylococcus haemolyticus; Streptococcus pneumoniae (penicillin-resistant isolates); Viridans group streptococci.

Gram-negative aerobes.

Acinetobacter calcoaceticus/baumannii complex; Aeromonas hydrophila; Citrobacter koseri; Enterobacter aerogenes; Haemophilus parainfluenzae; Klebsiella pneumoniae (including AmpC producing strains); Pasteurella multocida; Salmonella enterica ser. Enteritidis; Salmonella enterica ser. Paratyphi; Salmonella enterica ser. Typhi; Salmonella enterica ser. Typhimurium; Serratia marcescens; Shigella boydii; Shigella dysenteriae; Shigella flexneri; Shigella sonnei; Stenotrophomonas maltophilia.

Anaerobic bacteria.

Bacteroides ovatus; Clostridium difficile; Peptostreptococcus spp.; Porphyromonas spp.; Prevotella spp.

Atypical bacteria.

Mycobacterium abscessus; Mycobacterium chelonae; Mycobacterium fortuitum.
Resistant.

Gram-negative aerobes.

Pseudomonas aeruginosa and Proteeae (Proteus spp., Providencia spp. and Morganella spp.).

Anaerobic bacteria.

No naturally occurring species have been found to be inherently resistant to tigecycline.
Resistance. There has been no cross-resistance observed between tigecycline and other antibiotics caused by antibiotic-specific resistance mechanisms.
Tigecycline is not affected by the major tetracycline resistance mechanism of ribosomal protection and is not affected by many efflux systems. Acquired resistance to tigecycline has been demonstrated in several clinical isolates of Enterobacteriaceae due to overexpression of the AcrAB efflux system, a multi-drug efflux pump.
In in vitro studies, no antagonism has been observed between tigecycline and any other commonly used antibiotic class.

Clinical trials.

Complicated skin and skin structure infections.

Tigecycline was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomised, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with vancomycin (1 g IV every 12 hours)/aztreonam (2 g IV every 12 hours) for 5 to 14 days. Patients with complicated deep soft-tissue infections including wound infections and cellulitis (≥ 10 cm, requiring surgery/drainage or with complicated, underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies.
Patients with chronically infected ulcers, peripheral vascular disease requiring amputation, necrotising infections and contiguous osteomyelitis were not included in these studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See Table 4.
Clinical cure rates at test of cure (TOC) by pathogen in microbiologically evaluable patients with complicated skin and skin structure infections are presented in Table 5.

Complicated intra-abdominal infections.

Tigecycline was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomised, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg IV every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of the intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 6.
Clinical cure rates at test of cure (TOC) by pathogen in microbiologically evaluable patients with complicated intra-abdominal infections are presented in Table 7.

Methicillin-resistant staphylococcus aureus (MRSA).

Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI, and other infections) due to MRSA in Study 307.
Study 307 was a randomised, double-blind, active-controlled, multinational, multicenter study evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) and vancomycin (1 g IV every 12 hours) for the treatment of infections due to methicillin-resistant Staphylococcus aureus (MRSA). Patients with cIAI, cSSSI, and other infections were enrolled in this study. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 8 for MRSA.

5.2 Pharmacokinetic Properties

The mean pharmacokinetic parameters of tigecycline for this dosage regimen after single and multiple intravenous doses are summarised in Table 9.
Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes.

Absorption.

Tigecycline is administered intravenously, and therefore has 100% bioavailability.

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 microgram/mL). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving single or multiple doses of 14C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone, bone marrow, thyroid gland, kidney, spleen, and salivary gland. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues of humans.
Two studies examined the steady-state pharmacokinetic profile of tigecycline in specific tissues or fluids of healthy subjects receiving tigecycline 100 mg followed by 50 mg every 12 hours. In a bronchoalveolar lavage study, the tigecycline AUC0-12h (134 microgram.hr/mL) in alveolar cells was approximately 77.5-fold higher than the AUC0-12h in the serum of these subjects, and the AUC0-12h (2.28 microgram.hr/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. In a skin blister study, the AUC0-12h (1.61 microgram.hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of these subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Tissue concentrations at 4 hours after tigecycline administration were measured in the following tissue and fluid samples: gallbladder, lung, colon, synovial fluid and bone. Tigecycline attained higher concentrations in tissues versus serum in gallbladder (38-fold, n=6), lung (8.6-fold, n=1) and colon (2.1-fold, n=5). The concentration of tigecycline in these tissues after multiple doses has not been studied.

Metabolism.

Tigecycline is not extensively metabolised. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers, receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and faeces, but a glucuronide, an N-acetyl metabolite and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.

Excretion.

The recovery of total radioactivity in faeces and urine following administration of 14C-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.

Special populations.

Hepatic insufficiency.

In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and five patients with severe hepatic impairment (Child Pugh C) to 23 age- and weight-matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25%, and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). In addition, systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C).
Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in patients with mild-to-moderate hepatic impairment (Child Pugh A and Child Pugh B). However, in patients with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Patients with hepatic impairment).

Renal insufficiency.

A single-dose study compared six subjects with severe renal impairment (creatinine clearance ClCr ≤ 30 mL/min), four end stage renal disease patients receiving tigecycline 2 hours before haemodialysis, four end stage renal disease patients receiving tigecycline after haemodialysis, and six healthy control subjects. The pharmacokinetic profile of tigecycline was not altered in any of the renally impaired patient groups, nor was tigecycline removed by haemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing haemodialysis (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Patients with renal impairment).

Elderly.

No overall differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age > 75), and younger subjects (n=18) receiving a single, 100 mg dose of tigecycline. Therefore, no dosage adjustment is necessary based on age.

Children.

The pharmacokinetics of tigecycline in patients less than 18 years of age have not been established.

Gender.

In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.

Race.

In a pooled analysis of 73 Asian subjects, 53 black subjects, 15 Hispanic subjects, 190 white subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), white subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.

5.3 Preclinical Safety Data

Genotoxicity.

No mutagenic or clastogenic potential was found in a battery of tests, including an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo micronucleus assay.

Carcinogenicity.

Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

The following drugs should not be administered simultaneously through the same line as tigecycline: amphotericin B, chlorpromazine, esomeprazole, omeprazole, methylprednisolone, diazepam and voriconazole.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tigecycline Juno should be stored below 25°C prior to reconstitution.
Reconstitution and further dilution of Tigecycline Juno must be performed immediately before use.
Once reconstituted and diluted in the IV bag, to reduce microbiological hazard, use as soon as practicable after reconstitution/dilution. If storage is necessary, hold at 2°-8°C for not more than 24 hours. Use in one patient on one occasion only. Contains no antimicrobial preservatives.

6.5 Nature and Contents of Container

Tigecycline Juno is available as a sterile orange to orange-red lyophilised powder or cake supplied in single-dose 5 mL glass vials containing 50 mg of tigecycline.
Available in cartons of 10 vials.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Tigecycline Juno contains the active ingredient tigecycline, which is a tetracycline class antibiotic in the glycylcycline subcategory.

Chemical structure.


Tigecycline Juno contains the active ingredient tigecycline, which is a tetracycline class antibiotic in the glycylcycline subcategory. The structural formula of tigecycline is:

Chemical name.

(4S,4aS,5aR,12aS)-9-[2-(tert-butylamino) acetamido]-4,7- bis (dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,10,12,12a- tetrahydroxy-1,11- dioxo-2-naphthacene carboxamide.

CAS number.

220620-09-7.

Molecular weight.

585.65.

Molecular formula.

C29H39N5O8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes