Consumer medicine information

Tygacil

Tigecycline

BRAND INFORMATION

Brand name

Tygacil

Active ingredient

Tigecycline

Schedule

SUMMARY CMI

TYGACIL^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being treated with Tygacil?

Tygacil contains the active ingredient tigecycline. It 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 Tygacil because you have one of the following types of serious infections: infection of the skin, including those with resistant bacteria, or infection in the abdomen. For more information, see Section 1. Why am I being treated with Tygacil? in the full CMI.

2. What should I know before treatment with Tygacil?

You should not be given Tygacil if you have ever had an allergic reaction to Tygacil or an intolerance to lactose. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before treatment with Tygacil? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tygacil and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Tygacil given?

Tygacil is given through slow infusion “drip” into a vein by your doctor or nurse. More instructions can be found in Section 4. How is Tygacil given? in the full CMI.

5. What should I know during treatment with Tygacil?

Things you should do	Remind any doctor,dentist orpharmacist you visit that you are using Tygacil. If you get severe diarrhoea, tell your doctor or nurse immediately. Do this even if it happens several weeks after treatment with Tygacil has been stopped. Tell your doctor immediately if you develop severe abdominal pain, nausea and vomiting. Use an additional method of contraception. If you become pregnant while taking this medicine, tell your doctor immediately. For more information on "Things you should do" can be found in Section 6 in the full CMI.
Things you should not do	Do not breastfeed your baby without discussing the risks with your doctor.
Driving or using machines	Be careful driving or operating machinery until you know how Tygacil affects you.
Looking after your medicine	Tygacil is stored in the pharmacy or on the hospital ward under the correct conditions.

For more information, see Section 5. What should I know during treatment with Tygacil? in the full CMI.

6. Are there any side effects?

Side effects of this medicine may include nausea; vomiting; diarrhoea; dizziness; headache; loss of appetite; stomach pain or heartburn; skin rash and itchiness; low sugar levels in blood which can cause blurred vision, difficulty concentrating, slurred speech and drowsiness; bleed or bruise more easily than normal; yellowing of the skin or eyeballs (jaundice); injection site reaction (pain, redness, inflammation, swelling); abscesses or other infections; abnormal healing; sepsis (rapid heart beat / 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; bleeding following injury taking longer to clot; sudden swelling of the lips, face, throat or tongue (allergic reactions).For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

TYGACIL^®

Active ingredient(s): tigecycline

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tygacil. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Tygacil.

Where to find information in this leaflet:

1. Why am I being treated with Tygacil?
2. What should I know before treatment with Tygacil?
3. What if I am taking other medicines?
4. How is Tygacil given?
5. What should I know during treatment with Tygacil?
6. Are there any side effects?
7. Product details

1. Why am I being treated with Tygacil?

Tygacil contains the active ingredient tigecycline. It 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 Tygacil because you have one of the following types of serious infections:

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

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

2. What should I know before treatment with Tygacil?

Warnings

Do not use Tygacil if:

you are allergic to tigecycline or have an intolerance to lactose.

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.

Check with your doctor if you:

have previously had an allergic reaction to tetracycline antibiotics. You may have an increased chance of being allergic to Tygacil if you are allergic to tetracyclines.
have an intolerance to lactose.
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.

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

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Talk to your doctor if you are breastfeeding or intend to breastfeed.

As with many medicines, Tygacil may harm your developing or breastfeeding baby. This may include permanent staining of the child's teeth.

Use in children

There is no experience with the use of Tygacil in children under 18 years of age. Tygacil, like other tetracyclines, may cause enamel loss and staining in developing teeth.

There is no evidence that Tygacil is addictive.

3. What if I am taking other medicines?

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

Some medicines may interfere with Tygacil. These include:

medicines to treat infections that contain ketoconazole or rifampicin
medicines that contain ciclosporin or tacrolimus
warfarin, if you are taking warfarin, your doctor or nurse will check your blood clotting time.
oral contraceptives (birth control pills). Tygacil may interfere with birth control pills.

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

Your doctor or pharmacist has more information on medicines to be careful with or avoid while being given Tygacil.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Tygacil.

4. How is Tygacil given?

How much is given

Your doctor will decide what dose, and how long you will receive it. This depends on your condition and other factors, such as how well your liver is working.

How is Tygacil given

Tygacil is given through slow infusion “drip” into a vein by your doctor or nurse over a period of 30 - 60 minutes every 12 hours.

How long to receive Tygacil

It is very important that you continue to receive Tygacil for as long as your doctor prescribes it. Your doctor will decide how many days of treatment you need. How long you receive Tygacil will depend on how severe your infection is and how quickly you respond to treatment.

If you receive too much Tygacil

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

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

If you miss a dose of Tygacil

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

5. What should I know during treatment with Tygacil?

Things you should do

If you get severe diarrhoea, tell your doctor or nurse immediately. Do this even if it happens several weeks after treatment with Tygacil 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 being given Tygacil.

If you are about to start any new medicines, tell your doctor and pharmacist that you are being given Tygacil.

Tell all doctors, dentists and pharmacists who are treating you that you are being given Tygacil.

Things you should not do

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting with a pharmacist.

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 Tygacil.

Although antibiotics, including Tygacil, 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 30+ sunscreen.

Tygacil 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.

Driving or using machines

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

Drinking alcohol

No information is available.

Looking after your medicine

Tygacil is stored in the pharmacy or on the hospital ward under the correct conditions.

Disposal of Tygacil

The hospital staff will dispose of any leftover Tygacil.

6. Are there any side effects?

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

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

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
Nausea Vomiting Diarrhoea Constipation Increased cough Back pain Dizziness Headache Loss of appetite Heartburn Swelling of your feet, ankles, lower legs, hand or arms 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).	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

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
Sepsis (rapid heart beat, 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.

Call your doctor straight away if you notice any of these serious side effects.

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

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may 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 Tygacil.

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 these lists.

Do not be alarmed by the lists of possible side effects. You may not experience any of them.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Tygacil contains

Active ingredient (main ingredient)	tigecycline
Other ingredients (inactive ingredients)	lactose monohydrate sodium hydroxide hydrochloric acid

Do not take this medicine if you are allergic to any of these ingredients.

Each Tygacil vial contains 50 mg of tigecycline as the active ingredient.

What Tygacil looks like

Tygacil is an orange powder supplied in glass vials. Dissolving the powder in a sterile liquid makes a solution for injection. After mixing, the solution is a yellow to orange colour.

Aust R 147450

Who distributes Tygacil

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedicalinformation.com.au

This leaflet was prepared in June 2024.

^®Registered trademark

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Tygacil

Active ingredient

Tigecycline

Schedule

1 Name of Medicine

Tigecycline.

2 Qualitative and Quantitative Composition

Each vial contains 50 mg tigecycline.

Excipient(s) with known effect.

Each vial contains 100 mg of lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tigecycline is an orange lyophilised powder or cake. The reconstituted solution is yellow to orange solution free of particulate matter.

4 Clinical Particulars

4.1 Therapeutic Indications

Tygacil 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 comorbidities preventing the use of, other available agents.
Complicated intra-abdominal infections, where there is suspected or proven resistance to, intolerance of, or there are comorbidities 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.

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.

Method of administration.

Intravenous infusion.

The lyophilised powder should be reconstituted with 5.3 mL of 0.9% sodium chloride solution for injection, or 5% glucose solution for injection 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. Once reconstituted, tigecycline may be stored below 25°C for up to 6 hours, or refrigerated at 2°C to 8°C for up to 24 hours.
Tygacil 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, or 5% glucose injection. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line. (See Section 6.2 Incompatibilities).

Dosage adjustment.

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 impairment).

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 impairment).

Elderly.

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

Paediatrics.

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).

Race and gender.

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

4.3 Contraindications

Tygacil is contraindicated for use in patients who have known hypersensitivity to tigecycline or any of the excipients listed, see 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). Tygacil 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.

Tygacil 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.

Pancreatitis acute.

Pancreatitis acute, which can be fatal, has occurred (frequency: uncommon) in association with tigecycline treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). The diagnosis of pancreatitis acute should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of pancreatitis acute. 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 subgroup 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 may prolong and/or worsen the condition and should not be used.

Superinfection.

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 = 1,642), 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 impairment).

Use in the elderly.

Of the total number of subjects who received tigecycline in Phase 3 clinical studies (n = 2,514), 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 coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the C_max of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in C_max 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 ciclosporin) 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 Tygacil.

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.

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. 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 oestrous cycles at exposures up to 5 times the human daily dose based on AUC.
(Category D)
Tygacil may cause fetal harm when administered to a pregnant woman.
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, ¹⁴C-labelled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures.
The administration of tigecycline was associated with slight reductions in fetal 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 fetal loss was observed at exposures of 1.5 times the human daily dose based on AUC in rabbits, at dosages producing maternal toxicity.
There are no adequate and well controlled studies of tigecycline in pregnant women. Tygacil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Tygacil has not been studied for use during labour and delivery.
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 Tygacil is administered to a nursing woman. Results from animal studies using ¹⁴C-labelled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited 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.

4.7 Effects on Ability to Drive and Use Machines

Tygacil 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 1,415 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.

In Phase 3 clinical studies, infection related serious adverse events were more frequently reported for subjects treated with Tygacil (6.7%) vs. comparator (4.6%). Significant differences in sepsis/ septic shock with Tygacil (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 Tygacil vs. comparator, respectively.
AST and ALT abnormalities in Tygacil treated patients were reported more frequently in the post-therapy period than in those in comparator treated patients, which occurred more often on therapy.
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 9). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, or complications of infection or underlying comorbidities.

Postmarketing experience.

The following adverse reactions have been identified during post marketing use of Tygacil. 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 postmarketing use include (see Table 3).
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.

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 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 has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens.

Mechanism of resistance.

Tigecycline is known to evade two major tetracycline resistance mechanisms, ribosomal protection and efflux. However, in recent studies, resistance to tigecycline has been detected in Enterobacterales and other organisms, determined by an efflux pump mechanism and by mutations in a ribosomal protein.
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), macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerase).

In vitro susceptibility of bacteria to tigecycline.

For broth dilution tests for aerobic organisms, minimum inhibitory concentrations (MIC) must be determined using testing medium that is fresh (< 12 hours old). The disk diffusion procedure utilises disks impregnated with 15 microgram of tigecycline.

European committee on antimicrobial susceptibility testing (EUCAST) reference information.

Minimum inhibitory concentration (MIC) and disk inhibition zone breakpoints established by EUCAST are as follows.
Breakpoint tables for interpretation of MICs and zone diameters. See Table 4.

For anaerobic bacteria there is clinical evidence of efficacy in polymicrobial intra-abdominal infections, but no correlation between MIC values, PK/PD data and clinical outcome. Therefore, no breakpoint for susceptibility is given.
Quality control ranges for EUCAST susceptibility testing are in Table 5.

PK/PD relationship.

Human pharmacodynamic studies indicate a relationship between AUC/MIC and clinical efficacy as well as microbiological efficacy.

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.
The information below provides only approximate guidance on the probability as to whether the microorganism will be susceptible to tigecycline or not:

Pathogen.

Commonly susceptible species.

Gram-positive aerobes.

Enterococcus spp.^# (including vancomycin resistant isolates), Staphylococcus aureus* (including methicillin resistant isolates), Staphylococcus epidermidis (including methicillin resistant isolates), Staphylococcus haemolyticus, Streptococcus agalactiae*, Streptococcus pyogenes*, Viridans group streptococci^#.

Gram-negative aerobes.

Citrobacter freundii*, Citrobacter koseri, Escherichia coli*.

Anaerobes.

Clostridium perfringens*, Peptostreptococcus spp.^#
Species for which acquired resistance may be a problem.

Gram-negative aerobes.

Acinetobacter baumannii, Enterobacter cloacae*, Klebsiella aerogenes, Klebsiella oxytoca*, Klebsiella pneumoniae*, Salmonella spp., Shigella spp., Stenotrophomonas maltophilia.

Anaerobes.

Bacteroides fragilis group^#, Parabacteroides distasonis.
Inherently resistant organisms.

Gram-negative aerobes.

Morganella morganii, Serratia marcescens, Providencia spp., Proteus spp., Pseudomonas aeruginosa.
*Denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.
^#Activity in clinical studies has been demonstrated for vancomycin-susceptible Enterococcus faecalis; penicillin-susceptible pneumococci; among viridans streptococci for the Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus); among Peptostreptococcus spp. for P. micros; among Bacteroides spp. for B. fragilis, B, thetaiotaomicron, B. uniformis, B. ovatus and B. vulgatus.

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 coprimary populations of the clinically evaluable (CE) and clinical modified intent to treat (c-mITT) patients. See Table 6.

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 7.

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 coprimary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 8.

Clinical cure rates at test of cure (TOC) by pathogen in microbiologically evaluable patients with complicated intra-abdominal infections are presented in Table 9.

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 coprimary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See Table 10 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 11.
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 AUC_0-12h (134 microgram.hr/mL) in alveolar cells was approximately 77.5-fold higher than the AUC_0-12h in the serum of these subjects, and the AUC_0-12h (2.28 microgram.hr/mL) in epithelial lining fluid was approximately 32% higher than the AUC_0-12h in serum. In a skin blister study, the AUC_0-12h (1.61 microgram.hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_0-12h 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-labelled 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.