Consumer medicine information

Dificid

Fidaxomicin

BRAND INFORMATION

Brand name

Dificid

Active ingredient

Fidaxomicin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dificid.

SUMMARY CMI

DIFICID®

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 taking DIFICID?

DIFICID contains the active ingredient fidaxomicin. DIFICID is used to treat infections of the lining of the colon (large intestine) with certain bacteria called Clostridium difficile.

For more information, see Section 1. Why am I taking DIFICID? in the full CMI.

2. What should I know before I take DIFICID?

Do not use if you have ever had an allergic reaction to DIFICID or any of the ingredients listed at the end of the CMI.

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 I take DIFICID? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DIFICID and affect how it works.

Tell your doctor or pharmacist if you are taking any other medicines. For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take DIFICID?

  • Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.
  • The usual dose is one tablet (200 mg) twice daily (one tablet every 12 hours) for 10 days.

More instructions can be found in Section 4. How do I take DIFICID? in the full CMI.

5. What should I know while taking DIFICID?

Things you should do
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking DIFICID.
Things you should not do
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
  • Do not take DIFICID to treat any other complaints unless your doctor tells you to.
Driving or using machines
  • Be careful driving or operating machinery until you know how DIFICID affects you.
  • DIFICID is not expected to affect your ability to drive, use tools or machines.
Looking after your medicine
  • Keep your medicine in the original container.
  • If you take it out of its original container it may not keep well.

For more information, see Section 5. What should I know while taking DIFICID? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist if you notice any of the following and they worry you: nausea, vomiting, constipation, headache, dizziness.

Tell your doctor immediately or go to Accident & Emergency at your nearest hospital if you notice any of the following: shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

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

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

DIFICID®

Active ingredient: fidaxomicin


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

1. Why am I taking DIFICID?
2. What should I know before I take DIFICID?
3. What if I am taking other medicines?
4. How do I take DIFICID?
5. What should I know while taking DIFICID?
6. Are there any side effects?
7. Product details

1. Why am I taking DIFICID?

DIFICID contains the active ingredient fidaxomicin. DIFICID is an antibiotic that belongs to a new group of medicines called macrocyclic antibiotics.

It works by killing the bacteria which cause Clostridium difficile infections. DIFICID will not work against viral infections such as colds or flu or against infections with other types of bacteria.

DIFICID is used to treat infections of the lining of the colon (large intestine) with certain bacteria called Clostridium difficile. This serious illness can result in painful, severe diarrhoea.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I take DIFICID?

Warnings

Do not take DIFICID if:

  • you are allergic to Fidaxomicin, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

If you are not sure whether you should start taking this medicine, talk to your doctor.

Check with your doctor if you:

  • have allergies to any other medicines, foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell him/her before you start taking DIFICID.

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.

Your doctor can discuss with you the risks and benefits involved.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known whether fidaxomicin passes into breast milk. Your doctor can discuss with you the risks and benefits involved.

Addiction

There is no evidence that this medicine 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.

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

4. How do I take DIFICID?

How much to take

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

If you take the wrong dose, DIFICID may not work as well and your problem may not improve.

  • The usual dose is one tablet (200 mg) twice daily (one tablet every 12 hours) for 10 days.

When to take DIFICID

This medicine may be taken with or without food.

How to take DIFICID

Swallow the tablets whole with a glass of water.

How long to take DIFICID

Continue taking your medicine until you finish the pack or for as long as your doctor tells you.

If you do not complete the full course prescribed by your doctor, the infection may not clear completely, or your symptoms may return.

Do not stop taking it because you are feeling better.

If you forget to take DIFICID

Take the tablet as soon as you remember. However, if it is nearly time for the next dose, skip the missed dose.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much DIFICID

If you think that you have taken too much DIFICID, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking DIFICID?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking DIFICID.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.

Call your doctor straight away if you:

  • become pregnant while taking this medicine

Remind any doctor, dentist or pharmacist you visit that you are taking DIFICID.

Things you should not do

  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
    If you do not complete the full course prescribed by your doctor, all the organisms causing your infection may not be killed. These organisms may continue to grow and multiply so that your infection may not clear completely or may return.
  • Do not take DIFICID to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful driving or operating machinery until you know how DIFICID affects you.

DIFICID is not expected to affect your ability to drive, use tools or machines.

Looking after your medicine

  • Keep your medicine in the original container.
  • If you take it out of its original container it may not keep well.
  • Keep your medicine in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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.

Mild side effects

Mild side effectsWhat to do
  • nausea
  • vomiting
  • constipation
  • headache
  • dizziness

These are mild side effects of the medicine and are short-lived.

Speak to your doctor if you have any of these mild side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

These are signs of a serious allergic reaction, which may require medical attention. Serious side effects are rare.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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.

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 DIFICID contains

Active ingredient
(main ingredient)
Fidaxomicin 200 mg
Other ingredients
(inactive ingredients)

Microcrystalline Cellulose

Pregelatinised maize starch

Hyprolose

Butylated Hydroxytoluene

Sodium Starch Glycollate

Magnesium Stearate

Tablet Coating:

Polyvinyl Alcohol

Titanium Dioxide

Purified Talc

Macrogol 3350

Lecithin (Soy)

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

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

What DIFICID looks like

DIFICID 200 mg are white to off-white film-coated, oblong tablets; each tablet is marked with “FDX” on one side and “200” on the other side. They are available in bottles of 20 or 60 tablets. Not all pack sizes may be marketed.

DIFICID 200 mg film-coated tablet (bottle): AUST R 195623

Who distributes DIFICID

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park NSW, 2113, Australia

This leaflet was prepared in June 2022.

Based on PI dated 15 June 2022.

RCN: 000022820 - AU

Copyright © (2022) Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved.

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Dificid

Active ingredient

Fidaxomicin

Schedule

S4

 

1 Name of Medicine

Fidaxomicin.

2 Qualitative and Quantitative Composition

Fidaxomicin is the active ingredient in Dificid.
Each film-coated tablet contains 200 mg of fidaxomicin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dificid tablets are white to off-white film-coated, oblong tablets; each tablet is debossed with "FDX" on one side and "200" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Dificid (fidaxomicin) is indicated for the treatment of confirmed Clostridium difficile infection (CDI) in adults.

4.2 Dose and Method of Administration

The recommended dose is 200 mg (one tablet) administered twice daily (once every 12 hours) for 10 days.
Dificid can be taken before, during or after meals.

Adults and elderly (≥ 65 years of age).

No dose adjustment is recommended for elderly patients.

Patients with renal impairment.

No dose adjustment is recommended for patients with renal impairment. Due to the limited clinical data in this population, Dificid should be used with caution in patients with severe renal impairment (see Section 5.2).

Patients with hepatic impairment.

No dose adjustment is recommended for patients with hepatic impairment. Due to the limited clinical data in this population, Dificid should be used with caution in patients with moderate to severe hepatic impairment (see Section 5.2).

Patients undergoing dialysis.

No dose adjustment is recommended for patients undergoing dialysis.

Patients with concomitant disease.

No dose adjustment is recommended for patients with concomitant disease.

Children.

Safety and efficacy of Dificid in patients under the age of 18 has not been established. Therefore, Dificid is not recommended for use in children.

4.3 Contraindications

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

4.4 Special Warnings and Precautions for Use

General.

Not for systemic infections.

Since there is minimal systemic absorption of fidaxomicin, Dificid should not be used for the treatment of systemic infections.

Development of drug resistant bacteria.

Prescribing Dificid in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Cardiovascular.

Electrocardiogram (ECG) parameters and QT intervals (QTc) were measured in subjects participating in clinical studies. No clinically significant changes from baseline to end of therapy in mean ECG parameters were seen. There was no evidence of QTc prolongation with Dificid treatment and there was no association between QTc prolongation and plasma levels of fidaxomicin or OP-1118, its main metabolite.
In an in vitro electrophysiology study, fidaxomicin and its main metabolite, OP-1118, had no effect on the hERG channel.

Hypersensitivity reactions.

Acute hypersensitivity reactions, such as dyspnoea, rash, pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, Dificid should be discontinued and appropriate therapy should be instituted.
Some patients with hypersensitivity reactions also reported a history of allergy to macrolides. Physicians prescribing Dificid to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

Use in the elderly.

Of the total number of subjects with CDI enrolled in controlled trials of Dificid, almost half (272, 48.2%) of the Dificid-treated subjects were 65 years of age and over. In controlled trials, elderly subjects (≥ 65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly subjects (< 65 years of age) [see Section 5.2, Special populations]. However, the magnitudes of increase in exposures in elderly subjects were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

Paediatric use.

The safety and effectiveness of Dificid in patients < 18 years of age have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinically relevant metabolism of fidaxomicin by human cytochrome P450 (CYP) enzymes was observed. Fidaxomicin does not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 or CYP3A4/5 enzymes in vitro. Systemic inhibition of CYP enzymes is not expected due to the low plasma levels after oral dosing. Inhibition of CYP2C9 and CYP3A4/5 in the gastrointestinal tract is possible due to the high concentrations reached locally. No clinically relevant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1 was observed.
In vitro, fidaxomicin and its main metabolite, OP-1118, are substrates and inhibitors of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract. In vivo data suggest that fidaxomicin may be a mild to moderate inhibitor of intestinal P-gp.

Drug-drug interactions.

In vivo in healthy volunteers, fidaxomicin did not have a clinically relevant effect on the CYP2C9 substrate warfarin, CYP3A4/5 substrate midazolam, and CYP2C19 substrate omeprazole (Table 1). Based on these results, no dose adjustment is warranted when Dificid is co-administered with CYP substrate compounds.
Ciclosporin is an inhibitor of multiple transporters, including P-gp. When ciclosporin was co-administered with Dificid in healthy adult volunteers, plasma concentrations of fidaxomicin and OP-1118 were significantly increased, but the increase is not considered clinically significant as concentrations remained very low (in the nanogram/mL range). Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e. gastrointestinal tract) via P-gp inhibition; however, in controlled clinical trials in subjects with C. difficile infection, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of Dificid-treated subjects. Based on these results, Dificid may be co-administered with P-gp inhibitors and no dose adjustment is recommended.
When digoxin, a P-gp substrate, was co-administered with Dificid (200 mg twice daily) in healthy volunteers, digoxin Cmax and AUC increased by 14% and 12%, respectively. This effect of fidaxomicin on digoxin exposure is not considered clinically relevant and no dose adjustment is necessary. However, a larger effect on P-gp substrates with lower bioavailability more sensitive to intestinal P-gp inhibition, such as dabigatran etexilate, cannot be excluded.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A rat study was conducted to assess mating, fertility, and early embryonic development (through implantation). Male and female rats were dosed intravenously with up to 6.3 mg/kg/day, with male rats dosed daily beginning 28 days prior to mating, through mating to Day 28 post-mating (a total of 56 days) and female rats dosed daily beginning 14 days prior to mating, through mating to gestation Day 7 (a total of 21 days). No effects on mating, on male or female fertility, or on early embryonic development were observed in rats at fidaxomicin exposures up to approximately 100-fold higher compared to the measured human exposure following a single 200 mg dose, or up to approximately 50-fold higher compared to the estimated exposures at the recommended human dose of 200 mg twice daily.
(Category B1)
There are no adequate and well-controlled studies of Dificid in pregnant women. Embryo-fetal development studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively, administered during the period of organogenesis. There were no maternal toxicity or effects on embryo-fetal development observed at fidaxomicin exposures up to 193-fold higher in rats and 66-fold higher in rabbits and OP-1118 exposures up to 65-fold higher in rats and 245-fold higher in rabbits, compared to human exposures following a single 200 mg dose of fidaxomicin. Estimated exposure multiples at the recommended human dose of 200 mg twice daily are approximately half of the multiples following a single 200 mg dose. Because animal reproduction studies are not always predictive of human response, Dificid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether fidaxomicin and/or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, the development and health benefits of breastfeeding should be considered along with the mother's clinical needs for Dificid and any potential adverse effects on the breastfed child from Dificid or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Dificid on the ability to drive and use machines have been performed. Based on the adverse effects and pharmacokinetic profile of Dificid, it is not anticipated that the use of this drug will affect the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial adverse effects overview.

The safety of Dificid 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with C. difficile infection in two active-comparator, double-blind, controlled trials with 86.7% of patients receiving a full course of treatment.
In the Dificid Phase 3 clinical trials, the overall incidence of adverse events was similar for subjects in the Dificid (68.3%) and vancomycin (65.5%) groups. The overall incidence of mild, moderate, and severe adverse events was similar for the Dificid and vancomycin groups.
In the Phase 3 clinical trials, the incidence of an adverse event for which drug was stopped permanently or the subject discontinued from the study was low (< 10% across treatment groups). The overall incidence of adverse events leading to study withdrawal was similar for the Dificid (n=33, 5.9%) and comparator (n=40, 6.9%) groups. Vomiting was the primary adverse event leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin subjects in the pooled Phase 3 studies.
Compared to vancomycin, more patients treated with Dificid experienced neutropenia-related events (2.4% versus 1.0%). However, these events were considered not drug-related by the investigators.
All adverse events that occurred at an incidence ≥ 2% in the phase 3 clinical trials are provided in Table 2. (These include adverse events that may be attributable to the underlying disease).

Clinical trial adverse drug reactions overview.

The overall rate of adverse drug reactions assigned by the clinical investigators as being possibly or definitely related to Dificid in Phase 3 clinical trials was 10.6%. The most common adverse drug reactions in patients receiving Dificid were nausea (2.7%), constipation (1.2%), and vomiting (1.2%). The majority of adverse drug reactions were reported as mild or moderate in severity. No serious adverse drug reaction considered to be related to Dificid by the investigator was reported by more than 1 subject.
The following adverse drug reactions were reported in subjects in controlled clinical trials on treatment with Dificid in more than 1 subject (see Table 3):

Post-market experience.

The following adverse reactions have been identified during post approval use of Dificid. The frequency of these reactions is not known (cannot be estimated from the available data).

Immune system disorders.

Hypersensitivity reaction (rash, pruritus, angioedema, dyspnea).

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 cases of acute overdose have been reported in humans. No drug related adverse effects were seen in dogs dosed with 9600 mg fidaxomicin/day (over 100 times the human dose, scaled by weight) for 3 months.
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.

Fidaxomicin is a novel antibiotic agent and the first of a new class of antibacterials called macrocycles. Fidaxomicin is bactericidal against Clostridium difficile (C. difficile) in vitro, inhibiting RNA synthesis by RNA polymerases. It interferes with RNA polymerase at a site distinct from that of rifamycins.
Fidaxomicin has also been shown to inhibit C. difficile sporulation in vitro. Faecal spore counts (CFU count/g) in subjects who had received Dificid were found to be 2.3 log10 lower at 21 to 28 days post-therapy than in those subjects who had received vancomycin.

Microbiology.

Antimicrobial spectrum.

Fidaxomicin is a narrow spectrum antimicrobial drug with bactericidal activity against C. difficile. Fidaxomicin has an MIC90 of 0.25 microgram/mL versus C. difficile, and its main metabolite, OP-1118, has an MIC90 of 8 microgram/mL. Gram negative organisms are intrinsically not susceptible to fidaxomicin.
Inhibition of the clostridial RNA polymerase enzyme occurs at a concentration that is 20-fold lower than that for the E. coli enzyme (1 microM vs. 20 microM), partly explaining the significant specificity of fidaxomicin activity.

Resistance.

No cross-resistance has been discovered with any other antibiotic class including β-lactams, macrolides, metronidazole, quinolones, rifampin, and vancomycin. Specific mutations of RNA polymerase are associated with reduced susceptibility to fidaxomicin.

Breakpoints.

Fidaxomicin is a topically acting drug that cannot be used to treat systemic infections; therefore the establishment of a clinical breakpoint is not relevant. The epidemiological cut-off value for fidaxomicin and C. difficile, distinguishing the wild-type population from isolates with acquired resistance traits, is > 1.0 mg/L.

Mechanism of decreased susceptibility to Dificid.

In vitro studies indicate a low frequency of spontaneous resistance to Dificid in C. difficile (ranging from < 1.4 x 10-9 to 12.8 x 10-9). A specific mutation (Val-ll43-Gly) in the beta subunit of RNA polymerase is associated with reduced susceptibility to Dificid. This mutation was created in the laboratory and seen during clinical trials in a C. difficile isolate obtained from a subject treated with Dificid who had recurrence of CDAD. The C. difficile isolate from the treated subject went from a Dificid baseline minimal inhibitory concentration (MIC) of 0.06 microgram/mL to 16 microgram/mL.

Cross-resistance/synergy/post-antibiotic effect.

Dificid and its main metabolite OP-1118 do not exhibit any antagonistic interaction with other classes of antibacterial drugs. In vitro synergistic interactions of Dificid and OP-1118 have been observed in vitro with rifampicin and rifaximin against C. difficile (FIC values ≤ 0.5). Dificid demonstrates a post-antibiotic effect vs. C. difficile of 6 - 10 hrs.

Susceptibility testing.

The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial drug therapy.

Dilution techniques.

Quantitative anaerobic in vitro methods can be used to determine the MIC of Dificid needed to inhibit the growth of the C. difficile isolates. The MIC provides an estimate of the susceptibility of C. difficile isolate to Dificid. The MIC should be determined using standardized procedures. Standardized methods are based on an agar dilution method or equivalent with standardized inoculum concentrations and standardized concentration of Dificid powder.

Susceptibility test interpretive criteria.

In vitro susceptibility test interpretive criteria for Dificid have not been determined. The relation of the in vitro Dificid MIC to clinical efficacy of Dificid against C. difficile isolates can be monitored using in vitro susceptibility results obtained from standardized anaerobe susceptibility testing methods.

Quality control parameters for susceptibility testing.

In vitro susceptibility test quality control parameters were developed for Dificid so that laboratories determining the susceptibility of C. difficile isolate to Dificid can ascertain whether the susceptibility test is performing correctly. Standardized dilution techniques require the use of laboratory control microorganisms to monitor the technical aspects of the laboratory procedures. Standardized Dificid powder should provide the MIC with the indicated quality control strain shown in Table 4.

Pharmacodynamics.

Fidaxomicin acts locally in the gastrointestinal tract on C. difficile with minimal systemic absorption and faecal concentrations in the colon that exceed the MIC90 of C. difficile throughout the dosing interval. As a topical agent, systemic pharmacokinetic/pharmacodynamic relationships cannot be established; however, in vitro data show fidaxomicin to have time-dependent bactericidal activity and suggest time over minimal inhibitory concentration (MIC) may be the parameter most predictive of clinical efficacy.
In a clinical study, Dificid predominantly affected faecal concentrations of C. difficile with little to no effect on normal microflora such as Bacteroides and other major phylogenetic groups. This characteristic may explain the lower C. difficile recurrence rate observed in subjects treated with Dificid compared to vancomycin. Acquisition of vancomycin-resistant Enterococcus (VRE) faecal colonisation is also significantly less frequent in CDI subjects treated with Dificid than in those treated with vancomycin.
Fidaxomicin has a prolonged in vitro post-antibiotic effect (approximately 6 to 10 hours), allowing for twice daily dosing. In a dose-ranging trial of fidaxomicin using 50 mg, 100 mg, and 200 mg twice daily for 10 days, a dose-response relationship was observed for efficacy.

Clinical trials.

Clinical efficacy and safety. Dificid was studied for the treatment of C. difficile infection (CDI) in 2 randomised studies. See Table 5.
In two multi-national randomised, double-blinded studies, a non-inferiority design was utilised to demonstrate the efficacy of Dificid (200 mg twice daily for 10 days) compared to vancomycin (125 mg four times daily for 10 days) in adults with CDI (also known as C. difficile-associated diarrhoea, or CDAD).
Enrolled subjects were 18 years of age or older and received no more than 24 hours of pretreatment with vancomycin or metronidazole. CDI was defined by > 3 unformed bowel movements (or > 200 mL of unformed stool for subjects having rectal collection devices) in the 24 hours before randomisation, and presence of either C. difficile toxin A or B in the stool within 48 hours of randomisation. Enrolled subjects had either no prior CDI history or only one prior CDI episode in the past three months. Subjects with fulminant colitis and subjects with multiple episodes (defined as more than one prior episode within the previous 3 months) of CDI were also excluded in the studies.
The demographic profile and baseline CDI characteristics of enrolled subjects were similar in the two trials. Subjects had a median age of 64 years, were mainly white (90%), female (58%), and inpatients (63%). Almost half of the subjects (49.4%) were aged ≥ 65 years. Concomitant antibiotics were received by 27.5% (275/999) of subjects at some time during the studies and 19.2% (192/999) of subjects received antibiotics concurrently with study drug.
Approximately 84% of subjects had no prior CDI episode within the previous 3 months.

Study results.

The primary efficacy endpoint was the clinical response rate at the end of therapy, based upon improvement in diarrhoea or other symptoms such that, in the investigator's judgment, further CDI treatment was not needed. Additional efficacy endpoints were recurrence and sustained clinical response. Sustained clinical response was evaluated only for subjects who were clinical successes at the end of therapy. Sustained clinical response was defined as achieving clinical response at the end of therapy and not having a recurrence of CDI at any time up through 30 days beyond the end of therapy.
Dificid was demonstrated to be at least as effective as vancomycin in treating CDI (non-inferior), defined as clinical response rates at the end of therapy (88.2% vs. 85.7% respectively in study 101.1.C.003; 87.7% vs. 86.7% respectively in study 101.1.C.004). Notably, Dificid was associated with significantly greater improvements in the rate of sustained clinical response compared to vancomycin (74.4% vs. 64.2%, p=0.007 in study 101.1.C.003; 76.7% vs. 63.3%, p=0.001 in study 101.1.C.004). Since clinical response rates at the end of therapy and mortality rates were similar for both treatments, superiority in sustained clinical response was due to lower rates of proven or suspected CDI recurrence during the follow-up period, with significantly lower rates of CDI recurrence with Dificid than with vancomycin (15.7% vs. 25.1%, p=0.008 in study 101.1.C.003; 12.6% vs. 27.0%, p < 0.001 in study 101.1.C.004).
The results for sustained clinical response at 30 days post-therapy, also shown in Table 6, indicate that Dificid is superior to vancomycin for this endpoint.
Proven or suspected CDI recurrence rates 30 days post-therapy for those subjects who were clinical successes at the end of therapy are shown in Table 7. In both studies, the recurrence rate was significantly lower in the Dificid group compared to the vancomycin group.
Among subjects who experienced a recurrence of CDI, recurrence occurred later for Dificid subjects than for vancomycin subjects.
Results for all endpoints were consistent with the primary findings across most subgroups analysed (including age, sex, race, disease severity, use of concomitant antibiotics, and in-patient vs. out-patient status). For initial strain type of CDI, restriction endonuclease analysis was used to identify C. difficile baseline isolates in the BI group, isolates associated with increasing rates and severity of CDI in the years prior to the clinical trials. Similar rates of clinical response at the end of therapy and proven or suspected CDI during the follow-up period were seen in Dificid-treated and vancomycin-treated subjects infected with a BI isolate.
Amongst the per protocol population, in the absence of concomitant antibiotic use, Dificid and vancomycin were similar in achievement of clinical response by the end of therapy (92.3% vs. 92.8%; p=0.80). However, when subjects received one or more antibiotics concurrently with study drug, Dificid was superior to vancomycin in achieving clinical response (90.0% vs. 79.4%; p=0.04). When subjects received no additional antibiotics at any time during the study, the sustained clinical response rate was 80.8% for Dificid subjects and 69.1% for vancomycin subjects (p < 0.001). Sustained clinical response rates were substantially reduced in both treatment groups when subjects received concomitant antibiotics, but significantly more Dificid subjects achieved sustained clinical response compared to vancomycin (72.7% vs. 59.4%, p=0.02).
A study of subjects treated with Dificid demonstrated that concentrations of Bacteroides or other major phylogenetic groups in the faeces were left unaffected. This sparing effect of the microflora may explain the lower C. difficile recurrence rate that was observed in subjects treated with Dificid compared to vancomycin. Acquisition of vancomycin-resistant Enterococcus (VRE) faecal colonisation was significantly less frequent in CDI subjects treated with Dificid compared to those treated with vancomycin (7% vs. 31%; p < 0.001).
Efficacy and safety in patients with moderate or severe hepatic impairment, severe renal impairment and fulminant or life-threatening C. difficile infection (CDI). In a retrospective post-authorisation study, data from 576 patients treated with fidaxomicin for CDI were evaluated. Defined co-morbid conditions of specific medical interest present were moderate or severe hepatic impairment (50 patients), severe renal impairment (104 patients) and fulminant or life-threatening CDI based on the clinical judgment of the investigator (87 patients). The effectiveness of fidaxomicin treatment, defined as percentage of episodes with resolution of diarrhoea was 83.3% in patients without a medical condition of interest, 78.7% in patients with co-morbid moderate or severe hepatic impairment, 68% in patients with co-morbid severe renal impairment and 67.5% in patients with fulminant or life-threatening CDI.
Evaluation of the incidence of mortality, laboratory and ECG data did not indicate any additional safety concern in patients with a medical condition of interest compared with those who did not have any of these conditions.
Efficacy and safety in patients with inflammatory bowel disease (IBD). In the retrospective post-authorisation study 29 CDI patients with co-morbid IBD were included. The effectiveness of fidaxomicin treatment, defined as percentage of episodes with resolution of diarrhoea was 81.8% in CDI patients with IBD and 83.3% in CDI patients without a medical condition. Evaluation of the incidence of mortality, laboratory and ECG data did not indicate any additional safety concern in patients with IBD compared with those who did not have a medical condition of interest.
An open label, single arm, phase IIIB/IV study of fidaxomicin has been conducted to investigate the plasma PK of fidaxomicin and its main metabolite OP-1118 in CDI subjects with inflammatory bowel disease (IBD). Fourteen patients with Crohn's disease (CD) and 11 with ulcerative colitis (UC). Of the 25 subjects enrolled with active IBD, 24 fulfilled the criteria for the PK analysis set. The maximum plasma concentrations of fidaxomicin and its active metabolite OP-1118 in these subjects were within the measured range of concentration values found in earlier studies of fidaxomicin and OP-1118 involving CDI patients without IBD. This was associated with similar adverse event reporting as documented in previous studies with CDI patients without IBD. CDI clinical response after fidaxomicin treatment (Day 12) was reported in 20/25 (80%) (95% confidence interval 60.9-91.1%). Of 20 patients with CDI clinical response at Day 12, there were no recurrences at Day 26 and three patients had recurrence by Day 180.

5.2 Pharmacokinetic Properties

The pharmacokinetic parameters of fidaxomicin and its main metabolite OP-1118 in plasma following a single oral dose of 200 mg in healthy adult males (N=14) are summarised in Table 8.

Absorption.

Fidaxomicin has minimal systemic absorption following oral administration, with plasma concentrations of fidaxomicin and OP-1118 in the nanogram/mL range at the therapeutic dose. In Dificid-treated subjects with CDI in controlled trials, plasma concentrations of fidaxomicin and its main metabolite OP-1118 obtained within the Tmax window (1-5 hours) were approximately 2- to 6-fold higher than Cmax values in healthy adults.
Following administration of Dificid 200 mg twice daily for 10 days, OP-1118 plasma concentrations within the Tmax window were approximately 50-80% higher than on Day 1, while concentrations of fidaxomicin were similar on Day 1 and Day 10.

Distribution.

Fidaxomicin is mainly confined to the gastrointestinal tract following oral administration. In subjects with CDI treated with Dificid 200 mg twice daily for 10 days from controlled trials, faecal concentrations of fidaxomicin and OP-1118 obtained within 24 hours of the last dose ranged from 5.0-7630.0 microgram/g and 63.4-4170.0 microgram/g, respectively. In contrast, plasma concentrations of fidaxomicin and OP-1118 at 3-5 hours post-dose (Day 10) ranged between 0.3-191.0 nanogram/mL and 1.1-871.0 nanogram/mL, respectively.

Metabolism.

Fidaxomicin is primarily transformed by hydrolysis at the isobutyryl ester to form its main and microbiologically active metabolite, OP-1118. Metabolism of fidaxomicin and formation of OP-1118 are not dependent on cytochrome P450 (CYP) enzymes.
At the therapeutic dose, OP-1118 was the predominant circulating compound in healthy adults, followed by fidaxomicin.

Excretion.

Fidaxomicin is mainly excreted in faeces. In one trial of healthy adults (N=11), more than 92% of the dose was recovered in the stool as fidaxomicin and OP-1118 following single doses of 200 mg and 300 mg. In another trial of healthy adults (N=6), < 1% of the dose was recovered in urine as OP-1118 only following a single dose of 200 mg.

Special populations.

Renal impairment.

In controlled trials of patients treated with Dificid 200 mg twice daily for 10 days, plasma concentrations of fidaxomicin and OP-1118 within Tmax window (1-5 hours) did not vary by severity of renal impairment (based on creatinine clearance) between mild (51-79 mL/min), moderate (31-50 mL/min), and severe (≤ 30 mL/min) categories. No dose adjustment is recommended based on renal function.

Hepatic impairment.

The impact of hepatic impairment on the pharmacokinetics of fidaxomicin has not been evaluated. Because fidaxomicin and OP-1118 do not appear to undergo significant hepatic metabolism, elimination of fidaxomicin and OP-1118 is not expected to be significantly affected by hepatic impairment. Limited data from patients with an active history of chronic hepatic cirrhosis in the Phase 3 studies showed that median plasms levels of fidaxomicin and OP-1118 may be approximately 2 and 3 fold higher, respectively, than in non-cirrhotic patients.

Geriatric.

In controlled trials of patients treated with Dificid 200 mg twice daily for 10 days, mean and median values of fidaxomicin and OP-1118 plasma concentrations within the Tmax window (1-5 hours) were approximately 2-4 fold higher in elderly patients (≥ 65 years of age) versus non-elderly patients (< 65 years of age). Despite greater exposures in elderly patients, fidaxomicin and OP-1118 plasma concentrations remained in the nanogram/mL range. This difference is not considered to be clinically relevant.

Race, gender, and weight.

Plasma concentrations of fidaxomicin and OP-1118 within the Tmax window (1-5 hours) did not vary by gender, race or weight in patients treated with Dificid 200 mg twice daily for 10 days from controlled trials. No dose adjustment is recommended based on these parameters.

Inflammatory bowel disease.

The effect of concomitant inflammatory bowel disease (IBD) on the pharmacokinetics of fidaxomicin and OP-1118 was evaluated in CDI patients. Fidaxomicin and OP-1118 plasma levels in CDI patients with concomitant IBD were within the same range of levels found in CDI patients without IBD 1-5h post-dose on the last day of dosing (day 10).
Fidaxomicin and OP-1118 plasma levels in patients with CDI patients with concomitant inflammatory bowel disease (IBD) were within the same range of levels found in CDI patients without IBD 1-5h post-dose on the last day of dosing (day 10).

5.3 Preclinical Safety Data

Genotoxicity.

Fidaxomicin and OP-1118 were negative for mutagenic potential in the Ames assay. OP-1118 was negative in the in vitro chromosomal aberration assay in Chinese hamster ovary cells. Fidaxomicin was positive in the in vitro chromosomal aberration assay in Chinese hamster ovary cells but negative in the in vivo rat bone marrow micronucleus assay and the in vivo DNA damage Comet assay in rat liver and duodenum at exposures higher than the human exposure at the recommended clinical dose. The weight of evidence supports that fidaxomicin is not genotoxic in vivo and does not represent a risk of genotoxicity in clinical use.

Carcinogenicity.

Carcinogenicity studies have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablets.

Microcrystalline cellulose, pregelatinised maize starch, hyprolose, butylated hydroxytoluene, sodium starch glycollate, magnesium stearate.

Tablet coating.

Polyvinyl alcohol, titanium dioxide, purified talc, macrogol 3350, lecithin (soy).

6.2 Incompatibilities

Not applicable.

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

Store below 25°C.

6.5 Nature and Contents of Container

Dificid tablets are supplied in HDPE bottles containing 20 and 60 tablets and a desiccant and fitted with a child resistant cap.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

873857-62-6.
Chemical name: oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)- 2-O-methyl-β-D-mannopyranosyl]oxy]methyl]- 12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)- β-D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy- 18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)-.
Molecular weight: 1058.04.
Molecular formula: C52H74Cl2O18.
Fidaxomicin is freely soluble in tetrahydrofuran, dimethyl sulfoxide and methanol, soluble in acetone and sparingly soluble in ethyl acetate, ethanol (200 proof), dichloromethane and acetonitrile, and slightly soluble in isopropanol and practically insoluble in water.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes