Consumer medicine information

Mycamine

Micafungin

BRAND INFORMATION

Brand name

Mycamine

Active ingredient

Micafungin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mycamine.

SUMMARY CMI

Mycamine®

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 using MYCAMINE?

Mycamine contains the active ingredient micafungin (as sodium). Mycamine is used to treat a number of different conditions and illnesses (see Section 1. Why am I using MYCAMINE? in the CMI for full detail). The most common uses are to treat a serious fungal infection called invasive candidiasis; fungal infection in the food pipe (oesophagus); Candida (yeast) infection while undergoing a certain type of stem cell transplant or if you are expected to have white blood cell counts below a certain level.

2. What should I know before I use MYCAMINE?

Do not use if you have ever had an allergic reaction to Mycamine or any of the ingredients listed at the end of the CMI.
There are a number of circumstances in which a person should not use this medicine or may need to use caution. It is important to understand if these apply to you before taking Mycamine (see Section 2. What should I know before I use MYCAMINE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MYCAMINE 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 do I use MYCAMINE?

Mycamine must be prepared and given to you by a nurse or another health care professional. Your doctor will decide how much Mycamine you will receive each day.

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

5. What should I know while using MYCAMINE?

Things you should do
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are receiving Mycamine.
  • Tell any other doctors, dentists, and pharmacists who treat you that you are having this medicine.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are having this medicine. It may affect other medicines used during surgery.
  • If you become pregnant while receiving this medicine, tell your doctor immediately.
Driving or using machines
  • Mycamine is unlikely to have an effect on driving or using machines. Be careful when driving or operating machinery until you know how Mycamine affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Unopened vials should be kept in a cool dry place where the temperature stays below 25°C.

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

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). Some serious side effects may include swelling of the hands, ankles or feet; shortness of breath or difficulty in breathing; rash, itchiness or hives; fast heartbeat or irregular heartbeat; passing smaller amount of urine; yellowing of the skin or eyes.

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

Mycamine®

Active ingredient(s): Micafungin (as sodium)

Consumer Medicine Information (CMI)

This leaflet answers some common questions about Mycamine.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you having Mycamine against the benefits they expect it will have for you.

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

Keep this leaflet.

You may need to read it again.

Where to find information in this leaflet:

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

1. Why am I using MYCAMINE?

This medicine is used to treat:

  • adults, adolescents and children who have a serious fungal infection called invasive candidiasis (an infection caused by a yeast called Candida that has penetrated the body)
  • adults and adolescents 16 years of age and above who have a fungal infection in the food pipe (oesophagus) where treatment into a vein is appropriate
  • adults, adolescents and children who are at risk of developing a Candida (yeast) infection while undergoing a certain type of stem cell transplant or if you are expected to have white blood cell counts below a certain level.

This medicine belongs to a group of medicines called echinocandins which are used to treat infections caused by fungal or yeast cells called Candida.

It works by interfering with the production of a part of the fungal cell wall making the fungus unable to live and grow.

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 use MYCAMINE?

Warnings

Do not use MYCAMINE if you have an allergy to:

  • any medicine containing micafungin
  • any of the ingredients listed at the end of this leaflet
  • any other medicines belonging to the echinocandin group.

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

Do not have this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

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

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

Check with your doctor if you have or have had any of the following medical conditions:

  • haemolytic anaemia (anaemia due to breakdown of red blood cells) or haemolysis (breakdown of red blood cells)
  • kidney problems such as kidney failure or an abnormal kidney function test
  • liver problems such as liver failure, hepatitis or abnormal liver function tests.

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

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

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

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

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 and Mycamine may interfere with each other. These include:

  • itraconazole, medicines used to treat fungal infections
  • sirolimus, a medicine used to prevent kidney transplant rejection
  • nifedipine, a medicine used to treat high blood pressure.

These medicines may be affected by Mycamine. You may need different amounts of these medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while receiving this medicine.

4. How do I use MYCAMINE?

This medicine must be prepared and given to you in the hospital by a nurse or another health care professional.

How much you will be given

Your doctor will decide how much Mycamine you will receive each day.

For adults, adolescents 16 years of age and above and elderly:

  • the usual dose to treat an invasive Candida infection is 100 mg per day for patients weighing more than 40 kg, and 2 mg/kg per day for patients weighing 40 kg or less
  • the dose to treat a Candida infection of the oesophagus is 150 mg for patients weighing more than 40 kg and 3 mg/kg per day for patients weighing 40 kg or less
  • the usual dose for patients at risk of developing a Candida infection is 50 mg per day for patients weighing more than 40 kg and 1 mg/kg per day for patients weighing 40 kg or less.

For children and adolescents above 4 months of age and under 16 years of age:

  • the usual dose to treat an invasive Candida infection is 100 mg per day for patients weighing more than 40 kg, and 2 mg/kg per day for patients weighing 40 kg or less
  • the usual dose for patients at risk of developing a Candida infection is 50 mg per day for patients weighing more than 40 kg and 1 mg/kg per day for patients weighing 40 kg or less.

When Mycamine will be given

  • This medicine is given once daily by a slow infusion into a vein. The infusion usually lasts one hour.

How long will you be given Mycamine

For the treatment of an invasive Candida infection, you will usually receive this medicine for at least 14 days but treatment will usually continue for at least one week after symptoms and blood results show the infection has been cleared.

For a Candida infection of the oesophagus, treatment will usually continue for at least one week after symptoms have disappeared.

For the prevention of Candida infection, treatment will usually continue for at least one week after white blood cell numbers are back to normal.

If you miss a dose of Mycamine

Your doctor monitors your response and condition to determine how long treatment is needed. However, if you are concerned that you may have missed a dose, speak to your doctor or another health care professional immediately.

If you are given too much Mycamine (overdose)

Your doctor monitors your response and condition to determine what dose is needed. However, if you are concerned that you may have been given too much Mycamine, speak to your doctor or another health care professional immediately.

5. What should I know while using MYCAMINE?

Things you should do

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

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are having this medicine.

It may affect other medicines used during surgery.

If you become pregnant while receiving this medicine, tell your doctor immediately.

Driving or using machines

Mycamine is unlikely to have an effect on driving or using machines. Be careful when driving or operating machinery until you know how Mycamine affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Unopened vials should be kept in a cool dry place where the temperature stays below 25°C.
  • The prepared infusion solution should be used immediately and kept protected from light. If the infusion solution appears cloudy, it should not be used.

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?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are receiving Mycamine.

This medicine helps most people with prevention or treatment of fungal infections but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

Less serious side effects

Less serious side effectsWhat to do
  • Diarrhoea
  • Nausea or vomiting
  • Constipation
  • Fever or high temperature
  • Headache
  • Stomach pain or discomfort
  • Indigestion
  • Tiredness
  • Loss of appetite
  • Joint or back pain
  • Difficulty sleeping
  • Cough
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Swelling of the hands, ankles or feet
  • Shortness of breath or difficulty breathing
  • Rash, itchiness or hives
  • Fast heartbeat or changes in the way the heart beats
  • Difficulty passing urine
  • Yellowing of the skin or eyes
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.

Some of these side effects (for example, changes in blood test results or blood pressure) can only be found when your doctor does tests from time to time to check your progress.

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 MYCAMINE contains

Active ingredient
(main ingredient)		Mycamine contains 50 mg or 100 mg of micafungin (as sodium) as the active ingredient.
Other ingredients
(inactive ingredients)		Each vial also contains:
  • lactose monohydrate
  • citric acid
  • sodium hydroxide.

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

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

What MYCAMINE looks like

Mycamine 50 mg (AUST R 196108) is a white coloured powder for injection contained within a glass vial with a rubber stopper, blue flip off cap and UV protective shrink wrapping film.

Mycamine 100 mg (AUST R 196109) is a white coloured powder for injection contained within a glass vial with a rubber stopper, red flip off cap and UV protective shrink wrapping film.

Both strengths are available as packs of 1 vial.

Who distributes MYCAMINE

Mycamine is supplied in Australia by:

Astellas Pharma Australia Pty Ltd
Suite 2.01, 2 Banfield Road
Macquarie Park NSW 2113

Medical Information:
1800 751 755

® = Registered Trademark

This leaflet was prepared in July 2021.

Published by MIMS September 2021

BRAND INFORMATION

Brand name

Mycamine

Active ingredient

Micafungin

Schedule

S4

 

1 Name of Medicine

Micafungin.

2 Qualitative and Quantitative Composition

Mycamine 50 mg contains 50.86 mg micafungin sodium, corresponding to 50 mg micafungin. Mycamine 100 mg contains 101.73 mg micafungin sodium, corresponding to 100 mg micafungin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection vial.
Mycamine 50 mg and 100 mg is a white coloured powder for injection.
The powder must be diluted with either sodium chloride 0.9% or glucose 5% solution prior to use (see Section 4.2 Dose and Method of Administration).

4 Clinical Particulars

4.1 Therapeutic Indications

Mycamine is indicated for:
treatment of invasive candidiasis in children and adults;
treatment of oesophageal candidiasis in adults, adolescents ≥ 16 years of age and the elderly patients for whom intravenous therapy is appropriate;
prophylaxis of Candida infection in children and adult patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia (absolute neutrophil count < 500 cells/microL) for 10 or more days.

4.2 Dose and Method of Administration

Mycamine must be diluted with either sodium chloride 0.9% or glucose 5% solution prior to use.
Mycamine should be administered once daily by intravenous infusion. The dosage depends on the indication and bodyweight of the patient as shown in Tables 1, 2 and 3.

Treatment duration.

Invasive candidiasis.

The treatment duration for Candida infection should be a minimum of 14 days. The antifungal treatment should continue for at least one week after two sequential negative blood cultures have been obtained and after resolution of clinical signs and symptoms of infection.

Oesophageal candidiasis.

For the treatment of oesophageal candidiasis, Mycamine should be administered for at least one week after resolution of clinical signs and symptoms.

Prophylaxis of Candida infections.

For prophylaxis of Candida infection, Mycamine should be administered for at least one week after neutrophil recovery.

Paediatric population.

The safety and efficacy in children (including neonates) less than 4 months of age of doses of 4 and 10 mg/kg for the treatment of invasive candidiasis with CNS involvement has not been adequately established. Currently available data are described (see Section 4.8; Section 5.1; Section 5.2).
Treatment duration.

Invasive candidiasis.

The treatment duration for Candida infection should be a minimum of 14 days and should continue for at least one week after two sequential negative blood cultures have been obtained and after resolution of clinical signs and symptoms of infection.

Prophylaxis of Candida infections.

For prophylaxis of Candida infection, Mycamine should be administered for at least one week after neutrophil recovery. Experience in patients less than two years of age is limited.

Patients with hepatic impairment.

No dosage adjustment is required in patients with mild to severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment; Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Patients with renal impairment.

No dosage adjustment is required in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Instructions for reconstitution and dilution.

Mycamine must not be mixed or coinfused with any other medicinal products except those mentioned below. Mycamine has been shown to precipitate when mixed directly with a number of other commonly used medications.
Using aseptic techniques at room temperature, Mycamine should be reconstituted and diluted as follows:
1. Remove the plastic cap from the vial and disinfect the stopper with alcohol.
2. Five mL of sodium chloride 9 mg/mL (0.9%) solution for infusion or glucose 50 mg/mL (5%) solution for infusion (taken from a 100 mL bag/ bottle) should be aseptically and slowly injected into each vial along the side of the inner wall. Although the concentrate will foam, every effort should be made to minimise the amount of foam generated. A sufficient number of vials of Mycamine should be reconstituted to obtain the required dose as shown in Table 4.
3. The vial should be rotated gently. Do not shake. The powder will dissolve completely. The concentrate should be used immediately for further dilution. The product is for single use in one patient only. Discard any residue.
4. All of the reconstituted concentrate should be withdrawn from each vial and returned into the infusion bag/bottle from which it was originally taken. The diluted infusion solution should be used immediately.
5. The infusion bag/ bottle should be gently inverted to disperse the diluted solution but not agitated in order to avoid foaming. Do not use if the solution is cloudy or has precipitated.
6. The infusion bag/ bottle containing the diluted infusion solution should be inserted into a closable opaque bag for protection from light.

Administration.

An existing intravenous line should be flushed with sodium chloride 0.9% solution prior to infusion. Administer the reconstituted and diluted Mycamine solution intravenously over approximately one hour.

4.3 Contraindications

Mycamine is contraindicated in patients with hypersensitivity to any component of this medication or to other echinocandins (see Section 2 Qualitative and Quantitative Composition).

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

During administration of Mycamine, anaphylactic/ anaphylactoid reactions including shock may occur. If these reactions occur, Mycamine should be discontinued and appropriate treatment administered.

Skin and subcutaneous tissue disorders.

Exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. If patients develop a rash, they should be monitored closely and Mycamine discontinued if lesions progress.

Haemolysis.

Isolated cases of haemolysis including acute intravascular haemolysis or haemolytic anaemia have been reported in patients treated with micafungin. Patients who develop clinical or laboratory evidence of haemolysis during Mycamine therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/ benefit of continuing therapy.

Use in hepatic impairment.

Liver function should be carefully monitored during Mycamine treatment. Early discontinuation in the presence of significant and persistent elevation of ALT/AST is recommended. Mycamine treatment should be conducted on a careful risk/ benefit basis, particularly in patients having severe liver function impairment or chronic liver diseases known to represent pre-neoplastic conditions, such as advanced liver fibrosis, cirrhosis, viral hepatitis, neonatal liver disease or congenital enzyme defects, or receiving a concomitant therapy including hepatotoxic and/or genotoxic properties.

Use in the elderly.

No dosage adjustment is necessary for the elderly (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Paediatric use.

See Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations. The incidence of some adverse reactions was higher in paediatric patients than in adult patients (see Section 4.8 Adverse Effects (Undesirable Effects)).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Micafungin has a low potential for interactions with medicines metabolised via CYP3A mediated pathways as shown below.

Effects of other medicines on micafungin.

A total of 14 drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between micafungin and mycophenolate mofetil, cyclosporin, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, rifampicin, itraconazole, voriconazole and amphotericin B. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. Therefore, no Mycamine dose adjustments are necessary when these medicines are administered concomitantly.

Effects of micafungin on other medicines.

There was no effect of a single dose or multiple doses of micafungin on mycophenolate mofetil, cyclosporin, tacrolimus, prednisolone, fluconazole and voriconazole pharmacokinetics.
Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state micafungin compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42% respectively, in the presence of steady-state micafungin compared with nifedipine alone. Itraconazole AUC and Cmax were increased by 22% and 11% respectively. Therefore, patients receiving sirolimus, nifedipine or itraconazole in combination with Mycamine should be monitored for toxicity and the dosage of sirolimus, nifedipine or itraconazole reduced if necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Micafungin had no effect on the fertility of male and female rats at doses up to 32 mg/kg/day IV (4-fold the anticipated maximum clinical exposure, based on AUC). However, male rats treated for 9 weeks at 10-32 mg/kg/day IV micafungin (resulting in 1-4-fold the anticipated maximum clinical exposure, based on AUC) showed vacuolation of the epididymal ductal epithelial cells. A dose of 32 mg/kg/day also resulted in higher epididymis weights and reduced numbers of sperm cells. In a 39-week IV study in dogs, seminiferous tubular atrophy and decreased sperm in the epididymis were also observed at 10 and 32 mg/kg/day IV micafungin (resulting in 1-5-fold the anticipated maximum clinical exposure, based on AUC).
Testicular toxicity was observed in two animal species. Although the clinical relevance is unknown, micafungin may have the potential to affect male fertility in humans.
(Category B3)
There are no adequate and well controlled studies of micafungin in pregnant women.
Micafungin and/or its metabolites were shown to cross the placental barrier and distribute to the fetus in rats. No effects on embryo fetal development were observed in rats given IV doses of micafungin up to 32 mg/kg/day throughout organogenesis (2-3-fold the anticipated maximum clinical exposure, based on AUC). However, treatment of rabbits at doses of 32 mg/kg/day IV (2-fold the maximum anticipated clinical exposure, based on AUC) throughout organogenesis was associated with visceral abnormalities and increased abortion. Visceral abnormalities included abnormal lobation of the lung, levocardia, retrocaval ureter, anomalous right subclavian artery, and dilation of the ureter.
While animal studies are not always predictive of a human response, Mycamine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
 Micafungin and its metabolites were excreted in the milk of lactating rats. In a pre- and postnatal development study in rats, doses of 32 mg/kg/day IV micafungin (resulting in 2-3-fold the anticipated maximum clinical exposure, based on AUC) were associated with reduced pup birthweights and a possible delay in the time of eyelid opening and balanopreputial cleavage.
It is not known whether micafungin is excreted in human breast milk. Therefore caution should be exercised when Mycamine is administered during breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

Micafungin is unlikely to have an effect on driving or using machines. However, some people may feel dizzy when taking this medicine and if this happens to you, do not drive or use any tools or machines. Please inform your doctor if you experience any effects that may cause you to have problems with driving or using other machinery.

4.8 Adverse Effects (Undesirable Effects)

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.

Overall Mycamine safety experience in clinical trials.

The overall safety of Mycamine was assessed in 3083 patients and 501 volunteers in 41 clinical studies, including the invasive candidiasis, oesophageal candidiasis and prophylaxis studies, who received single or multiple doses of Mycamine, ranging from 12.5 mg to ≥ 150 mg/day. Treatment emergent adverse events which occurred in ≥ 5% of all patients who received Mycamine in these trials are shown in Table 5.
Overall, 2810 of 3083 (91.1%) patients who received Mycamine experienced an adverse event.
Clinically significant adverse events regardless of causality or incidence which occurred in these trials are listed below:

Blood and lymphatic system disorders.

Coagulopathy, febrile neutropenia, haemolysis, haemolytic anaemia, pancytopenia, thrombotic thrombocytopenic purpura, leukopenia.

Cardiac disorders.

Arrhythmia, atrial fibrillation, cardiac arrest, cyanosis, hypotension, myocardial infarction, tachycardia.

Gastrointestinal disorders.

Abdominal pain upper, dyspepsia.

General disorders and administration site conditions.

Injection site thrombosis.

Hepatobiliary disorders.

Hepatocellular damage, hepatomegaly, jaundice, hepatic failure.

Infections and infestations.

Infection, pneumonia, sepsis.

Investigations.

Hepatic enzyme increased, transaminases increased.

Metabolism and nutrition disorders.

Acidosis, anorexia, hyponatraemia.

Musculoskeletal, connective tissue and bone disorders.

Arthralgia.

Nervous system disorders.

Convulsions, encephalopathy, intracranial haemorrhage.

Psychiatric disorders.

Delirium.

Renal and urinary disorders.

Anuria, haemoglobinuria, oliguria, renal failure acute, renal tubular necrosis.

Respiratory, thoracic and mediastinal disorders.

Apnoea, dyspnoea, hypoxia, pulmonary embolism.

Skin and subcutaneous tissue disorder.

Erythema multiforme, skin necrosis, urticaria.

Vascular disorders.

Deep venous thrombosis, hypertension.

Post-marketing adverse reactions.

The following adverse reactions have been identified during the post-approval use of micafungin (as sodium) powder for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. A causal relationship to micafungin (as sodium) powder for injection could not be excluded for these adverse reactions, which included:

Blood and lymphatic system disorders.

White blood cell count decreased, haemolytic anaemia, disseminated intravascular coagulation, intravascular haemolysis.

Hepatobiliary disorders.

Hyperbilirubinaemia, hepatic function abnormal, hepatic disorder, hepatocellular damage.

Immune system disorders.

Anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock.

Renal and urinary disorders.

Acute renal failure, renal impairment.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome, toxic epidermal necrolysis.

Vascular disorders.

Shock.

Paediatric patients.

The incidence of some adverse events (AEs) in the clinical study database (thrombocytopenia, tachycardia, hypertension, hypotension, hyperbilirubinaemia, hepatomegaly, renal failure acute, blood urea increased) was higher in paediatric patients than adult patients. Additionally, paediatric patients < 1 year of age experienced about two times more often an increase in ALT, AST and AP than older paediatric patients. No clinically meaningful differences in the safety profile could be discerned by paediatric age strata of < 4 weeks, 4 weeks to < 1 year, 1 to 4 years, 5 to 8 years, 9 to 12 years and 13 to < 16 years.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
There is no experience with overdoses of micafungin. In case of overdose, general supportive measures and symptomatic treatment should be administered. Micafungin is highly protein bound and is therefore not dialysable.
Repeated daily doses of up to 4 mg/kg (median 1.2 mg/kg per day, maximum 4.6 mg/kg per day), and maximum doses of 8.6 mg/kg in paediatric patients and 8 mg/kg (median 50.0 mg per day, maximum 896 mg per day) in adult patients, have been administered in clinical trials with no reported dose limiting toxicity. A newborn patient received a high initial dose of 7.8 mg/kg/day in a clinical trial, which following its detection after 7 days was decreased to 2.0 mg/kg/day. No ill effects associated with this high dose were noted.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Micafungin, the active ingredient of Mycamine, is a member of the echinocandin lipopeptide family and noncompetitively inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls which is not present in mammalian cells.

Microbiology.

Micafungin exhibits fungicidal activity against most Candida species and inhibits actively growing hyphae of Aspergillus species.

In vitro activity.

Susceptibility testing was performed with modifications according to the Clinical and Laboratory Standards Institute (CLSI) methods M27-A2 (Candida species) and M38-A (Aspergillus species).
Micafungin displayed inhibitory activity against clinically relevant Candida species. The minimum inhibitory concentration (MIC) rank order was: C. albicans (including azole resistant strains) < C. tropicalis, C. glabrata < C. krusei < < C. parapsilosis, C. guilliermondii.
Micafungin displayed inhibitory activity against clinically relevant Aspergillus species (A. fumigatus, A. niger, A. flavus, A. nidulans, A. terreus and A. versicolor).
Micafungin has virtually no activity against Cryptococcus neoformans, Trichosporon cutaneum, Trichosporon asahii, Fusarium solani, Pseudallescheria boydii, Absidia corymbifera, Cunninghamella elegans, Rhizopus oryzae or Rhizopus microsporus.

In vivo activity.

Micafungin was effective in the treatment of disseminated candidiasis, as well as against oropharyngeal and oesophageal candidiasis as demonstrated in mouse models.

Resistance induction.

As for all antimicrobial agents, cases of reduced susceptibility and resistance have been reported and cross resistance with other echinocandins cannot be excluded. Reduced susceptibility to echinocandins has been associated with mutations in the Fks1 and Fks2 genes coding for a major subunit of glucan synthase.

Clinical trials.

Candidaemia and invasive candidiasis.

Micafungin (100 mg/day or 2 mg/kg/day) was as effective as and better tolerated than liposomal amphotericin B (3 mg/kg) as first-line treatment of candidaemia and invasive candidiasis in a randomised, double blind, multinational, noninferiority study. Micafungin and liposomal amphotericin B were received for a median duration of 15 days (range 4 to 42 days in adults and 12 to 42 days in children).
Noninferiority was proven for adult patients, and similar findings were demonstrated for the paediatric subpopulations (including neonates and premature infants). Efficacy findings were consistent, independent of the infective Candida species, primary site of infection and neutropenic status (see Table 6). Micafungin demonstrated a smaller mean peak decrease in estimated glomerular filtration rate during treatment (p < 0.001) and a lower incidence of infusion related reactions (p = 0.001) than liposomal amphotericin B.

Oesophageal candidiasis.

In a randomised, double blind study of micafungin versus fluconazole in the first line treatment of oesophageal candidiasis, 518 patients received at least a single dose of study drug. The median treatment duration was 14 days and the median average daily dose was 150 mg for micafungin (N = 260) and 200 mg for fluconazole (N = 258). Most patients in this study had HIV infection. An endoscopic grade of 0 (endoscopic cure) at the end of treatment was observed for 87.7% (228/260) and 88.0% (227/258) of patients in the micafungin and fluconazole groups, respectively (95% CI for difference: [-5.9%, 5.3%]). The lower limit of the 95% CI was above the predefined noninferiority margin of -10%, proving noninferiority. The odds of endoscopic cure was approximately 2.6 times higher in HIV patients with a baseline CD4 count ≥ 100 than in HIV patients with a baseline CD4 count < 100. All efficacy findings were consistent and showed micafungin to be as effective as fluconazole in adult oesophageal candidiasis patients, with similar rates of endoscopic cure, clinical resolution of the infection, mycological eradication, dynamics or improvement and incidence of relapse. The nature and incidence of adverse events were also similar between treatment groups.

Prophylaxis of invasive fungal infection.

Micafungin was more effective than fluconazole in preventing invasive fungal infections in a population of patients at high risk of developing a systemic fungal infection (patients undergoing haematopoietic stem cell transplantation [HSCT] in a randomised, double blind, multicentre study). Treatment success was defined as the absence of a proven, probable, or suspected systemic fungal infection through the end of therapy and absence of a proven or probable systemic fungal infection through the end of study. Most patients (97%, N = 882) had neutropenia at baseline (< 200 neutrophils/microL) and neutropenia persisted for a median of 13 days. There was a fixed daily dose of 50 mg (1.0 mg/kg) for micafungin and 400 mg (8 mg/kg) for fluconazole. The mean period of treatment was 19 days for micafungin and 18 days for fluconazole in the adult population (N = 798) and 23 days for both treatment arms in the paediatric population (N = 84). Table 7 summarises the main efficacy findings.
The rate of treatment success was statistically significantly higher for micafungin than fluconazole (1.6% versus 2.4% breakthrough infections). Breakthrough Aspergillus infections were observed in 1 versus 7 patients, and proven or probable breakthrough Candida infections were observed in 4 versus 2 patients in the micafungin and fluconazole groups, respectively. Other breakthrough infections were caused by Fusarium (1 and 2 patients, respectively) and Zygomycetes (1 and 0 patients, respectively). The nature and incidence of adverse reactions were similar between treatment groups.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetics of micafungin have been evaluated in healthy subjects, haematopoietic stem cell transplant recipients and patients with invasive and oesophageal candidiasis up to a maximum dose of 8 mg/kg. There is no evidence of systemic accumulation with repeated administration and increases in systemic exposure (AUC and Cmax) are proportional to increases in dose. Steady state is generally reached by day 4.

Distribution.

Following intravenous administration, concentrations of micafungin show a biexponential decline as the drug is rapidly distributed into tissues. Micafungin is highly protein bound (> 99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. Binding to albumin is independent of micafungin concentration (10 to 100 microgram/mL). Micafungin does not displace albumin bound bilirubin at clinically relevant concentrations.
In an in vitro study in which 14C-micafungin was added to whole human blood, the blood to plasma ratio was approximately 0.85 and was independent of concentration over the range of 0.1 to 10 microgram/mL micafungin. Micafungin was not extensively taken up by blood cells.
The volume of distribution of micafungin at terminal phase was 0.24 to 0.41 L/kg bodyweight.

Metabolism.

Unchanged micafungin is the principal circulating compound in the systemic circulation. Metabolism takes place in the liver where micafungin is metabolised to M1 (catechol form) by arylsulfatase, with further metabolism to M2 (methoxy form) by catechol-O-methyltransferase. M5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalysed by cytochrome P450 (CYP) isoenzymes. Exposure to these metabolites is generally low and they are not expected to contribute to the overall efficacy of micafungin. Although micafungin is a substrate for CYP3A in vitro, hydroxylation by CYP3A is not a major pathway for metabolism in vivo.

Excretion.

The mean terminal half-life of micafungin is approximately 10 to 17 hours and stays consistent across doses up to 8 mg/kg after single and repeated administration in patients and healthy volunteers. Faecal excretion is the major route of elimination. Following a single intravenous dose of 14C-micafungin (25 mg) to healthy volunteers, 11.6% of the radioactivity was recovered in the urine and 71.0% in the faeces over 28 days.

Pharmacokinetic characteristics in special populations.

Patients with hepatic impairment.

A single 1 hour infusion of 100 mg micafungin was administered to eight subjects with moderate hepatic impairment (Child-Pugh score 7 to 9) and eight age, gender and weight matched subjects with normal hepatic function. The pharmacokinetics of micafungin did not differ significantly from those in healthy subjects.
A single 1 hour infusion of 100 mg micafungin was administered to eight subjects with severe hepatic impairment (Child-Pugh score 10 to 12) and eight age, gender, ethnic and weight matched subjects with normal hepatic function. The Cmax and AUC values of micafungin were lower by approximately 30% in subjects with severe hepatic impairment compared to normal subjects. The Cmax and AUC values of M5 metabolite were approximately 2.3-fold higher in subjects with severe hepatic impairment compared to normal subjects. However, this exposure (parent and metabolite) was comparable to that in patients with systemic Candida infection. Therefore, no micafungin dose adjustment is necessary in patients with mild to severe hepatic impairment.

Patients with renal impairment.

A single 1 hour infusion of 100 mg micafungin was administered to nine subjects with severe renal impairment (creatinine clearance < 30 mL/min) and to nine subjects with normal renal function (creatinine clearance > 80 mL/min) who were age, gender and weight matched. The Cmax and AUC were not significantly altered by severe renal impairment. No dose adjustment is necessary for patients with renal impairment.

Elderly.

A single 1 hour infusion of 50 mg micafungin was administered to ten healthy subjects aged 66 to 78 years and ten healthy subjects aged 20 to 24 years. The pharmacokinetics of micafungin showed a similar time course profile in both the elderly and young, and there were no significant differences in the pharmacokinetic parameters. No dose adjustment is necessary for the elderly.

Paediatric use.

In paediatric patients, micafungin exposure is dose proportional in the dose range of 0.5-4 mg/kg, and up to 10 mg/kg in infants less than 4 months of age. Clearance is influenced by weight, with mean values of weight-adjusted clearance 1.35 times higher in younger children (4 months to 5 years) and 1.14 times higher in children aged 6 to 11 years. Older children (12-16 years) had mean clearance values similar to those determined in adult patients. Mean weight-adjusted clearance in infants less than 4 months of age is approximately 2.6-fold greater than older children (12-16 years) and 2.3-fold greater than in adults. Weight-adjusted clearance differences support weight-based dosing up to body weights within the range of 40 (treatment) to 50 kg (prophylaxis), above which adult dosing is recommended.
Micafungin dosed at 4 mg/kg in infants less than 4 months approximates drug exposures achieved in adults receiving 100 mg/day for the treatment of invasive candidiasis. Higher doses (e.g. 10 mg/kg) may be required to treat CNS infection in infants less than 4 months of age as demonstrated by a PK-PD bridging study that showed dose-dependent penetration of micafungin into the CNS to achieve maximum eradication of fungal burden in the CNS tissues. Population PK modelling demonstrated that a dose of 10 mg/kg in infants less than 4 months of age would be sufficient to achieve the target exposure for the treatment of CNS Candida infections.

Gender and race.

Gender or race (Caucasian, Black, Oriental) did not significantly influence the pharmacokinetic parameters of micafungin. No dose adjustment is required based on gender or race.

5.3 Preclinical Safety Data

Genotoxicity.

Micafungin was not genotoxic nor clastogenic in a standard battery of genotoxicity tests. Micafungin did not induce gene mutations in bacterial assays and did not induce chromosomal aberrations in Chinese hamster lung cells in vitro. There was no indication of an induction of micronuclei by micafungin in a micronucleus test in mice or unscheduled DNA synthesis in rat hepatocytes.

Carcinogenicity.

No standard carcinogenicity studies have been conducted with micafungin.
Hepatic carcinomas and adenomas were observed in 3 to 6 month repeat dose IV toxicity studies in rats at 32 mg/kg/day (resulting in 4-fold the maximum anticipated clinical exposure, based on AUC) with 12 to 20 month recovery periods. In shorter term studies, altered hepatocellular foci, which were likely precursors to the hepatic tumours, were observed. Exposure at the no observed adverse effect level for altered hepatocellular foci resulted in exposures similar to the maximum anticipated clinically, based on AUC.
It is not known whether the hepatic neoplasms observed in treated rats also occur in other species, or if there is a dose threshold for this effect. The relevance of the hepatocarcinogenic potential of micafungin in humans is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mycamine contains the following excipients: lactose monohydrate, citric acid, sodium hydroxide.

6.2 Incompatibilities

See Section 4.2 Dose and Method of Administration, Instructions for reconstitution and dilution.

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

Unopened vial.

Store below 25°C.

Reconstituted concentrate in vial.

Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25°C when reconstituted with sodium chloride 0.9% or glucose 5% solution.

Diluted infusion solution.

Chemical and physical in-use stability has been demonstrated for 96 hours at 25°C when diluted with sodium chloride 0.9% solution or glucose 5% solution and protected from light.
Mycamine contains no preservatives. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.

6.5 Nature and Contents of Container

Mycamine is presented in a 10 mL glass vial with a rubber stopper and flip-off cap. The vials are shrink wrapped with a UV-protective film.
Mycamine is supplied in packs containing 1 or 10* single-use vials.
(*Not marketed in Australia.)

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

Mycamine is a sterile, white, powder for injection containing the active ingredient micafungin as the sodium salt. Micafungin sodium is a light sensitive, hygroscopic, amorphous, white powder that is freely soluble in water, isotonic sodium chloride solution, N,N-dimethylformamide and dimethylsulfoxide, slightly soluble in methyl alcohol, and practically insoluble in acetonitrile, ethyl alcohol (95%), acetone, diethyl ether and n-hexane.

Chemical structure.


Chemical name: sodium 5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(R)-2-carbamoyl-1-hydroxyethyl]-11,20,21,25-tetrahydroxy-15-[(R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[4-[5-(4-pentyloxyphenyl)-isoxazol-3-yl]benzoylamino]-1,4,7,13,16,22-hexaazatricyclo-[22.3.0.09,13]heptacos-6-yl]-1,2-dihydroxyethyl] -2-hydroxyphenyl sulfate.
Molecular formula: C56H70N9NaO23S.

CAS number.

208538-73-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes