FUNGISOME™

Prescribing Information

For conventional AmphotericinB peak and trough concentrations were 0.9 and 0.28 µg/ml.

Pharmacokinetics after multiple dose administration of FUNGISOME™ in adults.

*Conventional AmphotericinB is micelle suspension of AmphotericinB in deoxycholate.


INDICATIONS
FUNGISOME™ is indicated in disseminated and invasive systemic fungal infections and also in patients of leishmaniasis.
It has been found to be effective even in cases resistant to standard antifungal drugs and antileishmanial drugs.


PREPARATION FOR ADMINISTRATION
Read this section carefully and follow the instructions before administration of FUNGISOME™

The unopened bottle must be sonicated as per instructions given below.


SONICATION
Instrument to be used: It is recommended to use only sonicator provided by Lifecare Innovations.

Procedure :
1. Fill the sonicator with water (at ambient temperature) almost to full capacity.
2. Clamp a bottle of FUNGISOME™ in such a way that the level of solution in the bottle matches with the level of water in the sonicator, ensuring that the cap of the bottle should always be above water level. Bottle should remain clamped at all times during sonication.
3. Maximum 2 bottles can be sonicated at a time.
4. Switch on the sonicator and run it for 45 minutes – neither less nor more.

Note : During the sonication the temperature of water in the sonicator is expected to rise a little. Take precautions that temperature does not rise above 45°C (keep ice or chilled water handy and if required add after stopping sonicator).


DILUTION
Dilution of FUNGISOME™ is usually not required except for the following :
The 1st , 2nd and 3rd doses of FUNGISOME™ are required to be diluted with sterile normal saline as given in “Doses & Administration” below. Do not use any other IV fluid for dilution.

If patient suffers adverse effects such as fever or rigors, FUNGISOME™ can be diluted with sterile normal saline I.P. To each 2 ml of FUNGISOME™, 1 ml of sterile normal saline I.P. can be added.


DOSES & ADMINISTRATION
FUNGISOME™ is given intravenously. The sealed bottle is subjected to sonication according to the above prescribed procedure. Sonicated FUNGISOME™ is diluted before administration as given below :

On the 1st day FUNGISOME™ is administered at the dosage of 0.1 mg/kg body wt. Calculate the volume of FUNGISOME™ required for dose of 0.1 mg/kg body wt for a given patient. Withdraw excess volume and discard. Leave the required volume of FUNGISOME™ in the bottle. Add “sterile normal saline” in the bottle to make up the volume in the bottle to 20 ml. From this, 1 ml is given as a test dose over a 5 minutes period. If no adverse effect viz. anaphylaxis, fall in blood pressure, increase in heart rate, bronchospasm etc. occur then 30 minutes later the remaining 19 ml dose is administrated over 15 minutes.

On the 2nd day the dose is 0.4 mg/kg body wt. Required volume is diluted to make 50 ml (if required) and administered over 30 minutes. (Dilution will not be required if patient weighs more than 125 kg).

On the 3rd day the dose is 1 mg/kg body wt. Required volume is diluted to make 50 ml and is to be administered over 60 minutes. (No dilution is required in patients above 50 kg body weight).
Subsequent doses and durations should be adjusted to specific requirements of each patient. Third day onwards therapy is usually given at a daily dose of 1 mg/kg of body weight and no further dilution is required. In a few patients dose may have to be increased but should not exceed 3 mg/kg body wt/day.


Example
For FUNGISOME™ administration a patient weighing 50 kg would require 5 mg of AmphotericinB on day one, 20 mg on day two, and 50 mg on day three and subsequent days unless otherwise individualised doses are recommended. For this, FUNGISOME™ should be diluted with sterile normal saline, on day one 5 ml to 20 ml; on day two 20 ml to 50 ml; and day three onwards administered without dilution. Dilutions should be made as recommended after sonication and before administration.
For Neonates and Children, the dose is 1mg/kg/day (can be given up to 3mg/kg/day), diluted in 10-20ml normal saline and infused over 1hr. While diluting FUNGISOME™ with normal saline, the treating physician should take into account volume of fluid and sodium content that can be infused.

The results of the studies done till now indicated the following dose schedule as mg/kg body wt/day in respective infections:

The duration of treatment should be decided on the basis of clinical, radiological, histopathological and microbiological assessment. It is advisable to discontinue FUNGISOMETM treatment after confirmation of clearance of infection as judged by histopathological and microbiological report.


SAFETY
FUNGISOME™ therapy has been administered for as long as 8.5 months (256 days) and maximum cumulative dose of 11.2g of AmphotericinB was administered without significant toxicity.


LEISHMANIASIS
FUNGISOME™ has been used in the treatment of visceral leishmaniasis in a dose of 1mg/kg body wt/day for 21 days. Successful results have also been achieved with the dose of 2mg/kg body wt/day for 10 days or 3mg/kg body wt/day for 7 days. In difficult to treat cases, physician may recommend the treatment for longer duration.


PEDIATRIC PATIENTS
Pediatric patients of systemic fungal infections and visceral leishmaniasis have been treated successfully with doses comparable to adults on a per kilogram body weight basis without any adverse effect. Dosage schedule for 1st, 2nd, 3rd and subsequent days including the test dose on day 1 as detailed above for adults on per kg body weight basis should be followed in pediatric patients also.


NEONATES
Candidemia in neonates has been treated with FUNGISOMETM. It is essential to monitor serum levels of electrolytes and withhold FUNGISOME™ if serum electrolyte values are below normal range. Mortality has been reported due to electrolyte imbalance possibly related to FUNGISOME™. If vomiting is induced by therapy, subsequent administration of FUNGISOME™ is recommended on empty stomach to minimize chances of related aspiration.


GERIATRIC PATIENTS
Based on studies done till now, no specific dosage alteration or precautions are recommended.


RENAL AND LIVER DISEASES
Patients with high creatinine levels have been administered FUNGISOME™. If rise in creatinine is noted following FUNGISOME™ administration, dose can be reduced to 0.8 mg/kg body wt/day.

In patients with high bilirubin or liver enzymes (SGOT, SGPT) before or during FUNGISOME™ treatment, dose should be reduced to 0.8 mg/kg body wt/day.

Further dose alterations or discontinuation should be individualized.


PREGNANCY OR LACTATION
In view of the toxicity of AmphotericinB, use of FUNGISOME™ is best avoided, unless the benefits outweigh the risks.


CONTRAINDICATIONS
FUNGISOME™ is contraindicated in patients who have developed serious hypersensitivity reaction during previous administration of FUNGISOME™ or its lipid constituents. Relative contraindications to FUNGISOME™ include previous serious reaction to other forms of AmphotericinB (conventional AmphotericinB or other lipid formulations of AmphotericinB). Experience with such cases is limited.
Three patients who developed bronchospasm after conventional AmphotericinB did not suffer bronchospasm with FUNGISOME™


PRECAUTIONS & WARNING
In a comparative study FUNGISOME™ produced fewer and less severe adverse effects than conventional AmphotericinB. Specifically, adverse effects viz. fever, chills, headache, backache, drowsiness, thrombophlebitis, nausea, vomiting, chest pain, palpitation, apnea, bronchospasm that occur with conventional AmphotericinB have been noted with FUNGISOME™ also, but to a much lesser degree.

The problem of fever or rigor could be avoided to some extent by lowering the rate of infusion.
If any serious adverse effects are noted, the infusion should be stopped and the drug withdrawn.

Renal, hepatic, hematological parameters along with serum electrolytes levels should be monitored regularly during treatment. If any deterioration occurs in these parameters, administration of the drug should cease immediately. Subsequent dosage should be administered on the basis of abovementioned parameters.

AmphotericinB is known to be nephrotoxic. If the creatinine exceeds 2.5 mg%, dosage should be reduced or discontinued till renal function improves. Hypokalemia during FUNGISOME™ therapy should be treated appropriately.

In neonates, if fall in packed cell volume (PCV) occurs, it should be treated with transfusions.

Do not mix any drug, diluent or fluid other than sterile normal saline with FUNGISOME™.

Do not use FUNGISOME™ if there is any evidence of crystals, foreign material or foreign particle in the bottle.


DRUG INTERACTIONS
Like with conventional AmphotericinB, avoid concomitant administration of nephrotoxic drugs and bone marrow suppressants.

Drug interactions due to possible hypokalemia with FUNGISOME™ must be borne in mind and hypokalemia appropriately managed.


STORAGE

a. Unopened bottles of FUNGISOME™ must be stored refrigerated at 2-8°C.
b. Protect FUNGISOME™ from exposure to light.
c. Sonicated FUNGISOME™ may be stored for upto 24 hours at 2-8°C. If not used within 24 hours of sonication, discard FUNGISOME™ .
d. If stored after sonication, shake well before use.
e. Do not store partially used vial for future patient use.