1. Name of the medicinal product

Amphotericin B for Injection 50mg USP
Amphotericin B for Injection 100mg USP

2. Qualitative and quantitative composition

a) Each vial contains:
sterile freeze-dried complex of
Amphotericin B USP                                        50mg
Deoxycholate sodium                                        q.s
Suitable  buffers                                                 q.s

b) Each vial contains:
sterile freeze-dried complex of
Amphotericin B USP                                        100mg
Deoxycholate sodium                                        q.s
Suitable  buffers                                                 q.s

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for Injection.

4. Clinical particulars

4.1 Therapeutic indications

Amphotericin B should be administered primarily to patients with progressive, potentially fatal infections. This potent drug should not be used to treat the common forms of fungal disease which show only positive skin or serological tests.

Amphotericin B is specifically intended to treat cryptococcosis (torulosis); North American blastomycosis; the disseminated forms of candidosis, coccidioidomycosis and histoplasmosis; mucormycosis (phycomycosis) caused by species of the genera Mucor, Rhizopus, Absidia, Entomophthora, and Basidiobolus sporotrichosis (Sporotrichum schenckii), aspergillosis (Aspergillus fumigatus).

Amphotericin B may be helpful in the treatment of American mucocutaneous leishmaniasis but is not the drug of choice in primary therapy.

4.2 Posology and method of administration

Non-equivalence of amphotericin products

Different amphotericin products (sodium deoxycholate, liposomal, lipid complex) are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing and so the products should not be used interchangeably without accounting for these differences. Both the trade name, common name and dose should be verified pre-administration.

Under no circumstances should a total daily dose of 1.5 mg/kg be exceeded. Amphotericin B overdoses can result in potentially fatal cardiac or cardiorespiratory arrest (see section 4.4 & 4.9).

Posology

Amphotericin B should be administered by intravenous infusion over a period of 2-6 hours. Reduction of the infusion rate may reduce the incidence of side-effects. Initial daily dose should be 0.25 mg/kg of body weight gradually increasing to a level of 1.0 mg/kg of body weight depending on individual response and tolerance. Within the range of 0.25-1.0 mg/kg the daily dose should be maintained at the highest level which is not accompanied by unacceptable toxicity.

In seriously ill patients the daily dose may be gradually increased up to a total of 1.5 mg/kg. Since amphotericin B is excreted slowly, therapy may be given on alternate days in patients on the higher dosage schedule. Several months of therapy are usually necessary; a shorter period of therapy may produce an inadequate response and lead to relapse.

When commencing all new courses of treatment, it is advisable to administer a test dose immediately preceding the first dose. A volume of the infusion containing 1 mg (i.e. 10 mL) should be infused over 20-30 minutes and the patient carefully observed for at least a further 30 minutes. It should be noted that patient responses to the test dose may not be predictive of subsequent severe side effects.

Patients with a severe and rapidly progressing fungal infection, with good cardiopulmonary function and who tolerates the test dose without a severe reaction, may then receive 0.3 mg/kg amphotericin B intravenously over a period of 2 to 6 hours. For patients with cardiopulmonary impairment or severe reaction to the test dose, a lower dose (i.e. 5 to 10 mg) is recommended.

Doses may gradually be increased by 5 to 10 mg per day to a final daily dosage of 0.5 to 1 mg/kg.

Whenever medication is interrupted for a period longer than seven days, therapy should be resumed by starting with the lowest dosage level, i.e. 0.25 mg/kg of body weight and increased gradually.

The recommended concentration for intravenous infusion is 10 mg/100 mL.

Paediatric population

Safety and effectiveness in paediatric patients have not been established through adequate and well-controlled studies. Systemic fungal infections have been treated in paediatric patients with reports of side effects similar to those seen in adults.

Older people

No specific dosage recommendations or precautions.

The use of Amphotericin B by other routes has been documented in the published literature:

Bladder irrigation/instillation (e.g. candiduria): Continuous irrigation with 50 mg Amphotericin B in 1 litre sterile water each day until urinary cultures are negative. Intermittent use of volumes of 100-400 mL (concentrations of 37.5-200 mcg/mL) has also been reported. The urine should be alkalinised (with potassium citrate) and antifungal ointment applied to the perineal area.

Lung inhalation (e.g. pulmonary aspergillosis): 8-40 mg amphotericin B (nebulised in sterile water or 5% Glucose) has been given daily in divided doses. Concurrent eradication of oral and intestinal yeast reservoirs is recommended.

Intrathecal (e.g. coccidiodal meningitis): Patients who do not respond to fluconazole or itraconazole would be candidates for intrathecal amphotericin B therapy with or without continuation of azole treatment. The intrathecal dosage of amphotericin B normally ranges between 0.1 mg and 1.5 mg per dose, administered at intervals ranging from daily to weekly, beginning at a low dosage and increasing the dosage until the appearance of patient intolerance. Amphotericin B is irritating when injected into the CSF.

Other: Other uses of solutions prepared using Amphotericin B include local instillations for the treatment of fungal infections of the ear, eye, peritoneum, lung cavities and joint spaces.

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance unless, in the opinion of the physician, the condition requiring treatment is life-threatening and amenable only to such therapy, or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Prolonged therapy with amphotericin B is usually necessary. Unpleasant reactions are quite common when the drug is given parenterally at therapeutic dosage levels. Some of these reactions are potentially dangerous. Hence amphotericin B should be used parenterally only in hospitalised patients, or those under close clinical observation.

Accidental overdose

Care must be taken when administering Amphotericin B to prevent overdose, which can result in potentially fatal cardiac or cardiorespiratory arrest. Verify the product name and dosage pre-administration, especially if the dose prescribed exceeds 1.5 mg/kg (see section 4.2 & 4.9).

Rapid intravenous infusion, over less than one hour, particularly in patients with renal insufficiency, has been associated with hyperkalaemia and arrhythmias and should therefore be avoided. Reduction of the infusion rate may reduce the incidence of side-effects (see section 4.2).

Infusion related reactions

While some patients may tolerate full intravenous doses of amphotericin B without difficulty, most will exhibit some intolerance particularly during the initiation of therapy. In patients experiencing adverse reactions these may be made less severe by giving aspirin, other antipyretics, antihistamines or anti-emetics. Pethidine (25 to 50 mg IV) has been used in some patients to decrease the duration or intensity of shaking chills and fever following amphotericin B therapy. Febrile reactions may be decreased by the intravenous administration of small doses of adrenal corticosteroids, e.g. 25 mg hydrocortisone.

This may be administered just prior to or during amphotericin B infusion. The dosage and duration of such corticosteroid therapy should be kept to a minimum. Administration of the drug on alternate days may decrease anorexia and phlebitis. Adding a small amount of heparin (1000 units per infusion) to the infusion, rotation of the injection site, the use of a paediatric scalp-vein needle and alternate day therapy may lessen the incidence of thrombophlebitis and coagulation problems. Extravasation may cause chemical irritation.

Corticosteroids should not be administered concomitantly unless they are necessary to control drug reactions.

Renal toxicity

Renal function test abnormalities are commonly observed and usually improve upon interruption of therapy; however, some permanent impairment often occurs, especially in those patients receiving large cumulative amounts (over 5 g) of amphotericin B. Concomitant diuretic therapy may be a predisposition for renal impairment, whereas sodium repletion or supplementation may reduce the occurrence of nephrotoxicity.

If serum creatinine exceeds 260 micromol/L the drug should be discontinued or the dosage markedly reduced until renal function is improved. Weekly blood counts and serum potassium determinations are also advisable. Low serum magnesium levels have also been noted during treatment with amphotericin B.

Hepatic toxicity

Therapy should be discontinued if liver function test results (elevated bromsulphalein, alkaline phosphatase and bilirubin) are abnormal.

Neurotoxicity

Leucoencephalopathy has been reported very occasionally following the use of amphotericin B injection in patients who received total body irradiation. Most of these patients received high cumulative doses of amphotericin B.

Reports of neurological events such as arachnoiditis, myelopathy, paresis and paralysis have been associated with the intrathecal route of administration, see section 4.2 Intrathecal (e.g coccidioidal meningitis).

Other nephrotoxic antibiotics and antineoplastic agents should not be given concomitantly except with great caution.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per Amphotericin B 50 mg vial, i.e. essentially ‘sodium free’.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant administration of nephrotoxic drugs or antineoplastics should be avoided if at all possible.

The hypokalaemia following amphotericin B therapy may potentiate the toxicity of digitalis glycosides or enhance the curariform actions of skeletal muscle relaxants.

Corticosteroids and Corticotrophin (ACTH) may increase the potassium loss due to amphotericin B.

Flucytosine toxicity may be enhanced during concomitant administration, possibly due to an increase in its cellular uptake and/or impairment of its renal excretion.

Acute pulmonary reactions have occasionally been observed in patients given amphotericin B during or shortly after leukocyte transfusions. It is advisable to separate these infusions as far as possible and to monitor pulmonary function.

4.6 Fertility, pregnancy and lactation

Pregnancy

Safety for use in pregnancy has not been established; therefore it should be used during pregnancy only if the possible benefits to be derived outweigh the potential risks involved.

Breastfeeding

It is not known whether amphotericin B is excreted in human milk. As excretion of amphotericin B in human milk is possible, and considering its potential toxicity, it should be used in nursing mothers only if the possible benefits to be derived outweigh the potential risks involved. In addition, it is prudent to advise a nursing mother to discontinue nursing.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The table below lists all adverse events. The list is presented by system organ class and frequency, which is defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

* see section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Amphotericin B overdoses can result in potentially fatal cardiac or cardio-respiratory arrest. If an overdose is suspected, discontinue therapy and monitor the patient’s clinical status (e.g cardio-respiratory, renal, and liver function, haematologic status serum electrolytes) and administer supportive therapy as required. Amphotericin B is not haemodialysable. Prior to reinstituting therapy, the patient’s condition should be stabilised (including correction of electrolyte deficiencies, etc.).

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-infectives for systemic use:

Amphotericin B is a polyene antifungal antibiotic active against a wide range of yeasts and yeast-like fungi including Candida albicans. Crystalline amphotericin B is insoluble in water; therefore, the antibiotic is solubilised by the addition of sodium desoxycholate to form a mixture which provides a colloidal dispersion for parenteral administration. Amphotericin B is fungistatic rather than fungicidal in concentrations obtainable in body fluids. It probably acts by binding to sterols in the fungal cell membrane with a resultant change in membrane permeability which allows leakage of intracellular components. Mammalian cell membranes also contain sterols and it has been suggested that the damage to human and fungal cells may share common mechanisms. No strains of Candida resistant to amphotericin B have been reported in clinical use, and although in vitro testing does produce a small number of resistant isolates this occurs only following repeated subcultures.

5.2 Pharmacokinetic properties

An initial intravenous infusion of 1 to 5 mg of amphotericin B per day, gradually increased to 0.65 mg/kg daily, produces peak plasma concentrations of approximately 2 to 4 mg/L which can persist between doses since the plasma half-life of amphotericin B is about 24 hours. It has been reported that amphotericin B is highly bound (more than 90%) to plasma proteins and is poorly dialysable.

Amphotericin B is excreted very slowly by the kidneys with 2 to 5% of a given dose being excreted in biologically active form. After treatment is discontinued the drug can be detected in the urine for at least seven weeks. The cumulative urinary output over a seven day period amounts to approximately 40% of the amount of drug infused.

Details of tissue distribution and possible metabolic pathways are not known.

5.3 Preclinical safety data

No further relevant data.

6. Pharmaceutical particulars

6.1 List of excipients

Other ingredients: desoxycholic acid, concentrated phosphoric acid, sodium hydroxide, disodium phosphate dodecahydrate, monosodium phosphate dehydrate.

6.2 Incompatibilities

Do not reconstitute with saline solutions. The use of any diluent other than the ones recommended or the presence of a bacteriostatic agent in the diluent may cause precipitation of the amphotericin B

6.3 Shelf life

2 years

The concentrate (5 mg per ml after reconstitution with 10 mL sterile Water for Injections) should be stored protected from light.

The absence of any antimicrobial preservative and the risk of contamination during reconstitution mean that the product should be stored for no more than 8 hours at room temperature (25°C) or 24 hours in a refrigerator (2-8°C). Should the need arise and a validated aseptic reconstitution technique is applied, the product is chemically stable when stored for 24 hours at room temperature or one week in a refrigerator. It is not intended as a multidose vial. Any unused material should be discarded. Solutions prepared for intravenous infusion (i.e. 10 mg or less amphotericin B per 100 mL) should be used promptly after preparation.

6.4 Special precautions for storage

Vials of powder for reconstitution should be stored in a refrigerator.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I flint glass vials closed with a grey chlorobutyl rubber stopper.

Vials of 50mg

6.6 Special precautions for disposal and other handling

Preparation of solutions:

Reconstitute as follows: An initial concentrate of 5 mg amphotericin B per ml is first prepared by rapidly expressing 10 mL sterile water for injection, without a bacteriostatic agent, directly into the lyophilised cake, using a sterile needle (minimum diameter: 20 gauge) and syringe. Shake the vial immediately until the colloidal solution is clear. The infusion solution, providing 10 mg/100 mL is obtained by further dilution (1:50) with 5% Glucose Injection of pH above 4.2. The pH of each container of Glucose Injection should be ascertained before use. Commercial Glucose Injection usually has a pH above 4.2; however, if it is below 4.2 then 1 or 2 ml of buffer should be added to the Glucose Injection before it is used to dilute a concentrated solution of amphotericin B. The recommended buffer has the following composition:

The buffer should be sterilised before it is added to the Glucose Injection, either by filtration through a bacterial filter, or by autoclaving for 30 mins at 15 lb pressure (121°C).

CAUTION:

Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present. Do not use the initial concentrate or the infusion solution if there is any evidence of precipitation of foreign matter.

An in-line membrane filter may be used for intravenous infusion of amphotericin B; however the mean pore diameter of the filter should not be less than 1.0 micron in order to assure passage of the amphotericin B dispersion.

Other preparations for injection should not be added to the infusion solution or administered via the cannula being used to administer Amphotericin B.

Aseptic technique must be strictly observed during the preparation of the concentrate, the buffer and the infusion.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Amphotericin B for Injection 50mg/100mg USP Taj Pharma

Please read all of this leaflet carefully before you start taking your medicine because it contains important information for you.

– Please keep this leaflet. You may need to read it again.

– If you have any further questions, ask your doctor.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet;

1. What Amphotericin B 50mg Powder for Sterile Concentrate is and what it is used for
2. What you need to know before being given your medicine
3. How you will be given your medicine
4. Possible Side Effects
5. How to store your medicine
6. Contents of the pack and other information

1. What Amphotericin B 50mg Powder for Sterile Concentrate is and what it is used for

The name of your medicine is Amphotericin B 50mg Powder for Sterile Concentrate. It contains the active ingredient amphotericin B, which belongs to a group of medicines called anti-fungal antibiotics.

Amphotericin B 50mg Powder for Sterile Concentrate is used to treat serious infections caused by yeasts and certain fungi.

2. What you need to know before being given your medicine

You should not be given this medicine if you:

– are allergic (hypersensitive) to amphotericin or any of the other ingredients in this medicine.

Take special care with Amphotericin B 50mg Powder for Sterile Concentrate if you:

– have any kidney or liver problems

If this applies to you, talk to your doctor before being given Amphotericin B 50mg Powder for Sterile Concentrate.

Taking other medicines

Always tell your doctor or pharmacist about other medicines you may be taking or have recently taken including those obtained without a prescription.

This is especially important if you are taking:

– any anti-cancer medicines (e.g. methotrexate, cyclophosphamide, cisplatin)

– any medicines which affect your kidney function (e.g. gentamicin, vancomycin)

– any muscle relaxants (e.g. baclofen, dantrolene, diazepam)

– any corticosteroids (e.g. beclamethasone) or corticotrophins

– any medicines to treat heart failure (e.g. digoxin)

– a medicine called flucytosine used to treat fungal infections

If you have recently had a specific type of transfusion called a leukocyte transfusion, please tell your doctor.

Pregnancy and breast-feeding

If you are pregnant, think you may be pregnant, or if you are breast-feeding, speak to your doctor before being given Amphotericin B 50mg Powder for Sterile Concentrate.

Driving and using machinery

Amphotericin B 50mg Powder for Sterile Concentrate should not affect your ability to drive.

Amphotericin B contains amphotericin B:

This medicinal product also contains less than 1mmol sodium (23mg) per dose, i.e. essentially ‘sodiumfree’.

3. How you will be given your medicine

Amphotericin B 50mg Powder for Sterile Concentrate will be given to you in hospital by a doctor or nurse. The daily dose is 0.25-1.0 mg per kg of your body weight. In some cases your doctor may consider it necessary to increase this dose to 1.5 mg/kg. If you are given too much of this medicine, you may experience life-threatening heart or lung problems. If you have any concerns about the amount of medicine you have been given, please speak to the person who has given you the infusion for further advice.

It will be given to you slowly through a drip into a vein (an infusion). This will usually take between 2-6 hours.

A test dose may be given before you start treatment with this medicine. Several months of treatment is usually necessary to get rid of the infection completely.

In some patients, the doctor may give other medicines to help reduce other unwanted effects.

These include:

– medicines to help stop you feeling sick or being sick,

– aspirin,

– an anti-allergy medicine (antihistamine),

– a corticosteroid,

– a medicine to stop your blood from clotting (anticoagulant).

4. Possible side effects

Like all medicines, Amphotericin B 50mg Powder for Sterile Concentrate can cause side effects, although not everybody gets them.

Treatment with Amphotericin B 50mg Powder for Sterile Concentrate may affect your blood cells, kidneys, liver or heart. For this reason, your doctor will want to monitor all these things before, during and after giving you this medicine.

If you notice any of the following, contact your doctor immediately:

– swelling of the face, lips, or tongue

– skin reactions including severe rash and itching

– difficulty breathing

As these may be signs of an allergic reaction.

There have been reports of blood disorders which may be characterised by fever or chills, sore throat, ulcers in the mouth or throat, unusual tiredness or weakness, unusual bleeding or unexplained bruises.

Tell your doctor immediately if you notice any of these symptoms.

Amphotericin B 50mg Powder for Sterile Concentrate can cause kidney problems. If you notice that you are more thirsty, need to go to the toilet more frequently, or the volume of urine increases, tell your doctor immediately.

Patients treated with Amphotericin B have reported the following side effects:

Very common: may affect more than 1 in 10 people

 Feeling sick and being sick

 High temperature (sometimes with shaking chills)

 Decrease in potassium in the blood

 Increase in creatinine in the blood

 Kidney problems which may lead to abnormal urine production, kidney stones and imbalances of substances in the blood (e.g. potassium)

 Difficulty in breathing

 Low blood pressure

Common: may affect up to 1 in 10 people

 Anaemia-low level of red blood cells

 Abnormal liver function shown by abnormal liver function tests

 Decreased magnesium in the blood

 Headache

 Diarrhoea

 Rash

 Decreased appetite

 Sudden loss of kidney function

 Pain at the injection site with or without swollen veins or a blood clot

Uncommon: may affect up to 1 in 100 people

 A rare form of anaemia where there is a low level of white blood cells

 Low counts of white blood cells in the blood

 Low counts of platelets in the blood

 Irregular heartbeat, sometime severe

 Impaired sensation or movement

 Spasm of the lungs

 Pain in the stomach

 Yellowing of the skin and eyes

 Pain in muscles

 Impaired or abnormal kidney function

 Flushing

Rare: may affect up to 1 in 1,000 people

 Abnormal blood clotting

 High counts of white blood cells in the blood

 Allergic reaction

 Increased potassium in the blood

 Altered mental state

 Convulsion

 Vision blurred or double vision

 Hearing loss, ringing in the ears

 Short-lived spinning sensation (vertigo)

 Heart attack or heart not working properly

 High blood pressure

 Shock

 Inflammation of the lungs and fluid in the lungs

 Stomach cramps, indigestion

 Bleeding in intestines, resulting in black faeces

 Loss of liver function

 Rash- characterized by a flat red area on the skin that is covered with small bumps

 Itching

 Flu like symptoms followed by a painful red or purple spreading rash

 Skin conditions including skin coming off in layers

 Pain in joints

 Abnormal kidney function including increased or decreased amounts of urine produced

 Pain and tiredness

 Decreased weight

5. How to store your medicine

Keep this medicine out of the sight and reach of children.

Unopened product will be stored in a refrigerator (2-8°C) in the pharmacy and should not be used after the

expiry date shown on the carton/label.

This medicine will be prepared in a special area before the doctor or nurse gives it to you. After being mixed

together the medicine will be kept for no more than 8 hours at room temperature (25°C) or 24 hours in a

refrigerator (2-8°C). It should be stored protected from light.

6. Contents of the pack and other information

What Amphotericin Powder for Sterile Injection contains

The active substance is amphotericin B.

a) Each vial contains:
sterile freeze-dried complex of
Amphotericin B USP                                        50mg
Deoxycholate sodium                                        q.s.
Suitable  buffers                                                 q.s.

b) Each vial contains:
sterile freeze-dried complex of
Amphotericin B USP                                        100mg
Deoxycholate sodium                                        q.s.
Suitable  buffers                                                 q.s.

The other ingredients are Concentrated phosphoric acid, sodium hydroxide, disodium phosphate dodecahydrate, monosodium phosphate dehydrate, water.

Supplied in glass vials.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com