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ABELCET 5MG/ML CONCENTRATE FOR SUSPENSION FOR INFUSION

Active substance(s): AMPHOTERICIN B / AMPHOTERICIN B / AMPHOTERICIN B

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The following adverse reactions have been reported with ABELCET during clinical
trials and/or post-marketing use.
Adverse reactions are listed below as MedDRA preferred term by system organ
class and frequency. Frequencies are defined as: very common (>1/10), common
(≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), not known (cannot be
estimated from the available data).
Blood and lymphatic system disorders
Common: Thrombocytopenia
Immune system disorders
Uncommon: Anaphylactic response
Metabolism and nutrition disorders
Common: Hyperbilirubinaemia, Hypokalaemia, Electrolyte imbalance including
blood potassium increased, blood magnesium decreased
Nervous system disorders
Common: Headache, Tremor
Uncommon: Convulsion, Neuropathy
Not known: Encephalopathy
Cardiac disorders
Common: Tachycardia, Cardiac Arrhythmias
Uncommon: Cardiac arrest
Vascular disorders
Common: Hypertension, Hypotension
Uncommon: Shock
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea, Asthma
Uncommon: Respiratory failure
Not known: Bronchospasm
Gastrointestinal disorders
Common: Nausea, Vomiting, Abdominal pain
Hepatobiliary disorders
Common: Liver function tests abnormal
Skin and subcutaneous tissue disorders
Common: Rash
Uncommon: Pruritus
Not known: Dermatitis exfoliative
Musculoskeletal and connective tissue disorders
Uncommon: Myalgia

Renal and urinary disorders
Common: Renal impairment including renal failure
Not known: Hyposthenuria, Renal tubular acidosis
General disorders and administration site conditions
Very common: Chills, Pyrexia
Uncommon: Injection site reaction
Investigations
Very common: Blood creatinine increased
Common: Blood alkaline phosphatase increased, blood urea increased
The undesirable effects listed with frequency “not known” (encephalopathy,
bronchospasm, dermatitis exfoliative, hyposthenuria, renal tubular acidosis)
have been observed during post-marketing use.
Adverse reactions that have been reported to occur with conventional amphotericin
B may occur with ABELCET. In general, the physician should monitor the patient for
any type of adverse event associated with conventional amphotericin B.
Infusion hypersensitivity reactions have been associated with abdominal pain,
nausea, vomiting, myalgia, pruritus, maculopapular rash, fever, hypotension, shock,
bronchospasm, respiratory failure (see section 3.4).
Patients in whom significant renal toxicity was observed following conventional
amphotericin B frequently did not experience similar effects when ABELCET was
substituted.
Declines in renal function, shown by increased serum creatinine and hypokalaemia,
have not typically required discontinuation of treatment.
Renal tubular acidosis has been reported including hyposthenuria and electrolyte
imbalance such as increased potassium and decreased magnesium.
Abnormal liver function tests have been reported with ABELCET and other
amphotericin B products. Although other factors such as infection,
hyperalimentation, concomitant hepatotoxic drugs and graft-versus-host disease
may be contributory, a causal relationship with ABELCET cannot be excluded.
Patients with abnormal liver function tests should be carefully monitored and
cessation of treatment considered if liver function deteriorates.
Undesirable effects observed in children are similar to those observed in adults.
In elderly patients, the adverse reaction profile was similar to that seen in adults
less than 65 years. Important exceptions were increases in serum creatinine and
dyspnoea which were reported in elderly patients for both ABELCET and
conventional amphotericin B with a greater frequency in this age group.

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.
3.9 Overdose
Dosages up to 10mg/kg/day have been administered in clinical studies with no
apparent dose-dependent toxicity.
Instances of overdose reported with ABELCET have been consistent with those
reported in clinical trials with treatment at standard doses (see section 3.8).
In addition, seizures and bradycardia were experienced by one paediatric patient
who received a dose of 25mg/kg.
In case of overdose, the status of the patient (in particular the cardio-pulmonary,
renal and hepatic function as well as the blood count and serum electrolytes)
should be monitored and supportive measures initiated. No specific antidote to
amphotericin B is known.
4. PHARMACOLOGICAL PROPERTIES
ABELCET consists of the antifungal agent, amphotericin B, complexed to two
phospholipids. Amphotericin B is a macrocyclic, polyene, broad-spectrum
antifungal antibiotic produced by Streptomyces nodosus. The lipophilic moiety
of amphotericin B allows molecules of the drug to be complexed in a ribbon-like
structure with the phospholipids.
4.1 Pharmacodynamic properties
Mechanism of action
Amphotericin B, the active antifungal agent in ABELCET, may be fungistatic or
fungicidal, depending on its concentration and on fungal susceptibility. The drug
probably acts by binding to ergosterol in the fungal cell membrane causing
subsequent membrane damage. As a result, cell contents leak from the fungal
cell, and, ultimately, cell death occurs. Binding of the drug to sterols in human cell
membranes may result in toxicity, although amphotericin B has greater affinity for
fungal ergosterol than for the cholesterol of human cells.
Microbiological activity
Amphotericin B is active against many fungal pathogens in vitro, including Candida
spp., Cryptococcus neoformans, Aspergillus spp., Mucor spp., Sporothrix schenckii,
Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum.
Most strains are inhibited by amphotericin B concentrations of 0.03-1.0 μg/ml.
Amphotericin B has little or no activity against bacteria or viruses. The activity of
ABELCET against fungal pathogens in vitro is comparable to that of amphotericin B.
However, activity of ABELCET in vitro may not predict activity in the infected host.

5. PRECAUTIONS FOR STORAGE
Store at 2 - 8°C. Do not freeze. Keep vial in the outer carton.
6. PRECAUTIONS FOR HANDLING
ABELCET is a sterile, pyrogen-free suspension to be diluted for intravenous
infusion only.
Preparation of the suspension for infusion
ASEPTIC TECHNIQUE MUST BE STRICTLY OBSERVED THROUGHOUT HANDLING
OF ABELCET, SINCE NO BACTERIOSTATIC AGENT OR PRESERVATIVE IS PRESENT.
Allow the suspension to come to room temperature.
Shake gently until there is no evidence of any yellow settlement at the bottom
of the vial.
Withdraw the appropriate dose of ABELCET from the required number of vials
into one or more sterile 20ml syringes using a 17 to 19 gauge needle.
Remove the needle from each syringe filled with ABELCET and replace with the
5 micron high flow filter needle (supplied by B. Braun Medical, Inc.) provided with
each vial. Insert the filter needle of the syringe into an IV bag containing 5.0%
Dextrose for Injection and empty the contents of the syringe into the bag using
either manual pressure or an infusion pump.
The final infusion concentration should be 1mg/ml. For paediatric patients and
patients with cardio-vascular disease the drug may be diluted with 5.0%
Dextrose for Injection to a final infusion concentration of 2mg/ml.
Do not use the agent after dilution with 5.0% Dextrose for Injection if there is
any evidence of foreign matter.
Vials are single use. Unused material should be discarded.
The infusion is best administered by means of an infusion pump.
DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR
ELECTROLYTES. The compatibility of ABELCET with these materials has not
been established. An existing intravenous line should be flushed with 5.0%
Dextrose for Injection before infusion of ABELCET or a separate infusion line
should be used.
The diluted ready for use suspension may be stored at 2°C -8°C for up to
24 hours prior to use. Shake vigorously before use. Do not store for later use.

H48030

Abelcet 5mg/ml Con for Sus for Inf ALL
CeUK PCI Services

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YS

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48030
LEAFLET
756 x 153mm

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PACKAGE LEAFLET: INFORMATION FOR THE USER

®

ABELCET 5mg/ml
Concentrate for Suspension
for Infusion
Amphotericin B Lipid Complex
Read all of this leaflet carefully before you start using this medicine.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor.
– This medicine has been prescribed for you. Do not pass it on to others.
It may harm them, even if their symptoms are the same as yours.
– If you get any side effects, talk to your doctor, pharmacist or nurse.
This includes any possible side effects not listed in this leaflet. See section 4.
In this leaflet:
1. What ABELCET is and what it is used for
2. Before you use ABELCET
3. How to use ABELCET
4. Possible side effects
5. How to store ABELCET
6. Further information
1. WHAT ABELCET IS AND WHAT IT IS USED FOR
ABELCET is a medicine to treat severe fungal infections such as blood infection with
candida, aspergillus, cryptococcus, fusarium, zygomycetes, blastomycetes or
coccidiodes, or cryptococcal meningitis (inflammation of the brain). Fungi are
common and are found throughout nature but do not normally cause infections.
However, under certain circumstances, for instance, when the body’s immune
system is not working properly, a few types of fungi can infect humans.
2. BEFORE YOU USE ABELCET
Do not use ABELCET
If you are allergic (hypersensitive) to amphotericin B or any of the other ingredients
of ABELCET. For a full list of ingredients please refer to section 6 (What ABELCET
contains).
Take special care with ABELCET
– Your doctor may need to monitor you carefully and do some extra tests while
you are being treated with ABELCET, particularly if you have had previous
problems with your kidneys or liver.
– If you have a kidney problem, your doctor will perform a blood test at least once
a week to check how your kidneys are working while you are receiving ABELCET.

Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken
any other medicines, including medicines obtained without a prescription.
ABELCET may interact with
– drugs which can affect your kidney function
– other drugs such as zidovudine (used to treat HIV infection) or ciclosporin
(a drug to suppress your immune system).
Amphotericin B has been reported to interact with the following drugs:
– drugs to treat cancer
– corticosteroids and corticotrophin (ACTH) (drugs given to treat a variety of
conditions such as allergies and hormone imbalances)
– digitalis glycosides (used to treat heart conditions)
– flucytosine (used to treat fungal infections)
– muscle relaxants.
Pregnancy and breast-feeding
Ask your doctor for advice before taking any medicine.
Inform your doctor if you are pregnant or breast feeding. S/He will decide if this
medication is suitable for you.
Driving and using machines
You should avoid driving a vehicle or operating machinery after treatment with
ABELCET as the side effects of ABELCET could affect your ability to drive safely.
Important information about some of the ingredients of ABELCET
This medicinal product contains 0.156 mmol (or 3.6 mg) sodium per mL.
This represents 3.12 mmol (or 71.8 mg) sodium per 20 mL vial. To be taken into
consideration by patients on a controlled sodium diet.
3. HOW TO USE ABELCET
Method and route of administration
ABELCET must be diluted with a dextrose (sugar) solution before use.
ABELCET must be administered as an infusion to the vein. This will be given by
a drip into a vein in your arm over about 2 hours.
Dosage and frequency of administration
ABELCET will normally be given to you by your doctor or by a nurse.
The recommended daily dose is 5.0 mg of ABELCET for every kg of your body
weight, given as a single infusion. A test dose of 1 mg is given initially to see if you
are sensitive to any of the ingredients. The number of days over which you will be
treated depends on many factors, but will probably be at least 14 days.
No change in dose is required for children, elderly people and those suffering
from kidney or liver disease.

Before you stop using ABELCET
It is important that you follow your doctor’s instructions and receive all the
medication prescribed for you even if you feel better.
If too much ABELCET is given
You should tell your doctor immediately if you think you received too much
ABELCET.
You may experience side effects as listed in section 4 “Possible side effects”.
You doctor may need to check your heart and breathing rates, your kidney and liver
function, your blood cell counts or the level of potassium in your body.
If a dose is missed
You should tell your doctor immediately, he will decide when you should be given
your next dose of ABELCET.
If you have any further questions on the use of this product, ask your doctor or
pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, ABELCET can cause side effects, although not everybody
gets them.
Uncommon allergic reactions (affecting 1 to 10 people in 1000)
Seek medical help immediately if you have any of the following symptoms
of a serious allergic reaction:
– Difficulty breathing and/or feeling dizzy or faint
– Severe itching of the skin or raised lumps on the skin
– Swelling of the face, lips, tongue and/or throat, which may cause difficulty
in swallowing
You should also seek urgent medical help if you have any of the following serious
side effects:
– Severe chest pain (heart attack) or difficulty breathing
– Encephalopathy (a disease of the brain, which may cause you to become
confused or behave strangely, and/or feel drowsy)
You may experience chills, fever, nausea (feeling sick), vomiting (being sick),
rash, itching, muscle pain, abdominal pain or convulsions (fits) although this will
probably only occur during the infusion or in the first 2 days of treatment. Your
nurse or doctor may be able to arrange some simple treatment to help control
these side effects.
ABELCET may affect your kidney, liver or blood. Your doctor will check for these and
other unwanted effects by carrying out appropriate tests, for example checking the
level of potassium in your body.

Very common side effects (occurring in more than 1 in 10 people)
Chills, fever, increased levels of a substance called creatinine in the blood.
Common side effects (affecting 1 to 10 people in 100)
Increased heart rate, irregular heartbeat, low or high blood pressure, low blood
platelets (which can lead to an increased risk of bleeding), breathing problems,
asthma, nausea (feeling sick), vomiting (being sick), headache, shaking, kidney
problems (signs include tiredness and passing less urine), kidney function tests
abnormal, increased or decreased blood potassium levels (which can make you
feel tired, confused, and have muscle weakness or cramps or make your heart
beat abnormally), decreased blood magnesium levels (which can give you
“pins and needles”, muscular pains, weakness or spasms), liver function tests
abnormal, rash.
Uncommon side effects (affecting 1 to 10 people in 1000)
Injection site reactions, convulsions (fits), neuropathy (nerve disease).
The following side effects have also been reported with the use of ABELCET but
it is not known how often they occur: Widespread flaking or scaling of the skin,
the production of large amounts of weak (watery) urine
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes
any possible side effects not listed in this leaflet. You can also report side effects
directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on the safety
of this medicine.
5. HOW TO STORE ABELCET
Keep out of the reach and sight of children.
Do not use ABELCET after the expiry date which is stated on the label.
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep vial in the outer carton.
6. FURTHER INFORMATION
What ABELCET contains
– The active substance is Amphotericin B.
– The other ingredients are L-α-dimyristoylphosphatidylcholine (DMPC),
L-α-dimyristoylphosphatidylglycerol (sodium and ammonium salts) (DMPG),
sodium chloride (common salt) and water for injection.

The following information is intended for medical or healthcare
professionals only:
Health Care Professional Leaflet

What ABELCET looks like and contents of the pack
ABELCET is supplied as a yellow concentrate for suspension for infusion.
Each vial contains 5 mg Amphotericin B per ml. Vials of 10 ml contain 50 mg
amphotericin B. Vials of 20 ml contain 100 mg amphotericin B. Vials are packaged
in cartons of 10 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Teva Pharma B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
Manufacturer
AndersonBrecon (UK) Limited
Wye Valley Business Park
Hay-on-Wye
Hereford
HR3 5PG
UK.
This leaflet was last revised in February 2017

ABELCET® 5mg/ml
Concentrate for Suspension
for Infusion
Amphotericin B Lipid Complex

H48030

18130-C

284924.02-GB

1. NAME OF THE MEDICINAL PRODUCT
ABELCET 5mg/mL Concentrate for Suspension for Infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Amphotericin B Lipid Complex. Each vial contains 5mg Amphotericin B per mL.
Excipients: 3.6 mg/mL of sodium (0.156 mmol); this represents 71.8 mg of
sodium (3.12 mmol) per 20 mL vial.
3. CLINICAL PARTICULARS
3.1 Therapeutic indications
ABELCET is indicated for the treatment of severe invasive candidiasis.
ABELCET is also indicated as second line therapy for the treatment of severe
systemic fungal infections in patients who have not responded to conventional
amphotericin B or other systemic antifungal agents, in those who have renal
impairment or other contra-indications to conventional amphotericin B, or in
patients who have developed amphotericin B nephrotoxicity. ABELCET
treatment is indicated as second line treatment for invasive aspergillosis,
cryptococcal meningitis and disseminated cryptococcosis in HIV patients,
fusariosis, coccidiomycosis, zygomycosis and blastomycosis.
3.2 Posology and method of administration
ABELCET is a sterile, pyrogen-free suspension which must be diluted for
intravenous infusion only.
ABELCET should be administered by intravenous infusion at 5 mg/kg at
a rate of 2.5 mg/kg/hr.
When commencing treatment with ABELCET for the first time it is recommended
to administer a test dose immediately prior to the first infusion. The first
infusion should be prepared according to the instructions then, over a period
of approximately 15 minutes, 1mg of the infusion should be administered to
the patient. After this amount has been administered the infusion should be
stopped and the patient observed carefully for 30 minutes.

If the patient shows no signs of hypersensitivity the infusion may be continued.
As for use with all amphotericin B products, facilities for cardiopulmonary
resuscitation should be readily at hand when administering ABELCET for the first
time, due to the possible occurrence of anaphylactoid reactions.
For severe systemic infections treatment is generally recommended for at least
14 days.
ABELCET has been administered for as long as 28 months, and cumulative doses
have been as high as 73.6 g without significant toxicity.
An in-line filter may be used for intravenous infusion of ABELCET. The mean pore
diameter of the filter should be no less than 15 microns.
Use in diabetic patients
ABELCET may be administered to diabetic patients.
Use in paediatric patients
Systemic fungal infections have been treated successfully in children ranging from
1 month to 16 years of age at doses comparable to the recommended adult dose
on a bodyweight basis. Adverse events seen in paediatric patients are similar to
those seen in adults.
Use in elderly patients
Systemic fungal infections in elderly patients have been treated successfully with
ABELCET at doses comparable to the recommended dose on a bodyweight basis.
Use in neutropenic patients
ABELCET has been used successfully to treat systemic fungal infections in patients
who are severely neutropenic as a consequence of haematological malignancy or
the use of cytotoxic or immunosuppressive drugs.
Use in patients with renal or liver disease
Systemic fungal infections in patients with renal or liver disease have been treated
successfully with ABELCET at doses comparable to the recommended dose on a
body weight basis (see section 3.4).
3.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients, unless in the
opinion of the physician the advantages of using ABELCET outweigh the risks of
hypersensitivity.
3.4 Special warnings and precautions for use
In patients for whom sodium intake is of medical concern (e.g. patients with
congestive heart failure, renal failure, nephrotic syndrome), the sodium content
of this product should be taken into account.

Infusion Hypersensitivity Reactions
Infusion related reactions (such as chills and pyrexia) recorded following the
administration of ABELCET have generally been mild or moderate, and have mainly
been recorded during the first 2 days of administration (see section 3.8).
Premedication (e.g. paracetamol) may be administered for the prevention of
infusion related adverse reactions.
Systemic Fungal Infections
ABELCET should not be used for treating common or superficial, clinically inapparent
fungal infections that are detectable only by positive skin or serologic tests.
Patients with renal Disease
Since ABELCET is a potentially nephrotoxic drug, monitoring of renal function
should be performed before initiating treatment in patients with pre-existing renal
disease or who have already experienced renal failure, and at least once weekly
during therapy. ABELCET can be administered to patients during renal dialysis
or haemofiltration. Serum potassium and magnesium levels should be
monitored regularly.
Patients with liver Disease
Patients with concurrent hepatic impairment due to infection, graft-versus-host
disease, other liver disease or administration of hepatotoxic drugs have been
successfully treated with ABELCET. In cases where serum bilirubin, alkaline
phosphatase or serum transaminases increased, factors other than ABELCET were
present and possibly accounted for the abnormalities. These factors included
infection, hyperalimentation, concomitant hepatotoxic drugs and graft-versus-host
disease.
3.5 Interaction with other medicinal products and other forms of interaction
Nephrotoxic Drugs
ABELCET is a potentially nephrotoxic drug, and particularly close monitoring of
renal function is required in patients receiving nephrotoxic drugs concomitantly.
Zidovudine
In dogs, exacerbated myelotoxicity and nephrotoxicity were observed when
ABELCET was administered concomitantly with zidovudine. If concomitant
treatment with zidovudine is required, renal and haematologic function should
be closely monitored.
Cyclosporin
Interaction data with amphotericin B containing products indicate that patients
receiving amphotericin B concomitantly with high dose cyclosporine experience an
increase in serum creatinine caused by simultaneous administration of these two
compounds. However, ABELCET has been shown to be less nephrotoxic than
conventional amphotericin B.

Other drugs
The interaction of ABELCET with other drugs has not been studied to date.
Conventional amphotericin B has been reported to interact with the following drugs,
and caution should be exercised during concomitant use with ABELCET:
antineoplasic agents, corticosteroids and corticotrophin (ACTH), digitalis glycosides,
flucytosine, and skeletal muscle relaxants.
Leukocyte transfusions
Acute pulmonary toxicity has been reported in patients receiving intravenous
conventional amphotericin B and leukocyte transfusions. It is not recommended
to administer ABELCET with leukocyte transfusions.
3.6 Pregnancy and lactation
Conventional amphotericin B has been used successfully to treat systemic fungal
infections in pregnant women with no obvious effects on the foetus, but only a
small number of cases have been reported. Reproductive toxicity studies of
ABELCET in rats and rabbits showed no evidence of embryotoxicity, foetotoxicity
or teratogenicity. However, safety for use in pregnant women has not been
established for ABELCET. ABELCET should only be administered to pregnant
women when the likely benefit exceeds the risk to the mother and foetus.
It is unknown whether ABELCET passes into breast milk. A decision on whether to
continue/discontinue nursing or whether to continue/discontinue ABELCET should
be made taking into account the benefit of breast-feeding to the child and the
benefit of ABELCET to the woman.
3.7 Effects on ability to drive and use machines
The effects of ABELCET on the ability to drive and /or use machines have not been
investigated. Some of the undesirable effects of ABELCET presented below may
impact the ability to drive and use machines. However, the clinical condition of
patients who require ABELCET generally precludes driving or operating machinery.
3.8 Undesirable effects
The most common clinical adverse reactions in randomised controlled and open
label clinical trials have been chills (16%), increased creatinine (13%), pyrexia (10%),
hypokalaemia (9%), nausea (7%) and vomiting (6%).
The incidence is based on analysis from pooled clinical trials of 709 ABELCET
treated patients.
There were 556 cases in emergency use studies and 153 in a randomised
controlled trial in invasive candidiasis (38% ≥ 65 years). In the emergency use
studies, patients had either shown intolerance to conventional amphotericin B
treatment, had renal impairment as a result of previous conventional amphotericin
B treatment, had pre-existing renal disease or were treatment failures.

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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