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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 07.04.2022
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L-Ampho Anfotericina B Biosano® (amphotericin b) is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See Description Of Clinical Studies).
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 L-Ampho Anfotericina B Biosano or other systemic antifungal agents, in those who have renal impairment or other contra-indications to conventional L-Ampho Anfotericina B Biosano, or in patients who have developed L-Ampho Anfotericina B Biosano 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.
L-Ampho Anfotericina B Biosano is indicated for the following:
- Empirical therapy for presumed fungal infection in febrile, neutropenic patients.
- Treatment of Cryptococcal Meningitis in HIV infected patients (see Description Of Clinical Studies).
- Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate.
- Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with L-Ampho Anfotericina B Biosano, relapse rates were high following initial clearance of parasites (see Description Of Clinical Studies).
See DOSAGE AND ADMINISTRATION for recommended doses by indication.
The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. L-Ampho Anfotericina B Biosano® (amphotericin b) should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.
Renal toxicity of L-Ampho Anfotericina B Biosano® (amphotericin b) , as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.
Preparation of Admixture for Infusion: Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of L-Ampho Anfotericina B Biosano® (amphotericin b) from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with L-Ampho Anfotericina B Biosano® (amphotericin b) and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of L-Ampho Anfotericina B Biosano® (amphotericin b) , since no bacteriostatic agent or preservative is present.
DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of L-Ampho Anfotericina B Biosano® (amphotericin b) with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of L-Ampho Anfotericina B Biosano® (amphotericin b) , or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER.
The diluted ready-for-use admixture is stable for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature.
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 L-Ampho Anfotericina B Biosano 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.
L-Ampho Anfotericina B Biosano should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes.
An in-line membrane filter may be used for the intravenous infusion of L-Ampho Anfotericina B Biosano; provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON.
NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of L-Ampho Anfotericina B Biosano. If this is not feasible, L-Ampho Anfotericina B Biosano must be administered through a separate line.
Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased.
The recommended initial dose of L-Ampho Anfotericina B Biosano for each indication for adult and pediatric patients is as follows:
| Indication | Dose (mg/kg/day) |
| Empirical therapy | 3 |
| Systemic fungal infections: Aspergillus Candida Cryptococcus | 3-5 |
| Cryptococcal meningitis in HIV infected patients (see Description Of Clinical Studies) | 6 |
Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events.
Doses recommended for visceral leishmaniasis are presented below:
| Visceral Leishmaniasis | Dose (mg/kg/day) |
| Immunocompetent patients | 3 (days 1-5) and 3 on days 14, 21 |
| Immunocompromised patients | 4 (days 1-5) and 4 on days 10, 17,24,31,38 |
For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful.
For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information see Description Of Clinical Studies.
Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning Reconstitution L-Ampho Anfotericina B Biosano must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of L-Ampho Anfotericina B Biosano containing 50 mg of amphotericin B are prepared as follows:
Reconstitution
- Aseptically add 12 mL of Sterile Water for Injection, USP to each L-Ampho Anfotericina B Biosano vial to yield a preparation containing 4 mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of L-Ampho Anfotericina B Biosano.
- Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the L-Ampho Anfotericina B Biosano. L-Ampho Anfotericina B Biosano forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed.
Filtration and Dilution
3. Calculate the amount of reconstituted (4 mg/mL) L-Ampho Anfotericina B Biosano to be further diluted.
4. Withdraw this amount of reconstituted L-Ampho Anfotericina B Biosano into a sterile syringe.
5. Attach the 5-micron filter, provided, to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection. (Use only one filter per vial of L-Ampho Anfotericina B Biosano.)
6. L-Ampho Anfotericina B Biosano must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.
Storage of L-Ampho Anfotericina B Biosano
Unopened vials of lyophilized material are to be stored at temperatures up to 25° C (77° F).
Storage of Reconstituted Product Concentrate
The reconstituted product concentrate may be stored for up to 24 hours at 2°-8° C (36°-46° F) following reconstitution with Sterile Water for Injection, USP. Do not freeze.
Storage of Diluted Product
Injection of L-Ampho Anfotericina B Biosano should commence within 6 hours of dilution with 5% Dextrose Injection.
As with all parenteral drug products, the reconstituted L-Ampho Anfotericina B Biosano should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in L-Ampho Anfotericina B Biosano or in the materials specified for reconstitution and dilution.
L-Ampho Anfotericina B Biosano® (amphotericin b) is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.
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.
L-Ampho Anfotericina B Biosano is contraindicated in those patients who have demonstrated or have known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.
WARNINGS
Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with L-Ampho Anfotericina B Biosano® (amphotericin b) with an incidence rate of < 0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of L-Ampho Anfotericina B Biosano® (amphotericin b).
PRECAUTIONS
General
As with any amphotericin B-containing product, during the initial dosing of L-Ampho Anfotericina B Biosano® (amphotericin b) , the drug should be administered under close clinical observation by medically trained personnel.
Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of L-Ampho Anfotericina B Biosano® (amphotericin b). These reactions are usually more common with the first few doses of L-Ampho Anfotericina B Biosano® (amphotericin b) and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.
Laboratory Tests
Serum creatinine should be monitored frequently during L-Ampho Anfotericina B Biosano® therapy (see ADVERSE REACTIONS). It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of L-Ampho Anfotericina B Biosano® (amphotericin b). The following in vitro (with and without metabolic activation) and in vivo studies to assess L-Ampho Anfotericina B Biosano® (amphotericin b) for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivo mouse micronucleus assay. L-Ampho Anfotericina B Biosano® (amphotericin b) was found to be without mutagenic effects in all assay systems. Studies demonstrated that L-Ampho Anfotericina B Biosano® (amphotericin b) had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).
Pregnancy
There are no reports of pregnant women having been treated with L-Ampho Anfotericina B Biosano® (amphotericin b). Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of L-Ampho Anfotericina B Biosano® (amphotericin b) up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, L-Ampho Anfotericina B Biosano® (amphotericin b) should be used during pregnancy only after taking into account the importance of the drug to the mother.
Nursing Mothers
It is not known whether L-Ampho Anfotericina B Biosano® (amphotericin b) is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from L-Ampho Anfotericina B Biosano® (amphotericin b) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with L-Ampho Anfotericina B Biosano® (amphotericin b) at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of L-Ampho Anfotericina B Biosano® (amphotericin b). No serious unexpected adverse events have been reported.
Geriatric Use
Forty-nine elderly patients, age 65 years or over, have been treated with L-Ampho Anfotericina B Biosano® (amphotericin b) at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.
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 (see section 2).
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 be recorded during the first 2 days of administration.
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.
WARNINGS
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including L-Ampho Anfotericina B Biosano. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of L-Ampho Anfotericina B Biosano.
PRECAUTIONS
General
As with any amphotericin B-containing product the drug should be administered by medically trained personnel. During the initial dosing period, patients should be underdose clinical observation. L-Ampho Anfotericina B Biosano has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur.
Laboratory Tests
Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium).
Drug-Laboratory Interactions: Serum phosphate false elevation
False elevations of serum phosphate may occur when samples from patients receiving L-Ampho Anfotericina B Biosano are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long term studies in animals have been performed to evaluate carcinogenic potential of L-Ampho Anfotericina B Biosano. L-Ampho Anfotericina B Biosano has not been tested to determine its mutagenic potential. A Segment I Reproductive Study in rats found an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in the high dose groups (10 and 15 mg/kg, doses equivalent to human doses of 1.6 and 2.4 mg/kg based on body surface area considerations). L-Ampho Anfotericina B Biosano did not affect fertility or days to copulation. There were no effects on male reproductive function.
Pregnancy Category B
There have been no adequate and well-controlled studies of L-Ampho Anfotericina B Biosano in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small.
Segment II studies in both rats and rabbits have concluded that L-Ampho Anfotericina B Biosano had no teratogenic potential in these species. In rats, the maternal non-toxic dose of L-Ampho Anfotericina B Biosano was estimated to be 5 mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of 1 to 5 mg/kg) and in rabbits, 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to 2 times the recommended human dose) of L-Ampho Anfotericina B Biosano experienced a higher rate of spontaneous abortions than did the control groups. L-Ampho Anfotericina B Biosano should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.
Nursing Mothers
Many drugs are excreted in human milk. However, it is not known whether L-Ampho Anfotericina B Biosano is excreted in human milk. Due to the potential for serious adverse reactions in breast-fed infants, a decision should be made whether to discontinue nursing or whether to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Pediatric patients, age 1 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with L-Ampho Anfotericina B Biosano. In studies which included 302 pediatric patients administered L-Ampho Anfotericina B Biosano, there was no evidence of any differences in efficacy or safety of L-Ampho Anfotericina B Biosano compared to adults. Since pediatric patients have received L-Ampho Anfotericina B Biosano at doses comparable to those used in adults on a per kilogram body weight basis, no dosage adjustment is required in this population. Safety and effectiveness in pediatric patients below the age of one month have not been established. (See Description Of Clinical Studies - Empirical Therapy in Febrile Neutropenic Patients and DOSAGE AND ADMINISTRATION).
Elderly Patients
Experience with L-Ampho Anfotericina B Biosano in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of L-Ampho Anfotericina B Biosano for this population. As with most other drugs, elderly patients receiving L-Ampho Anfotericina B Biosano should be carefully monitored.
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.
The total safety data base is composed of 921 patients treated with L-Ampho Anfotericina B Biosano® (amphotericin b) (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, non-comparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with L-Ampho Anfotericina B Biosano® (amphotericin b) , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug.
In general, the adverse events most commonly reported with L-Ampho Anfotericina B Biosano® (amphotericin b) were transient chills and/or fever during infusion of the drug.
Adverse Eventsa with an Incidence of ≥ 3% (N=556)
| Adverse Event | Percentage (%) of Patients |
| Chills | 18 |
| Fever | 14 |
| Increased Serum Creatinine | 11 |
| Multiple Organ Failure | 11 |
| Nausea | 9 |
| Hypotension | 8 |
| Respiratory Failure | 8 |
| Vomiting | 8 |
| Dyspnea | 7 |
| Sepsis | 7 |
| Diarrhea | 6 |
| Headache | 6 |
| Heart Arrest | 6 |
| Hypertension | 5 |
| Hypokalemia | 5 |
| Infection | 5 |
| Kidney Failure | 5 |
| Pain | 5 |
| Thrombocytopenia | 5 |
| Abdominal Pain | 4 |
| Anemia | 4 |
| Bilirubinemia | 4 |
| Gastrointestinal Hemorrhage | 4 |
| Leukopenia | 4 |
| Rash | 4 |
| Respiratory Disorder | 4 |
| Chest Pain | 3 |
| Nausea and Vomiting | 3 |
| a The causal association between these adverse events and L-Ampho Anfotericina B Biosano® is uncertain. | |
The following adverse events have also been reported in patients using L-Ampho Anfotericina B Biosano® (amphotericin b) in open-label, uncontrolled clinical studies. The causal association between these adverse events and L-Ampho Anfotericina B Biosano® (amphotericin b) is uncertain.
Body as a whole: malaise, weight loss, deafness, injection site reaction including inflammation
Allergic: bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions
Cardiopulmonary:cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation.
Dermatological: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme
Gastrointestinal:acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis
Hematologic:coagulation defects, leukocytosis, blood dyscrasias including eosinophilia
Musculoskeletal: myasthenia, including bone, muscle, and joint pains
Neurologic: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms
Urogenital: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria
Serum electrolyte abnormalities: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia
Liver function test abnormalities: increased AST, ALT, alkaline phosphatase, LDH
Renal function test abnormalities: increased BUN
Other test abnormalities: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia
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 (open-label, non comparative 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 L-Ampho Anfotericina B Biosano treatment, had renal impairment as a result of previous conventional L-Ampho Anfotericina B Biosano treatment, had pre-existing renal disease or were treatment failures.
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).
| System organ class | Adverse reaction | Frequency |
| Blood and lymphatic system disorders | ||
| Thrombocytopenia | Common | |
| Immune system disorders | ||
| Anaphylactic response | Uncommon | |
| Metabolism and nutrition disorders | ||
| Hyperbilirubinaemia, Hypokalaemia, Electrolyte imbalance including blood potassium increased, blood magnesium decreased | Common | |
| Nervous system disorders | ||
| Headache, Tremor | Common | |
| Convulsion, Neuropathy | Uncommon | |
| Encephalopathy | Not known | |
| Cardiac disorders | ||
| Tachycardia, Cardiac Arrhythmias | Common | |
| Cardiac arrest | Uncommon | |
| Vascular disorders | ||
| Hypertension, Hypotension | Common | |
| Shock | Uncommon | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnoea, Asthma | Common | |
| Respiratory failure | Uncommon | |
| Bronchospasm | Not known | |
| Gastrointestinal disorders | ||
| Nausea, Vomiting, Abdominal pain | Common | |
| Hepatobiliary disorders | ||
| Liver function tests abnormal | Common | |
| Skin and subcutaneous tissue disorders | ||
| Rash | Common | |
| Pruritus | Uncommon | |
| Dermatitis exfoliative | Not known | |
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | Uncommon | |
| Renal and urinary disorders | ||
| Renal impairment including renal failure | Common | |
| Hyposthenuria, Renal tubular acidosis | Not known | |
| General disorders and administration site conditions | ||
| Chills, Pyrexia | Very common | |
| Injection site reaction | Uncommon | |
| Investigations | ||
| Blood creatinine increased | Very common | |
| Blood alkaline phosphatase increased, blood urea increased | Common | |
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 L-Ampho Anfotericina B Biosano may occur with Abelcet. In general, the physician should monitor the patient for any type of adverse event associated with conventional L-Ampho Anfotericina B Biosano.
Infusion hypersensitivity reactions have been associated with abdominal pain, nausea, vomiting, myalgia, pruritus, maculopapular rash, fever, hypotension, shock, bronchospasm, respiratory failure.
Patients in whom significant renal toxicity was observed following conventional L-Ampho Anfotericina B Biosano 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 L-Ampho Anfotericina B Biosano 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 L-Ampho Anfotericina B Biosano 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.
The following adverse events are based on the experience of 592 adult patients (295 treated with L-Ampho Anfotericina B Biosano and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with L-Ampho Anfotericina B Biosano and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. L-Ampho Anfotericina B Biosano and amphotericin B were infused over two hours.
The incidence of common adverse events (incidence of 10% or greater) occurring with L-Ampho Anfotericina B Biosano compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table:
Empirical Therapy Study 94-0-002
Common Adverse Events
| Adverse Event by Body System | L-Ampho Anfotericina B Biosano n=343 % | Amphotericin B n=344 % |
| Body as a Whole | ||
| Abdominal pain | 19.8 | 21.8 |
| Asthenia | 13.1 | 10.8 |
| Back pain | 12 | 7.3 |
| Blood product transfusion react. | 18.4 | 18.6 |
| Chills | 47.5 | 75.9 |
| Infection | 11.1 | 9.3 |
| Pain | 14 | 12.8 |
| Sepsis | 14 | 11.3 |
| Cardiovascular System | ||
| Chest pain | 12 | 11.6 |
| Hypertension | 7.9 | 16.3 |
| Hypotension | 14.3 | 21.5 |
| Tachycardia | 13.4 | 20.9 |
| Digestive System | ||
| Diarrhea | 30.3 | 27.3 |
| Gastrointestinal hemorrhage | 9.9 | 11.3 |
| Nausea | 39.7 | 38.7 |
| Vomiting | 31.8 | 43.9 |
| Metabolic and Nutritional Disorders | ||
| Alkaline phosphatase increased | 22.2 | 19.2 |
| ALT (SGPT) increased | 14.6 | 14 |
| AST (SCOT) increased | 12.8 | 12.8 |
| Bilirubinemia | 18.1 | 19.2 |
| BUN increased | 21 | 31.1 |
| Creatinine increased | 22.4 | 42.2 |
| Edema | 14.3 | 14.8 |
| Hyperglycemia | 23 | 27.9 |
| Hypematremia | 4.1 | 11 |
| Hypervolemia | 12.2 | 15.4 |
| Hypocalcemia | 18.4 | 20.9 |
| Hypokalemia | 42.9 | 50.6 |
| Hypomagnesemia | 20.4 | 25.6 |
| Peripheral edema | 14.6 | 17.2 |
| Nervous System | ||
| Anxiety | 13.7 | 11 |
| Confusion | 11.4 | 13.4 |
| Headache | 19.8 | 20.9 |
| Insomnia | 17.2 | 14.2 |
| Respiratory System | ||
| Cough increased | 17.8 | 21.8 |
| Dyspnea | 23 | 29.1 |
| Epistaxis | 14.9 | 20.1 |
| Hypoxia | 7.6 | 14.8 |
| Lung disorder | 17.8 | 17.4 |
| Pleural effusion | 12.5 | 9.6 |
| Rhinitis | 11.1 | 11 |
| Skin and Appendages | ||
| Pruritus | 10.8 | 10.2 |
| Rash | 24.8 | 24.4 |
| Sweating | 7 | 10.8 |
| Urogenital System | ||
| Hematuria | 14 | 14 |
L-Ampho Anfotericina B Biosano was well tolerated. L-Ampho Anfotericina B Biosano had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate.
In pediatric patients (16 years of age or less) in this double-blind study, L-Ampho Anfotericina B Biosano compared to amphotericin B deoxycholate had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with L-Ampho Anfotericina B Biosano and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate.
The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with L-Ampho Anfotericina B Biosano 3 mg/kg, 81 patients were treated with L-Ampho Anfotericina B Biosano 5 mg/kg and 78 patients treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized double-blind, multi-center study in febrile, neutropenic patients. L-Ampho Anfotericina B Biosano and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table:
Empirical Therapy Study 97-0-034
Common Adverse Events
| Adverse Event by Body System | L-Ampho Anfotericina B Biosano 3 mg/kg/day n=85 % | L-Ampho Anfotericina B Biosano 5 mg/kg/day n=81 % | Amphotericin B Lipid Complex 5 mg/kg/day n=78 % |
| Body as a Whole | |||
| Abdominal pain | 12.9 | 9.9 | 11.5 |
| Asthenia | 8.2 | 6.2 | 11.5 |
| Chills/rigors | 40 | 48.1 | 89.7 |
| Sepsis | 12.9 | 7.4 | 11.5 |
| Transfusion reaction | 10.6 | 8.6 | 5.1 |
| Cardiovascular System | |||
| Chest pain | 8.2 | 11.1 | 6.4 |
| Hypertension | 10.6 | 19.8 | 23.1 |
| Hypotension | 10.6 | 7.4 | 19.2 |
| Tachycardia | 9.4 | 18.5 | 23.1 |
| Digestive System | |||
| Diarrhea | 15.3 | 17.3 | 14.1 |
| Nausea | 25.9 | 29.6 | 37.2 |
| Vomiting | 22.4 | 25.9 | 30.8 |
| Metabolic and Nutritional Disorders | |||
| Alkaline phosphatase increased | 7.1 | 8.6 | 12.8 |
| Bilirubinemia | 16.5 | 11.1 | 11.5 |
| BUN increased | 20 | 18.5 | 28.2 |
| Creatinine increased | 20 | 18.5 | 48.7 |
| Edema | 12.9 | 12.3 | 12.8 |
| Hyperglycemia | 8.2 | 8.6 | 14.1 |
| Hypervolemia | 8.2 | 11.1 | 14.1 |
| Hypocalcemia | 10.6 | 4.9 | 5.1 |
| Hypokalemia | 37.6 | 43.2 | 39.7 |
| Hypomagnesemia | 15.3 | 25.9 | 15.4 |
| Liver function tests abnormal | 10.6 | 7.4 | 11.5 |
| Nervous System | |||
| Anxiety | 10.6 | 7.4 | 9 |
| Confusion | 12.9 | 8.6 | 3.8 |
| Headache | 9.4 | 17.3 | 10.3 |
| Respiratory System | |||
| Dyspnea | 17.6 | 22.2 | 23.1 |
| Epistaxis | 10.6 | 8.6 | 14.1 |
| Hypoxia | 7.1 | 6.2 | 20.5 |
| Lung disorder | 14.1 | 13.6 | 15.4 |
| Skin and Appendages | |||
| Rash | 23.5 | 22.2 | 14.1 |
The following adverse events are based on the experience of 267 patients (266 adult patients and 1 pediatric patient) of whom 86 patients were treated with L-Ampho Anfotericina B Biosano 3 mg/kg, 94 patients were treated with L-Ampho Anfotericina B Biosano 6 mg/kg and 87 patients treated with amphotericin B deoxycholate 0.7 mg/kg in Study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in HIV positive patients. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table:
Cryptococcal Meningitis Therapy Study 94-0-013
Common Adverse Events
| Adverse Event by Body System | L-Ampho Anfotericina B Biosano 3 mg/kg/day n=86 % | L-Ampho Anfotericina B Biosano 6 mg/kg/day n=94 % | Amphotericin B 0.7 mg/kg/day n=87 % |
| Body as a Whole | |||
| Abdominal pain | 7 | 7.4 | 10.3 |
| Infection | 12.8 | 11.7 | 6.9 |
| Procedural Complication | 8.1 | 9.6 | 10.3 |
| Cardiovascular System | |||
| Phlebitis | 9.3 | 10.6 | 25.3 |
| Digestive System | |||
| Anorexia | 14 | 9.6 | 11.5 |
| Constipation | 15.1 | 14.9 | 20.7 |
| Diarrhea | 10.5 | 16 | 10.3 |
| Nausea | 16.3 | 21.3 | 25.3 |
| Vomiting | 10.5 | 21.3 | 20.7 |
| Hemic and Lymphatic System | |||
| Anemia | 26.7 | 47.9 | 43.7 |
| Leukopenia | 15.1 | 17 | 17.2 |
| Thrombocytopenia | 5.8 | 12.8 | 6.9 |
| Metabolic and Nutritional Disorders | |||
| Bilirubinemia | 0 | 8.5 | 12.6 |
| BUN increased | 9.3 | 7.4 | 10.3 |
| Creatinine increased | 18.6 | 39.4 | 43.7 |
| Hyperglycemia | 9.3 | 12.8 | 17.2 |
| Hypocalcemia | 12.8 | 17 | 13.8 |
| Hypokalemia | 31.4 | 51.1 | 48.3 |
| Hypomagnesemia | 29.1 | 48.9 | 40.2 |
| Hyponatremia | 11.6 | 8.5 | 9.2 |
| Liver Function Tests Abnormal | 12.8 | 4.3 | 9.2 |
| Nervous System | |||
| Dizziness | 7 | 8.5 | 10.3 |
| Insomnia | 22.1 | 17 | 20.7 |
| Respiratory System | |||
| Cough Increased | 8.1 | 2.1 | 10.3 |
| Skin and Appendages | |||
| Rash | 4.7 | 11.7 | 4.6 |
Infusion Related Reactions In Study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion related reaction was administered prior to the first dose of study drug (Day 1). L-Ampho Anfotericina B Biosano-treated patients had a lower incidence of infusion related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients.
The incidence of infusion related reactions on Day 1 in pediatric and adult patients is summarized in the following table:
Incidence of Day 1 Infusion Related Reactions (IRR) By Patient Age
| Pediatric Patients ( ≤ 16 years of age) | Adult Patients ( > 1 6 years of age) | |||
| L-Ampho Anfotericina B Biosano | Amphotericin B | L-Ampho Anfotericina B Biosano | Amphotericin B | |
| Total number of patients receiving at least one dose of study drug | 48 | 47 | 295 | 297 |
| Patients with fever† Increase ≥ 1.0°C | 6(13%) | 22 (47%) | 52(18%) | 128(43%) |
| Patients with chills/rigors | 4 (8%) | 22 (47%) | 59 (20%) | 165(56%) |
| Patients with nausea | 4 (8%) | 4 (9%) | 38(13%) | 31 (10%) |
| Patients with vomiting | 2 (4%) | 7(15%) | 19(6%) | 21 (7%) |
| Patients with other reactions | 10(21%) | 13(28%) | 47(16%) | 69 (23%) |
| †Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). |
Cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin B-treated patients as summarized in the following table:
Incidence of Infusion Related Cardiorespiratory Events
| Event | L-Ampho Anfotericina B Biosano n=343 | Amphotericin B n=344 |
| Hypotension | 12 (3.5%) | 28 (8.1%) |
| Tachycardia | 8 (2.3%) | 43 (12.5%) |
| Hypertension | 8 (2.3%) | 39 (11.3%) |
| Vasodilatation | 18 (5.2%) | 2 (0.6%) |
| Dyspnea | 16 (4.7%) | 25 (7.3%) |
| Hyperventilation | 4(1.2%) | 17 (4.9%) |
| Hypoxia | 1 (0.3%) | 22 (6.4%) |
The percentage of patients who received drugs either for the treatment or prevention of infusion related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in L-Ampho Anfotericina B Biosano-treated patients compared with amphotericin B deoxycholate-treated patients.
In the empirical therapy study 97-0-034, on Day 1, where no premedication was administered, the overall incidence of infusion related events of chills/rigors was significantly lower for patients administered L-Ampho Anfotericina B Biosano compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each L-Ampho Anfotericina B Biosano group compared with the amphotericin B lipid complex group. The infusion related event hypoxia was reported for 11.5% of amphotericin B lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day L-Ampho Anfotericina B Biosano and 1.2% of patients treated with 5 mg/kg per day L-Ampho Anfotericina B Biosano.
Incidence of Day 1 Infusion Related Reactions (IRR) Chills/Rigors
Empirical Therapy Study 97-0-034
| L-Ampho Anfotericina B Biosano | Amphotericin B lipid complex 5 mg/kg/day | |||
| 3 mg/kg/day | 5 mg/kg/day | BOTH | ||
| Total number of patients | 85 | 81 | 166 | 78 |
| Patients with Chills/Rigors (Day1) | 16 (18.8%) | 19 (23.5%) | 35 (21.1%) | 62 (79.5%) |
| Patients with other notable reactions: Fever ( > 1.0°C increase in temperature) | ||||
| Nausea | 20 (23.5%) | 16(19.8%) | 36 (21.7%) | 45 (57.7%) |
| Vomiting | 9(10.6%) | 7 (8.6%) | 16 (9.6%) | 9(11.5%) |
| Hypertension | 5 (5.9%) | 5 (6.2%) | 10 (6%) | 11 (14.1%) |
| Tachycardia | 4 (4.7%) | 7 (8.6%) | 11 (6.6%) | 12(15.4%) |
| Dyspnea | 2 (2.4%) | 8 (9.9%) | 10(6%) | 14(17.9%) |
| Hypoxia | 4 (4.7%) | 8 (9.9%) | 12(7.2%) | 8(10.3%) |
| 0 | 1 (1.2%) | 1 ( < 1%) | 9(11.5%) | |
| Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). | ||||
Patients were not administered premedications to prevent infusion related reactions prior to the Day 1 study drug infusion.
In Study 94-0-013, a randomized double-blind multicenter trial comparing L-Ampho Anfotericina B Biosano and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion related reactions were permitted. L-Ampho Anfotericina B Biosano treated patients had a lower incidence of fever, chill/rigors and respiratory adverse events as summarized in the following table:
Incidence of Infusion-Related Reactions Study 94-0-013
| L-Ampho Anfotericina B Biosano 3 mg/kg | L-Ampho Anfotericina B Biosano 6 mg/kg | Amphotericin B | |
| Total number of patients receiving at least one dose of study drug | 86 | 94 | 87 |
| Patients with fever increase of > 1 °C | 6 (7%) | 8 (9%) | 24 (28%) |
| Patients with chills/rigors | 5 (6%) | 8 (9%) | 42 (48%) |
| Patients with nausea | 11 (13%) | 13(14%) | 18(20%) |
| Patients with vomiting | 14(16%) | 13(14%) | 16(18%) |
| Respiratory adverse events | 0 | 1 (1%) | 8 (9%) |
There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with L-Ampho Anfotericina B Biosano administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within a few minutes after the start of infusion and disappeared rapidly when the infusion was stopped. The symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed.
Toxicity and Discontinuation of Dosing
In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the L-Ampho Anfotericina B Biosano group compared with the amphotericin B group. In addition, nearly three times as many patients administered amphotericin B required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion related reaction compared with those administered L-Ampho Anfotericina B Biosano.
In empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin B lipid complex group discontinued the study drug due to an adverse event than in the L-Ampho Anfotericina B Biosano groups.
Less Common Adverse Events
The following adverse events also have been reported in 2% to 10% of L-Ampho Anfotericina B Biosano-treated patients receiving chemotherapy or bone marrow transplantation, or had HIV disease in six comparative, clinical trials:
Body as a Whole
Abdomen enlarged, allergic reaction, cellulitis, cell mediated immunological reaction, face edema, graft versus host disease, malaise, neck pain, and procedural complication.
Cardiovascular System
Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing).
Digestive System
Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease.
Hemic & Lymphatic System
Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia.
Metabolic & Nutritional Disorders
Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis.
Musculoskeletal System
Arthralgia, bone pain, dystonia, myalgia, and rigors.
Nervous System
Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor.
Respiratory System
Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis.
Skin & Appendages
Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash.
Special Senses
Conjunctivitis, dry eyes, and eye hemorrhage.
Urogenital System
Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage.
Post-marketing Experience
The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis.
Clinical Laboratory Values
The effect of L-Ampho Anfotericina B Biosano on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in Study 94-0-002. The frequency and magnitude of hepatic test abnormalities were similar in the L-Ampho Anfotericina B Biosano and amphotericin B groups. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values increasing 100% or more over pretreatment levels in adult patients provided the peak creatinine concentration was > 1.2 mg/dL. Hypokalemia was defined as potassium levels ≤ 2.5 mmol/L any time during treatment.
Incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and, incidence of hypokalemia in the double-blind randomized study were lower in the L-Ampho Anfotericina B Biosano group as summarized in the following table:
Study 94-0-002 Laboratory Evidence of Nephrotoxicity
| L-Ampho Anfotericina B Biosano | Amphotericin B | |
| Total number of patients receiving at least one dose of study drug | 343 | 344 |
| Nephrotoxicity | 64 (18.7%) | 116 (33.7%) |
| Mean peak creatinine | 1.24 mg/dL | 1.52 mg/dL |
| Mean change from baseline in creatinine | 0.48 mg/dL | 0.77 mg/dL |
| Hypokalemia | 23 (6.7%) | 40 (11.6%) |
The effect of L-Ampho Anfotericina B Biosano (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure:
In empirical therapy study 97-0-034, the incidence of nephrotoxicity as measured by increases of serum creatinine from baseline was significantly lower for patients administered L-Ampho Anfotericina B Biosano (individual dose groups and combined) compared with amphotericin B lipid complex.
Incidence of Nephrotoxicity
Empirical Therapy Study 97-0-034
| L-Ampho Anfotericina B Biosano | Amphotericin B lipid complex 5 mg/kg/day | |||
| 3 mg/kg/day | 5 mg/kg/day | BOTH | ||
| Total number of patients | 85 | 81 | 166 | 78 |
| Number with nephrotoxicity | ||||
| 1.5X baseline serum creatinine value | 25 (29.4%) | 21 (25.9%) | 46 (27.7%) | 49 (62.8%) |
| 2X baseline serum creatinine value | 12(14.1%) | 12(14.8%) | 24 (14.5%) | 33 (42.3%) |
Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of L-Ampho Anfotericina B Biosano® (amphotericin b) between 7-13 mg/kg. None of these patients had a serious acute reaction to L-Ampho Anfotericina B Biosano® (amphotericin b). If an overdose is suspected, discontinue therapy, monitor the patient's clinical status, and administer supportive therapy as required. L-Ampho Anfotericina B Biosano® (amphotericin b) is not hemodialyzable.
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. 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 L-Ampho Anfotericina B Biosano is known.
The toxicity of L-Ampho Anfotericina B Biosano due to overdose has not been defined. Repeated daily doses up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients have been administered in clinical trials with no reported dose-related toxicity.
Management
If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Particular attention should be given to monitoring renal function. Hemodialysis or peritoneal dialysis do not appear to significantly affect the elimination of L-Ampho Anfotericina B Biosano.
ATC Code
J02A A01
Mechanism of action
L-Ampho Anfotericina B Biosano, 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 L-Ampho Anfotericina B Biosano has greater affinity for fungal ergosterol than for the cholesterol of human cells.
Microbiological activity
L-Ampho Anfotericina B Biosano 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 L-Ampho Anfotericina B Biosano concentrations of 0.03-1.0 μg/ml. L-Ampho Anfotericina B Biosano has little or no activity against bacteria or viruses. The activity of Abelcet against fungal pathogens in vitro is comparable to that of L-Ampho Anfotericina B Biosano. However, activity of Abelcet in vitro may not predict activity in the infected host.
The assay used to measure amphotericin B in the blood after the administration of L-Ampho Anfotericina B Biosano® does not distinguish amphotericin B that is complexed with the phospholipids of L-Ampho Anfotericina B Biosano® from amphotericin B that is uncomplexed.
The pharmacokinetics of amphotericin B after the administration of L-Ampho Anfotericina B Biosano® (amphotericin b) are nonlinear. Volume of distribution and clearance from blood increase with increasing dose of L-Ampho Anfotericina B Biosano® (amphotericin b) , resulting in less than proportional increases in blood concentrations of amphotericin B over a dose range of 0.6-5 mg/kg/day. The pharmacokinetics of amphotericin B in whole blood after the administration of L-Ampho Anfotericina B Biosano® and amphotericin B desoxycholate are:
Pharmacokinetic Parameters of Amphotericin B in Whole Blood in Patients Administered Multiple Doses of L-Ampho Anfotericina B Biosano® or Amphotericin B Desoxycholate
| Pharmacokinetic Parameter | L-Ampho Anfotericina B Biosano® (amphotericin b) 5 mg/kg/day for 5-7 days Mean ± SD | Amphotericin B 0.6 mg/kg/day for 42 daysa Mean ± SD |
| Peak Concentration (µg/mL) | 1.7 ± 0.8 (n=10)b | 1.1 ± 0.2 (n=5) |
| Concentration at End of Dosing Interval (µg/mL) | 0.6 ± 0.3 (n=10)b | 0.4 ± 0.2 (n=5) |
| Area Under Blood Concentration-Time Curve (AUC0-24h) (ng*h/mL) | 14 ± 7 (n=14)b,c | 17.1 ± 5 (n=5) |
| Clearance (mL/h*kg) | 436 ± 188.5 (n=14)b,c | 38 ±15 (n=5) |
| Apparent Volume of Distribution (Vdarea) (L/kg) | 131 ± 57.7 (n=8)c | 5 ± 2.8 (n=5) |
| Terminal Elimination Half-Life (h) | 173.4 ± 78 (n=8)c | 91.1 ± 40.9 (n=5) |
| Amount Excreted in Urine Over 24 h After Last Dose (% of dose)d | 0.9 ± 0.4 (n=8)c | 9.6 ± 2.5 (n=8) |
| a Data from patients with mucocutaneous leishmaniasis. Infusion rate was 0.25 mg/kg/h. b Data from studies in patients with cytologically proven cancer being treated with chemotherapy or neutropenic patients with presumed or proven fungal infection. Infusion rate was 2.5 mg/kg/h. c Data from patients with mucocutaneous leishmaniasis. Infusion rate was 4 mg/kg/h. d Percentage of dose excreted in 24 hours after last dose. |
The large volume of distribution and high clearance from blood of amphotericin B after the admistration of L-Ampho Anfotericina B Biosano® (amphotericin b) probably reflect uptake by tissues. The long terminal elimination half-life probably reflects a slow redistribution from tissues. Although amphotericin B is excreted slowly, there is little accumulation in the blood after repeated dosing. AUC of amphotericin B increased approximately 34% from day 1 after the administration of L-Ampho Anfotericina B Biosano® (amphotericin b) 5 mg/kg/day for 7 days. The effect of gender or ethnicity on the pharmacokinetics of L-Ampho Anfotericina B Biosano® (amphotericin b) has not been studied.
Tissue concentrations of amphotericin B have been obtained at autopsy from one heart transplant patient who received three doses of L-Ampho Anfotericina B Biosano® (amphotericin b) at 5.3 mg/kg/day:
Concentration in Human Tissues
| Organ | Amphotericin B Tissue Concentration (µg/g) |
| Spleen | 290 |
| Lung | 222 |
| Liver | 196 |
| Lymph Node | 7.6 |
| Kidney | 6.9 |
| Heart | 5 |
| Brain | 1.6 |
This pattern of distribution is consistent with that observed in preclinical studies in dogs in which greatest concentrations of amphotericin B after L-Ampho Anfotericina B Biosano® (amphotericin b) administration were observed in the liver, spleen, and lung; however, the relationship of tissue concentrations of amphotericin B to its biological activity when administered as L-Ampho Anfotericina B Biosano® (amphotericin b) is unknown.
L-Ampho Anfotericina B Biosano is complexed to phospholipids in Abelcet. The pharmacokinetic properties of Abelcet and conventional L-Ampho Anfotericina B Biosano are different. Pharmacokinetic studies in animals showed that, after administration of Abelcet, L-Ampho Anfotericina B Biosano levels were highest in the liver, spleen and lung. L-Ampho Anfotericina B Biosano in Abelcet was rapidly distributed to tissues. The ratio of drug concentrations in tissues to those in blood increased disproportionately with increasing dose, suggesting that elimination of the drug from the tissues was delayed. Peak blood levels of L-Ampho Anfotericina B Biosano were lower after administration of Abelcet than after administration of equivalent amounts of conventional drug. Administration of conventional L-Ampho Anfotericina B Biosano resulted in much lower tissue levels than did dosing with Abelcet. However, in dogs, conventional L-Ampho Anfotericina B Biosano produced 20-fold higher kidney concentrations than did Abelcet given at comparable doses.
The pharmacokinetics of Abelcet in whole blood were determined in patients with mucocutaneous leishmaniasis. Results for mean pharmacokinetic parameters at 5.0 mg/kg/day were as follows:
|
| Abelcet |
| Dose: (mg/kg/day) | 5.0 |
| Peak blood level Cmax: (μg/ml) | 1.7 |
| Area under time-concentration curve AUC0-24: (μg.hr/ml) | 9.5 |
| Clearance: (ml/hr.kg) | 211.0 |
| Volume of distribution Vd: (l/kg) | 2286.0 |
| Half-life T½: (hr) | 173.4 |
The rapid clearance and large volume of distribution of Abelcet result in a relatively low AUC and are consistent with preclinical data showing high tissue concentrations. The kinetics of Abelcet are linear, the AUC increases proportionately with dose.
Details of the tissue distribution and metabolism of Abelcet in humans, and the mechanisms responsible for reduced toxicity, are not well understood. The following data are available from necropsy in a heart transplant patient who received Abelcet at a dose of 5.3 mg/kg for 3 consecutive days immediately before death:
| Organ | Abelcet tissue concentration expressed as L-Ampho Anfotericina B Biosano content (mg/kg) |
| Spleen | 290.0 |
| Lung | 222.0 |
| Liver | 196.0 |
| Kidney | 6.9 |
| Lymph node | 7.6 |
| Heart | 5.0 |
| Brain | 1.6 |
The assay used to measure amphotericin B in the serum after administration of L-Ampho Anfotericina B Biosano does not distinguish amphotericin B that is complexed with the phospholipids of L-Ampho Anfotericina B Biosano from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of L-Ampho Anfotericina B Biosano is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin B was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of 1 to 5 mg/kg/day L-Ampho Anfotericina B Biosano for 3 to 20 days.
The pharmacokinetics of amphotericin B after administration of L-Ampho Anfotericina B Biosano is nonlinear such that there is a greater than proportional increase in serum concentrations with an increase in dose from 1 to 5 mg/kg/day. The pharmacokinetic parameters of total amphotericin B (mean ± SD) after the first dose and at steady state are shown in the table below.
Pharmacokinetic Parameters of L-Ampho Anfotericina B Biosano
| Dose (mg/kg/day): | 1 | 2.5 | 5 | |||
| Day | 1 n = 8 | Last n = 7 | 1 n = 7 | Last n = 7 | 1 n = 12 | Last n = 9 |
| Parameters | ||||||
| Cmax (mcg/mL) | 7.3 ± 3.8 | 12.2 ±4.9 | 17.2 ±7.1 | 31.4 ±17.8 | 57.6 ±21 | 83 ± 35.2 |
| AUC0-24 (mcg»hr/mL) | 27 ±14 | 60 ±20 | 65 ±33 | 197 ±183 | 269 ± 96 | 555 ± 31 1 |
| t1/2 (hr) | 10.7 ±6.4 | 7 ±2.1 | 8.1 ±2.3 | 6.3 ±2 | 6.4 ±2.1 | 6.8 ±2.1 |
| Vss (L/kg) | 0.44 ± 0.27 | 0.14 ±0.05 | 0.40 ± 0.37 | 0.16 ±0.09 | 0.16±0.10 | 0.10 ±0.07 |
| Cl (mL/hr/kg) | 39 ±22 | 17±6 | 51 ±44 | 22 ±15 | 21 ±14 | 11 ±6 |
Distribution
Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of L-Ampho Anfotericina B Biosano, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of L-Ampho Anfotericina B Biosano, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably a slow redistribution from tissues. Steady state concentrations were generally achieved within 4 days of dosing.
Although variable, mean trough concentrations of amphotericin B remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum.
Metabolism
The metabolic pathways of amphotericin B after administration of L-Ampho Anfotericina B Biosano are not known.
Excretion
The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of L-Ampho Anfotericina B Biosano has not been studied.
Acute toxicity studies in rodents showed that Abelcet was 10-fold to 20-fold less toxic than conventional L-Ampho Anfotericina B Biosano. Multiple-dose toxicity studies in dogs lasting 2-4 weeks showed that on a mg/kg basis, Abelcet was 8-fold to 10-fold less nephrotoxic than conventional L-Ampho Anfotericina B Biosano. This decreased nephrotoxicity was presumably a result of lower drug concentrations in the kidney.
Since conventional L-Ampho Anfotericina B Biosano first became available, there have been no reports of drug-related carcinogenicity, mutagenicity, teratogenicity or adverse effect on fertility. Abelcet has been shown not to be mutagenic by the in vivo mouse micronucleus assay, in vitro bacterial and lymphoma mutation assays, and an in vivo cytogenetic assay. It has been shown not to be teratogenic in mice and rabbits.
Phospholipids are essential constituents of human cell membranes. The average diet provides several grams of phospholipids each day. There is no evidence that phospholipids, including DMPC and DMPG, are carcinogenic, mutagenic or teratogenic.
Abelcet should not be mixed with other drugs or electrolytes.
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 20 ml 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 1 mg/ml. For paediatric patients and patients with cardiovascular disease the drug may be diluted with 5.0% Dextrose for Injection to a final infusion concentration of 2 mg/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.
