Essentiale Forte

Essentiale Forte® (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 Essentiale Forte or other systemic antifungal agents, in those who have renal impairment or other contra-indications to conventional Essentiale Forte, or in patients who have developed Essentiale Forte 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.

Essentiale Forte 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 Essentiale Forte, 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. Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (amphotericin b) with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of Essentiale Forte® (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 Essentiale Forte 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.

Essentiale Forte 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 Essentiale Forte; 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 Essentiale Forte. If this is not feasible, Essentiale Forte 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 Essentiale Forte for each indication for adult and pediatric patients is as follows:

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:

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 Essentiale Forte must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of Essentiale Forte containing 50 mg of amphotericin B are prepared as follows:

Reconstitution

1. Aseptically add 12 mL of Sterile Water for Injection, USP to each Essentiale Forte 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 Essentiale Forte.
2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the Essentiale Forte. Essentiale Forte 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) Essentiale Forte to be further diluted.

4. Withdraw this amount of reconstituted Essentiale Forte 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 Essentiale Forte.)

6. Essentiale Forte 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 Essentiale Forte

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 Essentiale Forte should commence within 6 hours of dilution with 5% Dextrose Injection.

As with all parenteral drug products, the reconstituted Essentiale Forte 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 Essentiale Forte or in the materials specified for reconstitution and dilution.

Essentiale Forte® (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.

Essentiale Forte 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 Essentiale Forte® (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 Essentiale Forte® (amphotericin b).

PRECAUTIONS

General

As with any amphotericin B-containing product, during the initial dosing of Essentiale Forte® (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 Essentiale Forte® (amphotericin b). These reactions are usually more common with the first few doses of Essentiale Forte® (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 Essentiale Forte® 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 Essentiale Forte® (amphotericin b). The following in vitro (with and without metabolic activation) and in vivo studies to assess Essentiale Forte® (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. Essentiale Forte® (amphotericin b) was found to be without mutagenic effects in all assay systems. Studies demonstrated that Essentiale Forte® (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 Essentiale Forte® (amphotericin b). Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of Essentiale Forte® (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, Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of Essentiale Forte.

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. Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte. Essentiale Forte 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). Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte had no teratogenic potential in these species. In rats, the maternal non-toxic dose of Essentiale Forte 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 Essentiale Forte experienced a higher rate of spontaneous abortions than did the control groups. Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte. In studies which included 302 pediatric patients administered Essentiale Forte, there was no evidence of any differences in efficacy or safety of Essentiale Forte compared to adults. Since pediatric patients have received Essentiale Forte 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 Essentiale Forte in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of Essentiale Forte for this population. As with most other drugs, elderly patients receiving Essentiale Forte should be carefully monitored.

The total safety data base is composed of 921 patients treated with Essentiale Forte® (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 Essentiale Forte® (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 Essentiale Forte® (amphotericin b) were transient chills and/or fever during infusion of the drug.

Adverse Events^a with an Incidence of ≥ 3% (N=556)

The following adverse events have also been reported in patients using Essentiale Forte® (amphotericin b) in open-label, uncontrolled clinical studies. The causal association between these adverse events and Essentiale Forte® (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 Essentiale Forte treatment, had renal impairment as a result of previous conventional Essentiale Forte 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).

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 Essentiale Forte may occur with Abelcet. In general, the physician should monitor the patient for any type of adverse event associated with conventional Essentiale Forte.

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 Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with Essentiale Forte and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. Essentiale Forte and amphotericin B were infused over two hours.

The incidence of common adverse events (incidence of 10% or greater) occurring with Essentiale Forte 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

Essentiale Forte was well tolerated. Essentiale Forte 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, Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte 3 mg/kg, 81 patients were treated with Essentiale Forte 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. Essentiale Forte 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

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 Essentiale Forte 3 mg/kg, 94 patients were treated with Essentiale Forte 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

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). Essentiale Forte-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

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

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 Essentiale Forte-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 Essentiale Forte compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each Essentiale Forte 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 Essentiale Forte and 1.2% of patients treated with 5 mg/kg per day Essentiale Forte.

Incidence of Day 1 Infusion Related Reactions (IRR) Chills/Rigors
Empirical Therapy Study 97-0-034

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 Essentiale Forte and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion related reactions were permitted. Essentiale Forte 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

There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte.

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 Essentiale Forte groups.

Less Common Adverse Events

The following adverse events also have been reported in 2% to 10% of Essentiale Forte-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 Essentiale Forte 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 Essentiale Forte 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 Essentiale Forte group as summarized in the following table:

Study 94-0-002 Laboratory Evidence of Nephrotoxicity

The effect of Essentiale Forte (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 Essentiale Forte (individual dose groups and combined) compared with amphotericin B lipid complex.

Incidence of Nephrotoxicity
Empirical Therapy Study 97-0-034

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 Essentiale Forte® (amphotericin b) between 7-13 mg/kg. None of these patients had a serious acute reaction to Essentiale Forte® (amphotericin b). If an overdose is suspected, discontinue therapy, monitor the patient's clinical status, and administer supportive therapy as required. Essentiale Forte® (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 Essentiale Forte is known.

The toxicity of Essentiale Forte 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 Essentiale Forte.

The assay used to measure amphotericin B in the blood after the administration of Essentiale Forte® does not distinguish amphotericin B that is complexed with the phospholipids of Essentiale Forte® from amphotericin B that is uncomplexed.

The pharmacokinetics of amphotericin B after the administration of Essentiale Forte® (amphotericin b) are nonlinear. Volume of distribution and clearance from blood increase with increasing dose of Essentiale Forte® (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 Essentiale Forte® and amphotericin B desoxycholate are:

Pharmacokinetic Parameters of Amphotericin B in Whole Blood in Patients Administered Multiple Doses of Essentiale Forte® or Amphotericin B Desoxycholate

The large volume of distribution and high clearance from blood of amphotericin B after the admistration of Essentiale Forte® (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 Essentiale Forte® (amphotericin b) 5 mg/kg/day for 7 days. The effect of gender or ethnicity on the pharmacokinetics of Essentiale Forte® (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 Essentiale Forte® (amphotericin b) at 5.3 mg/kg/day:

Concentration in Human Tissues

This pattern of distribution is consistent with that observed in preclinical studies in dogs in which greatest concentrations of amphotericin B after Essentiale Forte® (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 Essentiale Forte® (amphotericin b) is unknown.

Essentiale Forte is complexed to phospholipids in Abelcet. The pharmacokinetic properties of Abelcet and conventional Essentiale Forte are different. Pharmacokinetic studies in animals showed that, after administration of Abelcet, Essentiale Forte levels were highest in the liver, spleen and lung. Essentiale Forte 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 Essentiale Forte were lower after administration of Abelcet than after administration of equivalent amounts of conventional drug. Administration of conventional Essentiale Forte resulted in much lower tissue levels than did dosing with Abelcet. However, in dogs, conventional Essentiale Forte 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:

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:

The assay used to measure amphotericin B in the serum after administration of Essentiale Forte does not distinguish amphotericin B that is complexed with the phospholipids of Essentiale Forte from amphotericin B that is uncomplexed. The pharmacokinetic profile of amphotericin B after administration of Essentiale Forte 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 Essentiale Forte for 3 to 20 days.

The pharmacokinetics of amphotericin B after administration of Essentiale Forte 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 Essentiale Forte

Distribution

Based on total amphotericin B concentrations measured within a dosing interval (24 hours) after administration of Essentiale Forte, the mean half-life was 7-10 hours. However, based on total amphotericin B concentration measured up to 49 days after dosing of Essentiale Forte, 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 Essentiale Forte are not known.

Excretion

The mean clearance at steady state was independent of dose. The excretion of amphotericin B after administration of Essentiale Forte has not been studied.