INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo EXOMAX (Intravenous Infusion)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form)

EXOMAX (Intravenous Infusion)

COMPOSITION:
Each 100 mL of the intravenous infusion contains 200,00 mg of
fluconazole.

PHARMACOLOGICAL CLASSIFICATION
A 20.2.2 Antimicrobial (chemotherapeutic) agents. Fungicides.

PHARMACOLOGICAL ACTION
Fluconazole is a triazole antifungal agent. Fluconazole exerts its antifungal effect by inhibition of sterol 14-alpha-demethylase impairing the biosynthesis of ergosterol, the principal sterol in the fungal cell membrane. This damages the cell membrane, producing alterations in membrane function and permeability.
Pharmacokinetics
Fluconazole is well absorbed after oral administration. Oral bioavailability is more than 90%. Oral bioavailability is not altered by foods or gastric acidity. The time to peak plasma concentrations is 1 to 2 hours. Protein binding is low (12%). The elimination half-life in adults is approximately 30 hours and is increased in patients with impaired renal function. Fluconazole is primarily excreted by the kidneys. Approximately 80% of the dose is excreted unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. However, accumulation is significant over 15 days and concentrations may rise 2 to 3 fold. A small amount of fluconazole undergoes hepatic metabolism. Fluconazole is cleared from the body faster in children than in adults. The half-life in children is 23 hours. During the first 2 weeks of life the half-life is approximately 74 hours on day one and 47 hours on day 13.

INDICATIONS
Once the results of the cultures and other laboratory studies become available, anti-infective therapy should be adjusted.
EXOMAX is indicated for the treatment of the following conditions in adults:
Cryptococcal meningitis in mentally alert patients without localising neurological signs and as a follow up therapy after amphotericin B therapy
Maintenance therapy to prevent relapse of cryptococcal disease in patients with acquired immunodeficiency syndrome (AIDS)
Systemic candidiasis
Oropharyngeal and oesophageal candidiasis
Prophylaxis of fungal infections in patients receiving cytotoxic chemotherapy and/or radiation therapy
Vaginal candidiasis - Acute or recurrent infections and as prophylaxis to reduce the incidence of recurrent infections
Candidial balanitis
Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis) and dermal candida infections

EXOMAX is indicated for the treatment of the following conditions in children:
Cryptococcal meningitis in mentally alert patients without localising neurological signs and as a follow up therapy after amphotericin B therapy
Maintenance therapy to prevent relapse of cryptococcal disease in patients with acquired immunodeficiency syndrome (AIDS)
Systemic candidiasis
Oropharyngeal and oesophageal candidiasis
Prophylaxis of candidiasis in patients receiving cytotoxic chemotherapy and/or radiation therapy

CONTRA-INDICATIONS
Hypersensitivity to EXOMAX, other azole antifungal agents or to any of the excipients.
Co-administration of terfenadine in patients receiving multiple doses of EXOMAX in doses of 400 mg per day or greater (see INTERACTIONS).
Co-administration of cisapride (see INTERACTIONS).
Pregnancy and lactation (see PREGNANCY AND LACTATION).
Multiple dose therapy is contra-indicated in patients with renal impairment
Concurrent use with astemizole should be avoided


WARNINGS
EXOMAX has been associated with cases of serious hepatotoxicity, including fatalities related to dose and duration of use, primarily in patients with serious underlying medical conditions. Hepatotoxicity may be reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during EXOMAX therapy should be monitored for the development of more serious hepatic injury. EXOMAX should be discontinued if clinical signs or symptoms consistent with the liver disease develop that may be attributable to EXOMAX.
Patients have less frequently developed pruritus, rashes, urticaria, angioedema, dry skin, abnormal odour, exfoliative cutaneous reactions such as Steven-Johnson Syndrome and toxic epidermal necrolysis during treatment with EXOMAX. AIDS patients are more prone to the development of severe cutaneous reaction to many medicines. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and EXOMAX discontinued if bullous lesions or erythema multiforme develop.

INTERACTIONS
EXOMAX may interfere with the metabolism of some medicines if given concomitantly, mainly through inhibition of the cytochrome P450 isoenzymes CYP3A4 and CYP2C9. Co-administration of EXOMAX and medicines metabolised by cytochrome P450 can result in increased serum concentrations of the medicines metabolised by the same enzyme system.
EXOMAX increases plasma concentrations of the following medicines when given concomitantly:
Warfarin - Anticoagulant effects are increased, resulting in an increase in prothrombin time/INT ratio. Monitoring of the prothrombin time is required and adjustment of the warfarin dose may be necessary.
Sulfonylurea hypoglycaemics - The plasma concentration of these agents may be increased and hypoglycaemia can result. Blood glucose concentrations should be monitored and the dose of the sulfonylurea may need to be reduced.
Phenytoin - Decreased metabolism of phenytoin, resulting in increased plasma concentrations and possible phenytoin toxicity.
Theophylline - Decreased clearance of theophylline which leads to increased theophylline plasma concentrations and possibly toxicity. Theophylline concentrations should be monitored.
Zidovudine - Increased plasma concentrations of zidovudine. Patients should be monitored for zidovudine related adverse effects.
Terfenadine - The concurrent use of terfenadine and doses of 400 mg of more of EXOMAX is contra-indicated. If co-administration of terfenadine and EXOMAX at doses less than 400 mg is considered essential, terfenadine concentrations should be closely monitored (see CONTRA-INDICATIONS).
Astemizole has also been reported to interact with EXOMAX and concurrent use should be avoided (see CONTRA-INDICATIONS).
Cisapride - The concomitant administration of EXOMAX with cisapride is contra-indicated because of the possible increase in serum cisapride concentrations which can increase the risk of serious and life-threatening cardiac arrhythmias including torsade de pointes (see CONTRA-INDICATIONS).
Cyclosporine - Clinically significant rises in cyclosporine serum concentrations of two to threefold have been observed in some patients when given fluconazole. Therefore cyclosporine plasma concentrations should be monitored in all patients receiving EXOMAX.
Midazolam and triazolam - EXOMAX increases the serum concentrations of midazolam and triazolam and their psychomotor effects. This effect appears to be more pronounced following oral administration of EXOMAX than with EXOMAX administered intravenously. If these medicines are to be used concurrently a reduced dose of the benzodiazepine may be necessary and the patient should be monitored.
Rifabutin - Increase in serum concentration of rifabutin which carries an increased risk of uveitis. Patients on this combination need to be carefully monitored.
Tacrolimus - Tacrolimus concentrations are considerably increased by EXOMAX. Patients on this combination need to have serum concentrations of tacrolimus be monitored and dose reduction is necessary.
The following medicine increases plasma concentrations of EXOMAX when given concomitantly:

•        Hydrochlorothiazide.

The following medicine decreases plasma concentrations of EXOMAX when given concomitantly:

•        Rifampicin - Increased metabolism of EXOMAX, resulting in lower plasma concentrations of EXOMAX.

Other information on interactions
Co-administration of fluconazole and nevirapine resulted in approximately 100% increase in nevirapine exposure as compared with historical data where nevirapine was administered alone. Because of the risk of increased exposure to nevirapine, caution should be exercised if nevirapine and EXOMAX are given concomitantly and patients should be monitored closely.

PREGNANCY AND LACTATION
The use of EXOMAX during pregnancy has resulted in congenital malformations and should be avoided (see CONTRA-INDICATIONS).
EXOMAX should not be given to breast-feeding women (see CONTRA-INDICATIONS).
EXOMAX is distributed into the breast milk at concentrations similar to those in plasma.

DOSAGE AND DIRECTIONS FOR USE
Cryptococcal meningitis
Adults: Initial dose is 400 mg on the first day; followed by 200 mg to 400 mg daily depending on the clinical response. Duration of therapy is based on clinical mycological response, but is usually 8 weeks, following amphotericin B therapy and 10 weeks with EXOMAX monotherapy.
Children over 4 weeks of age: 6 mg/kg/day to 12 mg/kg/day depending on the severity of the infection.
Maintenance therapy to prevent relapse of cryptococcal meningitis in patients with AIDS
Adults: 100 mg to 200 mg per day.
Systemic candidiasis
Adults: Initial dose is 400 mg on the first day; followed by 200 mg. The dose may be increased to 400 mg daily depending on the clinical response.
Children over 4 weeks of age: 6 mg/kg/day to 12 mg/kg/day depending on the severity of the infection.
Duration of therapy is based on clinical and mycological response.
Oropharyngeal candidiasis
Adults: 50 mg to 100 mg daily for 7 to 14 days. Severely immune compromised patients may require longer treatment periods.
To prevent relapse in AIDS patients: 150 mg of EXOMAX may be given once a week.
Children over 4 weeks of age: Initial dose is 6 mg/kg on the first day; followed by 3 mg/kg once daily. Duration of treatment is at least 2 weeks to decrease the risk of relapse.
Oesophageal candidiasis
Adults: Initial dose is 200 mg in the first day; followed by 100 mg to 200 mg daily. Doses up to 400 mg once a day may be used if there is no clinical response after 14 days on the lower dose. Duration of treatment is at least 3 weeks and for an additional 2 weeks after symptoms have resolved.
Children over 4 weeks of age: Initial dose is 6 mg/kg on the first day; followed by 3 mg/kg once daily. Dose may be increased to 12 mg/kg/day based on the condition of the patient and the response to the medicine. Duration of treatment is for at least 3 weeks and for an additional 2 weeks after the symptoms have resolved.
Prophylaxis of fungal infections in patients who receive cytotoxic chemotherapy and/or radiation therapy
Adults: 50 mg to 400 mg daily depending on the patients risk for developing fungal infections. Treatment should be started several days before the onset of neutropenia is expected and continued for 7 days after the neutrophil count rises above 1000 cells per mm3.
Children over 4 weeks of age: 3 to 12 mg/kg/day depending on the extent and duration of the induced neutropenia.
Vaginal candidiasis
Adults: 150 mg administered as a single dose.
Recurrent vaginal candidiasis
Adults: 150 mg administered as a single dose, once a month. The duration of therapy is individualised but ranges from 4 to 12 months.
Candida balanitis
Adults: 150 mg administered as a single dose.
Dermal Infections including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis) and dermal candida infections
Adults: 150 mg administered as a single dose once a week. Duration of treatment is usually 2 to 4 weeks but tinea pedis may require up to 6 weeks of treatment. For tinea unguium treatment should continue until the infected nail grows out and is replaced with an uninfected nail. Fingernails generally require 3 to 6 months to re-grow and toenails 6 to 12 months.

Safety and efficacy of EXOMAX in children has not been established for the following indications:
Recurrent vaginal candidiasis, candida balanitis dermal infections including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis) and dermal candida infections.
Elderly: See dosage in renal failure.
Normal dosage recommendations are used in the elderly unless the patient has decreased renal function, in which case an adjustment in dosage or dosing interval is required.

Dosage in renal failure
EXOMAX should be used with caution in patients with renal function impairment. EXOMAX is excreted through the kidneys. A dosage reduction or increase in dosing interval is recommended:
1. The normal loading dose or the initial dose should be given on the first day of treatment.
2. Subsequent doses should be adjusted according to the creatinine clearance.
If creatinine clearance is >50 mL/min the normal dose can be given.
If creatinine clearance is <50 mL/min and patient is not receiving dialysis, 50% of the normal dose can be given.
Patients on regular haemodialysis should receive a standard dose of EXOMAX after each dialysis session.
The patient’s creatinine clearance (Ccr) can be estimated by using the following formula:
Ccr male = Weight (kg) x (140 –age)
  72 x (plasma creatinine (micromol/litre)

Ccr female = 0,85 x Weight (kg) x (140 –age)
  72 x (plasma creatinine (micromol/litre)

The pharmacokinetics of EXOMAX has not been studied in children with impaired renal function. Recommendations for dosage reduction in such children should parallel the recommendations for adults.
The dose of EXOMAX and the duration of treatment should be based on the site of infection and the individual’s response to therapy.
Treatment should be continued until clinical parameters and laboratory tests indicate that active fungal infection has subsided.
AIDS patients with cryptococcal meningitis or recurrent oropharyngeal candidiasis require maintenance therapy to prevent relapse.
For infants under 2 weeks of age the above children’s doses should be used, but only given once every 72 hours.

For those aged between 2 and 4 weeks the dose should be given every 48 hours. The maximum adult daily dose (i.e. 400 mg) should not be exceeded in children.
Normal dosage recommendations are used in the elderly population unless the patient has decreased renal function. In which case an adjustment in dosage or dosing interval is required.
Intravenous Infusion
EXOMAX is formulated in 0,9% sodium chloride solution, each 200 mg (100 mL bottle or bag) containing 15 mmol each of sodium and chloride ions.
Because EXOMAX is available as a dilute saline solution, consideration should be given to the rate of fluid administration in patients requiring sodium or fluid restriction.
EXOMAX is compatible with the following administration fluids:
Dextrose 20%
Ringer’s solution
Normal saline
Potassium chloride in dextrose
Sodium bicarbonate 4,2%
EXOMAX may be infused at a maximum rate of approximately 200 mg/hour through an existing line with one of the above listed fluids. Although no specific incompatibilities have been noted, mixing with any other drug prior to infusion is not recommended.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Haematological
Less frequent: Leucopoenia, neutropenia, agranulocytosis and thrombocytopenia.
Central nervous system
Frequent: Headache.
Less frequent: Dizziness, vertigo, seizures, insomnia, nervousness, fatigue, rigors, malaise, hyperkinesia.
Endocrine/Metabolic
Less frequent: Hypokalaemia, hypercholesterolaemia, hypertriglyceridaemia.
Gastro-intestinal
Frequent: Nausea, vomiting, abdominal pain, diarrhoea, flatulence.
Less frequent: Taste perversion, dyspepsia, thirst.
Kidney/Genitourinary
Less frequent: Female sexual dysfunction, intermenstrual bleeding, menorrhagia, leukorrhoea, polyuria.
Liver
Frequent: Hepatotoxicity (including elevated serum concentrations of alkaline phosphatase, bilirubin, ALT and AST).
Less frequent: Hepatic failure, hepatitis, hepatocellular necrosis, jaundice.
Musculoskeletal
Less frequent: Hypertonia.
Ocular
Less frequent: Abnormal vision.
Skin
Frequent: Rash.
Less frequent: Alopecia, urticaria, dry skin, abnormal odour, exfoliative cutaneous reactions such as Steven-Johnson Syndrome and toxic epidermal necrolysis.
Other
Less frequent: Anaphylaxis, (including angio-oedema, facial oedema, pruritus), flushing.
Special precautions
Liver function should be monitored periodically in all patients receiving continuous treatment with EXOMAX for more than one month or when a patient develops signs or symptoms suggestive of liver dysfunction. EXOMAX should be discontinued if abnormalities in enzyme values persist, worsen or if they are accompanied by symptoms of hepatotoxicity.
EXOMAX should be used with caution in patients with underlying disease such as AIDS or malignancy. Abnormalities in haematological, hepatic and renal function have been observed.

KNOWN SYMPTOMS FOR OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE EFFECTS AND SPECIAL PRECAUTIONS).
Symptoms of overdose: The following have been reported with an overdose of EXOMAX: Insomnia, irritability, vomiting, diarrhoea, abdominal pains/cramps, anorexia, bulging fontanel, elevation of alkaline phosphates and gamma glutamyl transpeptidases, increase in serum calcium, renal failure, fatigue, facial rash, skin erythema, generalised urticaria, arthralgia, itching, numbness of the tongue and depressed mood.
Treatment of overdose: Treatment is symptomatic and supportive. There is no specific antidote.
EXOMAX is largely excreted in the urine. Forced diuresis may increase the elimination rate.
Elimination of EXOMAX can be facilitated by haemodialysis. The concentration of EXOMAX can be decreased by about 50% by a three hour haemodialysis session.

IDENTIFICATION
EXOMAX Intravenous Infusion is a clear and almost colourless solution, practically free from visible particles on visual examination of the contents.

PRESENTATION
EXOMAX Intravenous Infusion is packed into a 100 mL clear glass bottle (USP Type I), with a grey siliconized rubber stopper and a navy blue flip-off seal. The glass bottle is packed in an outer carton.
OR
EXOMAX Intravenous Infusion is available in 100 mL clear, colourless PPP 200 INFU 9 bags with a connecting port and an additional port on one side with provision for the bag to hang at the other side. The bag is vacuum packed in an outer aluminium pouch.

STORAGE CONDITIONS
Store below 25ºC.
Do not freeze. For single use only. Discard any remaining contents after use.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
A40/20.2.2/0115

NAME AND BUSINESS ADDRESS OF HOLDER OF THE REGISTRATION CERTIFICATE
Pharmaplan (Pty) Ltd
106 16th Road
Midrand

DATE OF PUBLICATION OF PACKAGE INSERT
16 August 2005

New addition to this site: May 2014
Source: Pharmaceutical Industry

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