Diflucan 50 mg/150 mg/200 mg/5 mL Capsules

Once the results of cultures and other laboratory studies become available, anti-infective therapy should be adjusted accordingly. DIFLUCAN is indicated for the treatment of the following conditions in adults and 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
• Prevention of fungal infections in patients with malignancy who are predisposed to such infections as a result of cytotoxic chemotherapy and radiotherapy

When systemic treatment is indicated and appropriate, DIFLUCAN 150 mg capsules is used in adults for the following conditions:

• Vaginal candidiasis, acute or recurrent and prophylaxis to reduce the incidence of recurrent vaginal candidiasis
• Candidial balanitis
• Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis), and dermal Candida infections

Posology

The daily dose of DIFLUCAN should be based on the nature and severity of the fungal infection. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.

Use in adults

1. For cryptococcal meningitis the usual dose is 400 mg on the first day followed by 200 mg once daily. Depending on the clinical response of the patient this dose may be increased to 400 mg daily. Usually, duration of treatment for cryptococcal meningitis is 6 to 8 weeks. For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, DIFLUCAN may be administered at a daily dose of 100 mg to 200 mg until the CD4 count has stabilised at more than 250 cells/mm3.
2. For systemic candidiasis, the usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response, the dose may be increased to 400 mg daily. Duration of treatment is based upon the clinical response.
3. For oropharyngeal candidiasis, the usual dose is 50 mg to 100 mg once daily for 7 to 14 days. If necessary, treatment can be continued for longer periods in patients with severely compromised immune function. For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the patient receives a full course of primary therapy, DIFLUCAN may be administered at a 150 mg once weekly dose. For oesophageal candidiasis, the recommended dose is 200 mg on the first day, followed by 100 mg to 200 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patientu2019s response to therapy. Patients with oesophageal candidiasis should be treated for a minimum of 3 weeks and for at least 2 weeks following resolution of symptoms.
4. The recommended DIFLUCAN dosage for the prevention of candidiasis is 50 mg to 400 mg once daily, based on the patientu2019s risk for developing fungal infection. For patients at high risk of systemic infection e.g. patients who are anticipated to have profound or prolonged neutropenia, a dose of 400 mg once daily has been used. DIFLUCAN administration should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1 000 cells per mm3.
5. DIFLUCAN 150 mg capsules For vaginal candidiasis DIFLUCAN 150 mg should be administered as a single oral dose. To reduce the incidence of recurrent vaginal candidiasis, a 150 mg once monthly dose may be used. The duration of therapy should be individualised but ranges from 4 to 12 months. Some patients may require more frequent dosing. For Candida balanitis, DIFLUCAN 150 mg should be administered as a single oral dose. For dermal infections including tinea pedis, corporis, cruris and Candida infections the recommended dosage is 150 mg once weekly. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. For tinea unguium, the recommended dosage is 150 mg once weekly. Treatment should be continued until infected nail is replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally require 3 to 6 months and 6 to 12 months, respectively. However, growth rates may vary widely in individuals and by age. After successful treatment of long-term chronic infections, nails occasionally remain disfigured.

Special populations

Use in elderly patients Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For patients with renal impairment (creatinine clearance < 50 mL/min) the dosage schedule should be adjusted as described below.

Use in patients with impaired renal function DIFLUCAN is cleared primarily by renal excretion as unchanged medicine. No adjustments in single dose therapy are necessary. Multiple-dose therapy should be carefully monitored in patients with renal impairment. In patients (including children) with impaired renal function, an initial dose of 50 mg to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:

Creatinine clearance (mL/min) DIFLUCAN Percent of recommended dose

• > 50 100 %
• < 50 (no dialysis) 50 %
• Haemodialysis 100 % after each haemodialysis

Patients on haemodialysis should receive 100 % of the recommended dose after each haemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance. These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance:

Males: [140 u2013 age] x Wt (kg) x constant Scr (mmol/L) Constant = 1,23 for males

Females: [140 u2013 age] x Wt (kg) x constant Scr (mmol/L) Constant = 1,04 for females (0,85 x 1,23 = 1,04) Scr = serum creatinine

Paediatric population As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum adult daily dosage should not be exceeded in children. DIFLUCAN is administered as a single daily dose.

1. The recommended dosage of DIFLUCAN for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.
2. For the treatment of oesophageal candidiasis, the recommended dosage of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patientu2019s response to therapy. Patients with oesophageal candidiasis should be treated for a minimum of 3 weeks and for at least 2 weeks following the resolution of symptoms.
3. For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6 mg/kg/day u2013 12 mg/kg/day, depending on the severity of the disease.
4. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 mg/kg/day u2013 12 mg/kg daily, depending on the extent and duration of the induced neutropenia.

For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults, dependent on the degree of renal impairment.

Use in children 4 weeks of age and younger Neonates excrete DIFLUCAN slowly. In the first 2 weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 and 4 of life the same dose should be given every 48 hours.

Method of administration

DIFLUCAN capsules For oral use. DIFLUCAN IV infusion For intravenous infusion. DIFLUCAN may be infused at a maximum rate of approximately 200 mg/hour through an existing line with one of the fluids listed in section 6.6. DIFLUCAN IV infusion is formulated in 0,9 % sodium chloride solution, each 200 mg (100 mL bottle) containing 15 mmol each of Na+ and Cl-. Because DIFLUCAN IV infusion is available as a dilute saline solution, in patients requiring sodium or fluid restriction, consideration should be given to the rate of fluid administration. For instructions on dilution of DIFLUCAN IV infusion, see section 6.6.

DIFLUCAN powder for oral suspension For oral use. For instructions on reconstitution of DIFLUCAN powder for oral suspension, see section 6.6.

• DIFLUCAN should not be used in patients with known hypersensitivity to fluconazole or to related azole medicines or any of the excipients of DIFLUCAN (listed in section 6.1).
• Co-administration of terfenadine is contraindicated in patients receiving DIFLUCAN at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Co-administration of other medicines known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine are contraindicated in patients receiving DIFLUCAN (see sections 4.4 and 4.5).
• Pregnancy and lactation.

Hepatobiliary system

DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Hepatotoxicity may be reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more serious hepatic injury. DIFLUCAN should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to DIFLUCAN.

Dermatological reactions

Patients have less frequently developed pruritus, rashes, urticaria, angioedema, dry skin, abnormal odour, exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis during treatment with DIFLUCAN. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. AIDS patients are more prone to the development of severe cutaneous reactions to many medicines. If a rash, which is considered attributable to DIFLUCAN, develops in a patient treated for a superficial fungal infection, further therapy with DIFLUCAN should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and DIFLUCAN discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

Anaphylaxis has been reported with the use of DIFLUCAN.

Cardiovascular system

DIFLUCAN has been associated with prolongation of the QT interval on the electrocardiogram. DIFLUCAN causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicines (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. During post-marketing surveillance, there have been cases of QT prolongation and torsades de pointes in patients taking DIFLUCAN. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medicines that may have been contributory. Patients with hypokalaemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular dysrhythmias and torsades de pointes. DIFLUCAN should be administered with caution to patients with these potentially prodysrhythmic conditions.

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of DIFLUCAN and halofantrine is therefore not recommended (see section 4.5).

Renal system

DIFLUCAN should be administered with caution to patients with renal dysfunction (see section 4.2).

Adrenal insufficiency

DIFLUCAN may cause adrenal insufficiency relating to concomitant treatment with prednisone (see section 4.5, The effect of DIFLUCAN on other medicines).

Cytochrome P450

DIFLUCAN is a moderate CYP2C9 and CYP3A4 inhibitor. DIFLUCAN is also a strong inhibitor of CYP2C19. DIFLUCAN-treated patients who are concomitantly treated with medicines with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see section 4.5).

Terfenadine

The co-administration of DIFLUCAN at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5).

Candidiasis

Studies have shown an increasing prevalence of infections with Candida species other than C. albicans. These are often inherently resistant (e.g. C. krusei and C. auris) or show reduced susceptibility to DIFLUCAN (C. glabrata). Such infections may require alternative antifungal therapy secondary to treatment failure. Therefore, health care providers are advised to take into account the prevalence of resistance in various Candida species to DIFLUCAN.

Excipients

DIFLUCAN capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

DIFLUCAN IV infusion contains 15 mmoL sodium per 100 mL dose. This should be taken into consideration by patients on a controlled sodium diet.

DIFLUCAN powder for oral suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Concomitant use of the following other medicines is contraindicated:

Cisapride

There have been reports of cardiac events including torsades de pointes in patients to whom DIFLUCAN and cisapride were co-administered. A controlled study found that concomitant DIFLUCAN 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with DIFLUCAN and cisapride is contraindicated in patients receiving DIFLUCAN (see section 4.3).

Terfenadine

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of DIFLUCAN failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of DIFLUCAN demonstrated that DIFLUCAN taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of DIFLUCAN at doses of 400 mg or greater with terfenadine is contraindicated. The coadministration of DIFLUCAN at doses lower than 400 mg per day with terfenadine should be carefully monitored (see section 4.3).

Astemizole

Concomitant administration of DIFLUCAN with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and torsades de pointes. Co-administration of DIFLUCAN and astemizole is contraindicated (see section 4.3).

Pimozide

Although not studied in vitro or in vivo, concomitant administration of DIFLUCAN with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and torsades de pointes. Co-administration of DIFLUCAN and pimozide is contraindicated (see section 4.3).

Quinidine

Although not studied in vitro or in vivo, concomitant administration of DIFLUCAN with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and torsades de pointes. Co-administration of DIFLUCAN and quinidine is contraindicated (see section 4.3).

Erythromycin

Concomitant use of DIFLUCAN and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden death. Co-administration of DIFLUCAN and erythromycin is contraindicated (see section 4.3).

Concomitant use of the following other medicines cannot be recommended:

Halofantrine

DIFLUCAN can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of DIFLUCAN and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4).

Concomitant use that should be used with caution:

Amiodarone

Concomitant administration of DIFLUCAN with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of DIFLUCAN and amiodarone is necessary, notably with high dose DIFLUCAN (800 mg) (see section 4.4).

Concomitant use of the following medicines leads to precautions and dose adjustments:

The effect of other medicines on DIFLUCAN

Hydrochlorothiazide

In a pharmacokinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving DIFLUCAN increased plasma concentrations of DIFLUCAN by 40 %. An effect of this magnitude may necessitate a change in the DIFLUCAN dose regimen in subjects receiving concomitant diuretics.

Rifampicin

Concomitant administration of DIFLUCAN and rifampicin resulted in a 25 % decrease in the AUC and a 20 % shorter half-life of DIFLUCAN. In patients receiving concomitant rifampicin, an increase of the DIFLUCAN dose should be considered.

Interaction studies have shown that when oral DIFLUCAN is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of absorption occurs.

The effect of DIFLUCAN on other medicines

DIFLUCAN is a moderate inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 3A4. DIFLUCAN is also a strong inhibitor of the isoenzyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other medicines metabolised by CYP2C9, CYP2C19 and CYP3A4 co-administered with DIFLUCAN. Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of DIFLUCAN persists for 4 u2013 5 days after discontinuation of DIFLUCAN treatment due to the long half-life of DIFLUCAN (see section 4.3).

Women of childbearing potential/contraception in males and females

Effective contraceptive measures must be used in women of childbearing potential and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.

Pregnancy

DIFLUCAN is contraindicated for use during pregnancy (see section 4.3). There have been reports of congenital abnormalities in infants whose mothers were treated with DIFLUCAN. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) DIFLUCAN therapy for coccidioidomycosis. A few published case reports describe a distinctive and a rare pattern of birth defects among infants whose mother received high-dose (400 to 800 mg/day) DIFLUCAN during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease.

Breastfeeding

DIFLUCAN is found in breast milk at concentrations similar to plasma. DIFLUCAN should not be used in mothers breastfeeding their infants.

When driving vehicles or operating machines, it should be taken into account that dizziness or seizures may occur.

Summary of the safety profile

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and haematological function test results and hepatic abnormalities have been observed during treatment with DIFLUCAN. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with DIFLUCAN treatment (see section 4.4).

Tabulated summary of adverse reactions

The following undesirable effects have been observed and reported during treatment with DIFLUCAN with the following frequencies: Very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to u2264 1/100); rare (u2265 1/10 000 to u2264 1/1 000); very rare (u2264 1/10 000); not known (cannot be estimated from the available data).

System organ class Frequency Undesirable effects

• Blood and lymphatic system disorders Rare Agranulocytosis, leukopenia, neutropenia, thrombocytopenia
• Immune system disorders Rare Anaphylaxis
• Metabolism and nutrition disorders Rare Hypertriglyceridaemia, hypercholesterolaemia, hypokalaemia
• Psychiatric disorders Uncommon Insomnia, somnolence
• Nervous system disorders Common Headache
• Uncommon Seizures, dizziness, paraesthesia, taste perversion
• Rare Tremor
• Ear and labyrinth disorders Uncommon Vertigo
• Cardiac disorders Rare Torsades de pointes, QT prolongation
• Gastrointestinal disorders Common Abdominal pain, diarrhoea, nausea, vomiting
• Uncommon Dyspepsia, flatulence, dry mouth
• Hepato-biliary disorders Common Increased alanine aminotransferase, increased aspartate aminotransferase, increased blood alkaline phosphatase
• Uncommon Cholestasis, jaundice, increased bilirubin
• Rare Hepatic toxicity including fatal cases, hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage
• Skin and subcutaneous tissue disorders Common Rash
• Uncommon Pruritus, urticaria, increased sweating, drug eruption (including fixed drug eruption)
• Rare Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous-pustulosis, exfoliative dermatitis, angioedema, face oedema, alopecia
• Not known Drug reaction with eosinophilia and systemic symptoms (DRESS)
• Musculoskeletal and connective tissue disorders Uncommon Myalgia
• General disorders and administration site conditions Uncommon Fatigue, malaise, asthenia, fever

Paediatric population

The pattern and incidence of adverse events and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There have been reports of overdose with DIFLUCAN accompanied by hallucinations and paranoid behaviour. In the advent of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. DIFLUCAN is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50 %.