Fluconazole 50mg capsules

1. Name Of The Medicinal Product

Fluconazole 50 mg capsules, hard

2. Qualitative And Quantitative Composition

Each capsule, hard contains 50 mg fluconazole.

Excipient: 50.56 mg lactose/hard capsule

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Capsules, hard

Size '4' hard gelatin capsule filled with white to off-white powder and imprinted with 'E' on white to off-white opaque cap and '95' on white to off-white opaque body with yellow ink.

4. Clinical Particulars

4.1 Therapeutic Indications

Acute or recurrent vaginal candidiasis when systemic therapy is considered appropriate.

Mucosal candidal infection. These include oropharyngeal, oesophageal, mucocutaneous and non-invasive bronchopulmonary candidiasis and candiduria, in patients with compromised immune function.

Systemic candidiasis in non-neutropenic patients.

Acute cryptococcal meningitis in adults. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.

Prophylaxis of deep-seated candida infections (particularly Candida albicans) in patients with neutropenia due to bone marrow transplantation.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

Paediatric use

Not all indications are applicable for paediatric patients; see details in section 4.2.

Fluconazole should not be used for tinea captis.

4.2 Posology And Method Of Administration

Oral use, capsules should be swallowed whole, independent of food intake.

The dose is depending on the type and severity of the fungal infection. The treatment of infections requiring multiple dosing must be continued until clinical parameters or laboratory results show that the active fungal infection has declined. An insufficient treatment period may lead to recurrence of the active infection.

Depending on the severity of the disease and the clinical state of the patients intravenous administration may be required. It is not necessary to change the daily dose of fluconazole when changing the route of administration from intravenous to oral.

Adults:

Vaginal candidiasis: 150 mg as a single dose.

Mucous membrane candidiasis:

Oropharyngeal candidiasis: Normal daily dose: 50-100 mg for 7-14 days. Duration of treatment depends on clinical response.

Oesophageal mucocutaneous, non-invasive bronchopulmonary candidiasis and candiduria: Normal dose is 50 mg daily for 14-30 days. In severe and particular recurrent cases the dose can be increased to 100 mg.

Systemic candidiasis:

The dose in candidaemia and other invasive Candida infections is 400-800 mg on the first day and 200-400 mg daily thereafter. The dose depends on the type and severity of the infection. In most cases a loading dose of 800 mg on the first day followed by 400 mg daily thereafter may be preferable. The duration of treatment, often up to several weeks, is determined by the clinical response.

Prevention of candida infections in neutropenic patients:

400 mg once daily. Prophylaxis with fluconazole should begin in time before the appearance of expected neutropenia. Treatment should be continued for 7 days after the neutrophil counts have increased to > 1x10⁹/ l.

Cryptococcal meningitis in immunosuppressed patients: For infections with cryptococcal meningitis the usual dose is 400 mg on the first day followed by 200-400 mg once daily. Duration of treatment for cryptococcal infections depends on the clinical response, but is usually at least 6-8 weeks for cryptococcal meningitis.

For the prevention of relapse of cryptococcal meningitis in patients with AIDS, fluconazole may be administered at a daily dose of 200 mg.

Duration of maintenance treatment in AIDS patients should be carefully justified, because of the increased risk of resistance to fluconazole.

Paediatric use:

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazole is administered as a single daily dose.

The capsules formulation may be unsuitable for children younger than 5-6 years.

For children with impaired renal function, see dosing in “Use in patients with impaired renal function”.

Children over four weeks of age:

The recommended dose of fluconazole for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly.

For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6 - 12 mg/kg daily, depending on the severity of the disease.

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 - 12 mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).

A maximum dosage of 400 mg daily should not be exceeded in children.

Children four weeks of age and younger:

Neonates excrete fluconazole slowly. In the first two weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 - 4 of life the same dose should be given every 48 hours. There are few PK data to support this Posology in term newborn babies (see section 5.2).

A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children below two weeks of life. For children between 3 - 4 weeks of life 12 mg/kg every 48 hours should not be exceeded.

The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.

Use in the elderly

The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be adjusted as described below.

Use in patients (adults and paediatric) with impaired renal function

Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients with impaired renal function who will receive multiple doses of fluconazole, the normal recommended dose (according to indication) should be given on day 1 and 2, followed by a daily dose based on the following table:

Creatinine clearance (ml/min.)	Percentage of recommended dose
>50	100%
	50%
Regular dialysis	100% after each dialysis

The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.

4.3 Contraindications

• Hypersensitivity to fluconazole or to related azole compounds or to any of the excipients.

• Co-administration of terfenadine is contra-indicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study.

• Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, pimozide and quinidine are contra-indicated in patients receiving fluconazole (see sections 4.4 and 4.5).

4.4 Special Warnings And Precautions For Use

Fluconazole should be administered with caution to patients with liver dysfunction (see also section 4.2).

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.

Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this agent should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.

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

In rare cases, as with other azoles, anaphylaxis has been reported.

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.

Fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions.

Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9 and CYP3A4, should be monitored (see section 4.5).

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of the following other medicinal products is contraindicated:

Cisapride: There have been reports of cardiac events including Torsades de pointes in patients to whom fluconazole and cisapride were co-administered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QT interval. Concomitant treatment with fluconazole and Cisapride is contra-indicated (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 fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

Concomitant use of the following other medicinal products cannot be recommended:

Erythromycin: Concomitant use of fluconazole and erythromycin 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.

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

The effect of other medicinal products on fluconazole

Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.

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

The effect of fluconazole on other medicinal products

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

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T_½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitnptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary

Amphotericine B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Anticoagulants: In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.

Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Benzodiazepines (Short Acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.

Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 85% and 75%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

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

4.6 Pregnancy And Lactation

Pregnancy

Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the foetus.

There have been reports of multiple congenital abnormalities in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear.

Animal studies show teratogenic effects (see section 5.3).

Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.

Lactation

Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Fluconazole has no or negligible influence on the ability to drive and use machines.

However when driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.

4.8 Undesirable Effects

Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see section 4.4) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

The following frequency data are used in the evaluation of undesirable effects:

Very common: (

Common: (

Uncommon: (

Rare (

Very rare (< 1/10,000, not known (cannot be estimated from the available data)

System Organ Class	Frequency	Undesirable effects
Blood and the lymphatic system disorders	Rare	Agranulocytosis, leukopenia, neutropenia, thrombocytopenia
Immune system disorders	Rare	Anaphylaxis
Metabolism and nutrition disorders	Uncommon	Hypokalaemia
Rare	Hypertriglyceredaemia, hypercholesterolaemia
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	Torsade de pointes, QT prolongation
Gastrointestinal disorders	Common	Abdominal pain, diarrhoea, nausea, vomiting
Uncommon	Dyspepsia, flatulence, dry mouth
Hepato-biliary disorders	Common	Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased
Uncommon	Cholestasis, jaundice, bilirubin increased
Rare	Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage
Skin and subcutaneous tissue disorders	Common	Rash
Uncommon	Pruritus, urticaria, increased sweating, drug eruption
Rare	Toxic epidermal necrolysis , Stevens-Johnson syndrome, acute generalised exanthematous-pustulosis, dermatitis exfoliative, angioedema, face oedema, alopecia
Musculoskeletal, connective tissue and bone disorders	Uncommon	Myalgia
General disorders and administration site conditions	Uncommon	Fatigue, malaise, asthenia, fever

Pediatric population: The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric use are comparable to those seen in adults.

4.9 Overdose

Symptoms:

There have been reports of overdose with fluconazole and hallucination and paranoid behaviour have been concomitantly reported.

Treatment:

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.

Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour hemodialysis session decreases plasma levels by approximately 50%.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Antimycotics for systemic use, Triazole derivatives;

ATC code: J02AC01.

Type of action

Fluconazole is a substance, which belongs to the triazole derivative class of drugs. The agent is particularly effective against Candida species and cryptococci.

Mechanism of action

Fluconazole has a highly specific effect on cytochrome-P450-dependent fungal enzymes and is a potent and specific inhibitor of fungal sterol synthesis.

Spectrum of activity

Fluconazole has a wide spectrum of antimycotic activity. In various in-vivo animal activity studies (p.o. and i.v.), fluconazole is active in superficial and systemic infections with Candida, Cryptococcus and various dermatophytes.

Candida krusei is resistant to fluconazole. The susceptibility of Candida glabrata is variable. Candida dubliniensis is not primarily resistant but shows a high tendency towards resistance, mainly during therapy. Fluconazole has little of no activity against Aspergillus, Mucor, Microsporum and Trichophyton species.

In animal experimental models of endemic mycosis, fluconazole was shown to be effective, including in infections with Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum in normal and immunosuppressed animals. As with other azoles, due to the lack of a standardised procedure, the results of in-vitro tests are of lesser significance in terms of predicting clinical efficacy than the results of in-vivo studies.

In volunteers, 200–400 mg fluconazole daily have no clinically relevant effect on endogenous serum steroid concentrations or ACTH-stimulated cortisol release.

The efficacy of fluconazole in tinea captis has been studied in 2 randomised controlled trials in a total of 878 patients, comparing fluconazole with griseofulvin. Fluconazole at 6 mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11 mg/kg/day for 6 weeks. The overall success rate at 6 weeks was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all the treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.

5.2 Pharmacokinetic Properties

Absorption:

Fluconazole is well absorbed after oral intake. The absolute bioavailability is above 90%. The oral absorption is not affected by concomitant food intake. The maximum fasting plasma concentration is reached 0.5 - 1.5 hours after dose intake.. 90% of the steady-state level is reached 4-5 days after dosing once daily.

Plasma concentration is proportional to the dose. After administration of 200 mg fluconazole, C_max is around 4.6 mg/l and plasma concentrations at steady-state after 15 days are around 10 mg/l. After administration of 400 mg of fluconazole, C_max is around 9 mg/l and plasma concentrations at steady state after 15 days are around 18 mg/l.

Intake of a double dose on day 1 results in plasma concentrations of approximate 90% of steady-state on day 2.

Distribution:

The volume of distribution corresponds to the total body water. The protein binding in plasma is low (11-12%).

The concentration in saliva corresponds to the plasma concentration. In patients with fungal meningitis the concentration of fluconazole in the cerebrospinal fluid is approximately 80% of the corresponding plasma concentration.

In stratum corneum, epidermis-dermis and in exocrine sweat higher concentrations of fluconazole are reached compared to those in serum. Fluconazole is accumulated in the stratum corneum. At a dose of 150 mg once weekly the concentration of fluconazole in stratum corneum was after 2 doses 23.4 µg/g and seven days after the second dosing it was still 7.1 µg/g..

Elimination:

Fluconazole is mainly renally excreted. Approximately 80% of the administered dose is excreted in the urine in non-metabolized form. Fluconazole clearance is proportional to the creatinine clearance. Circulating metabolites have not been demonstrated.

The half-life in plasma is approximately 30 hours.

Pharmacokinetics in Children

Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single dose studies, 2 multiple dose studies and a study in premature neonates. Data from 1 study were not interpretable due to changes in formulation partway through the study. Additional data were available from a compassionate use study.

In children, the following pharmacokinetic data have been reported:

Age Studied	Dose (mg/kg)	Half-life (hours)	AUC (μg.h/ml)
11 days - 11 months	Single IV 3 mg/kg	23	110.1
9 months - 13 years	Single - oral 2 mg/kg	25.0	94.7
9 months - 13 years	Single - oral 8 mg/kg	19.5	362.5
5 years - 15 years	Multiple IV 2 mg/kg	17.4*	67.4
5 years - 15 years	Multiple IV 4 mg/kg	15.2*	139.1
5 years - 15 years	Multiple IV 8 mg/kg	17.6*	196.7
Mean age 7 years	Multiple oral 3 mg/kg	15.5	41.6

*Denotes final day

After administration of 2 - 8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 pg.h/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 Kg (range 0.75-1.10 Kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients completed the protocol; a maximum of five 6 mg/Kg

Hypaque Injection

Dosage Form: Injection, USP 50%

Sterile Aqueous Injection

For Excretory Urography

Cerebral Angiography

Peripheral Angiography

Aortography

Intraosseous Venography

Direct Cholangiography

Hysterosalpingography

Splenoportography

NOT FOR INTRATHECAL USE

Rx ONLY

Hypaque Injection Description

HYPAQUE sodium, brand of diatrizoate sodium, is a radiopaque diagnostic agent, water-soluble organic iodide contrast medium. In pure form, it contains 59.87 percent organically bound iodine.

The 50 percent (w/v) solution contains 300 mg iodine per mL and 0.8 mEq (18.1 mg) sodium per mL. It has an osmolality of 1515 mosm/kg (determined by VPO), and is hypertonic to blood. As a point of information only, a 10 percent solution (w/v) is isotonic. The viscosity (cp) is about 3.25 at 25° C and 2.34 at 37° C. Sodium carbonate and hydrochloric acid have been added to adjust pH between 6.5 and 7.7.The pKa is 3.4 for diatrizoic acid. If a solution of this medium is chilled, crystals may form but readily dissolve if the vial is placed in moderately hot water before use; cool to body temperature before injecting.

The sterile aqueous solution is clear and nearly colorless. It is relatively thermostable and may be autoclaved without harmful effects, although it should be protected from strong light. The 50 percent solution contains edetate calcium disodium 1:10,000 as a sequestering stabilizing agent.

Diatrizoate sodium is a triiodinated benzoic acid derivative, the sodium salt of 3,5-diacetamido-2,4,6-triiodobenzoate with a molecular weight of 635.90, and has the following structural formula:

Hypaque Injection - Clinical Pharmacology

Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs.

At physiologic pH, the water-soluble contrast media are completely dissociated into a radiopaque anion and a solubilizing cation. While circulating in tissue fluids, the compound remains ionized. However, it is not metabolized but excreted unchanged in the urine, each diatrizoate molecule remaining "obligated" to its sodium moiety.

Following intravenous injection, the radiopaque diagnostic agents are immediately diluted in the circulating plasma. Equilibrium is reached with the extracellular compartment at about 10 minutes. Hence, the plasma concentration at 10 minutes is closely related to the dose corrected to body size.

The pharmacokinetics of the intravenously administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slow beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives were respectively 30 minutes and 120 minutes for diatrizoate. But in patients with renal functional impairment, the elimination half-life for the beta phase can be prolonged up to several days.

Injectable radiopaque diagnostic agents are excreted either through the liver or through the kidneys. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be governed by the affinity of the contrast medium for serum albumin. From 0% to 10% of diatrizoate sodium is bound to serum protein.

Diatrizoate salts are excreted unchanged predominantly through the kidneys by glomerular filtration. The amount excreted by the kidney during any period of time is determined by the filtered load; ie, the product of plasma contrast media concentration and glomerular filtration rate. The plasma concentration is dependent upon the dose administered and the body size. The glomerular filtration rate varies with the body size, sex, age, circulatory dynamics, diuretic effect of the drug, and renal function. In patients with normal renal function the maximum urinary concentration of diatrizoate sodium occurs within 10 minutes with 12 percent of the administered dose being excreted. The mean values of cumulative urinary excretion for diatrizoate sodium expressed as percentage of administered dose are 38 percent at 60 minutes, 45 percent at 3 hours, and 94 to 100 percent at 24 hours.

Urinary excretion of contrast media is delayed in infants younger than 1 month and in patients with urinary tract obstruction. The urinary iodine concentration is higher with the sodium salt of diatrizoic acid than with the meglumine salt.

The liver and small intestine provide the major alternate route of excretion for diatrizoate. In patients free of severe renal disease, the fecal recovery is less than 2 percent of the administered dose. In patients with severe renal impairment the excretion of these contrast media through the gallbladder and into the small intestine sharply increases; up to 20 percent of the administered dose has been recovered in the feces in 48 hours.

Saliva is a minor secretory pathway for injectable radiopaque diagnostic agents. In patients with normal renal function, minimal amounts of contrast media are secreted unchanged. However, in uremic patients small amounts of free iodides resulting from deiodination prior to administration or in vivo, have been detected in the saliva.

Diatrizoate salts cross the placental barrier in humans by simple diffusion and appear to enter fetal tissue passively. No apparent harm to the fetus was observed when diatrizoate sodium and diatrizoate meglumine were injected intravenously 24 hours prior to delivery. However, abnormal neonatal opacification of the small intestine and colon were detected 4 to 6 days after delivery. Procedures including radiation involve a certain risk related to the exposure of the fetus. (See PRECAUTIONS—General, Pregnancy Category C.)

Injectable radiopaque diagnostic agents are excreted unchanged in human milk. (See PRECAUTIONS—General, Nursing Mothers.)

Computerized Tomography

HYPAQUE sodium 50 percent can be administered as an intravenous bolus for brain tissue enhancement using computerized tomography. Increased tissue contrast differential for the scan is achieved either because of increased vascular (arterial, venous, or capillary bed) contrast or by blood brain barrier penetration of the medium (or its absence) in certain localized areas of disrupted vascular permeability. The degree of tissue enhancement caused by increased blood contrast is directly related to blood iodine content. However, the degree of enhancement due to extravascular accumulation of iodine resulting from blood brain barrier disruption will depend on the extent of disruption, the blood level of iodine, and the time delay prior to scanning. The nature of the pathology will determine whether an immediate or delayed scan is optimal.

Effects of Steroid Therapy

The anti-inflammatory and antiedema effects in patients receiving steroid therapy have interfered with the expected distribution of CT tissue enhancement on the scan in certain diseases.

Indications and Usage for Hypaque Injection

HYPAQUE sodium 50 percent is indicated for excretory urography, cerebral and peripheral angiography, aortography, intraosseous venography, direct cholangiography, hysterosalpingography, splenoportography, and contrast enhancement of computed tomographic head imaging.

UROGRAPHY

Diatrizoate salts are used in small, medium, and large dose urography (see Dosage and Administration—EXCRETORY UROGRAPHY). Visualization of the urinary tract can be achieved by either direct intravenous bolus injection, intravenous drip infusion, or incidentally following intra-arterial procedures.Visualization of the urinary tract is delayed in infants less than 1 month old, and in patients with urinary tract obstruction (see CLINICAL PHARMACOLOGY).

CONTRAST ENHANCEMENT OF COMPUTED TOMOGRAPHIC HEAD IMAGING

Injectable radiopaque contrast media may be used to refine diagnostic precision in areas of the brain which may not otherwise have been satisfactorily visualized.

Tumors

Radiopaque diagnostic agents may be useful to investigate the presence and extent of certain malignancies such as: gliomas including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas, ependymomas, medulloblastomas, meningiomas, neuromas, pinealomas, pituitary adenomas, craniopharyngiomas, germinomas, and metastatic lesions.

The usefulness of contrast enhancement for the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been demonstrated.

In calcified lesions, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement.

The opacification of the inferior vermis following contrast media administration has resulted in false-positive diagnosis in a number of normal studies.

Nonneoplastic Conditions

The use of injectable radiopaque diagnostic agents may be beneficial in the image enhancement of nonneoplastic lesions. Cerebral infarctions of recent onset may be better visualized with contrast enhancement, while some infarctions are obscured if contrast media are used. The use of iodinated contrast media results in contrast enhancement in about 60 percent of cerebral infarctions studied from one to four weeks from the onset of symptoms.

Sites of active infection may also be enhanced following contrast media administration.

Arteriovenous malformations and aneurysms will show contrast enhancement. For these vascular lesions, the enhancement is probably dependent on the iodine content of the circulating blood pool.

Hematomas and intraparenchymal bleeders seldom demonstrate any contrast enhancement. However, in cases of intraparenchymal clot, for which there is no obvious clinical explanation, contrast media administration may be helpful in ruling out the possibility of associated arteriovenous malformation.

ANGIOGRAPHY

Diatrizoate salts are used for radiographic studies throughout the cardiovascular system.

Intravascular radiopaque diagnostic agents of high concentration are not recommended for cerebral or spinal angiography (see CONTRAINDICATIONS—General), and contrast agents with the lowest compatible viscosity and higher concentration of iodine (310 mg/mL to 480 mg/mL of bound iodine) must be used for angiocardiography. Contrast media approaching serum ionic content and osmolality have less potential for deleterious effects on the myocardium (see PRECAUTIONS—General, Drug Interactions).

Addition of chelating agents may contribute to toxicity in coronary angiography, and the sodium content of angiographic agents used in coronary arteriography is of crucial importance.

In addition to the following general CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS, there are additional listings in these categories under the particular procedures.

CONTRAINDICATIONS—General

HYPAQUE sodium 50 percent has no absolute contraindications in its recommended uses (see general WARNINGS and PRECAUTIONS).

Do not use HYPAQUE sodium 50 percent for myelography or for examination of dorsal cysts or sinuses which might communicate with the subarachnoid space. Even a small amount in the subarachnoid space may produce convulsions and result in fatality. (See also AORTOGRAPHY, Warnings.) Epidural injection is also contraindicated.

Urography and large dose vascular procedures are contraindicated in dehydrated azotemic patients. (See also PRECAUTIONS—General.)

WARNINGS—General

SEVERE ADVERSE EVENTS—INADVERTENT INTRATHECAL ADMINISTRATION

Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, come, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally.

Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media. Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Excretory urography is potentially hazardous in patients with multiple myeloma. In some of those patients, therapeutically resistant anuria resulting in progressive uremia, renal failure, and eventually death has followed this procedure. Although neither the contrast agent nor dehydration has been proved separately to be the cause of anuria in myelomatous patients, it has been speculated that the combination of both may be causative. The risk of excretory urography in myelomatous patients is not a contraindication to the procedure; however, they require special precautions. Partial dehydration in the preparation of these patients for the examination is not recommended since this may predispose to the precipitation of myeloma protein in the renal tubules. Myeloma, which occurs most commonly in persons over age 40, should be considered before instituting urographic procedures.

Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when the material is injected intravenously or intra-arterially.

Administration of radiopaque materials to patients known or suspected of having pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available.

Recent reports of thyroid storm occurring following the intravascular use of iodinated radiopaque diagnostic agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be evaluated in such patients before use of HYPAQUE sodium.

Contrast media administered for cardiac catheterization and angiocardiography may cause cellular injury to circulating lymphocytes. Chromosomal damage in humans includes inhibition of mitosis, increases in the number of micronuclei, and chromosome aberrations. The damages appear to be related to the contrast medium itself rather than to the x-ray radiation. It is to be noted that those agents have not been adequately tested in animal or laboratory systems.

Urography should be performed with caution in patients with severely impaired renal function and patients with combined renal and hepatic disease.

Subcutaneous extravasation, chiefly because of hypertonic cellulitis, causes transitory stinging. If the volume extravasated is small, ill effects are very unlikely. However, if the extravasation is extensive especially in poorly vascularized areas (eg, dorsum of the foot or hand), and especially in the presence of vascular disease, skin slough may occur. Injection of sterile water to dilute or addition of spreading agents to speed absorption have not been successful and may aggravate the condition.

Selective spinal arteriography or arteriography of trunks providing spinal branches can cause mild to severe muscle spasm. However, serious neurologic sequelae, including permanent paralysis, have occasionally been reported. (See also ANGIOGRAPHY, Precaution.)

In patients with subarachnoid hemorrhage, a rare association between contrast administration and clinical deterioration, including convulsions and death, has been reported. Therefore, administration of intravascular iodinated ionic contrast media in these patients should be undertaken with caution.

PRECAUTIONS—General

Diagnostic procedures which involve the use of radiopaque diagnostic agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reactions to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions have occurred (see ADVERSE REACTIONS—General).

The possibility of a reaction, including serious, life-threatening, fatal, anaphylactic or cardiovascular reactions should always be considered (see ADVERSE REACTIONS). It is of utmost importance that a course of action be carefully planned in advance for immediate treatment of serious reactions, and that adequate and appropriate personnel be readily available in case of any reaction.

Preparatory dehydration for angiography and CT procedures is unnecessary and may be dangerous, contributing to acute renal failure in infants, young children, the elderly, patients with preexisting renal insufficiency, patients with advanced vascular disease, and diabetic patients. Dehydration in these patients seems to be enhanced by the osmotic diuretic action of urographic agents. Overnight fluid restriction for urography may be undesirable and is considered unnecessary when using this relatively high (50%) concentration.

Although azotemia is not a contraindication, the medium should be used with great care in patients with advanced renal destruction associated with severe uremia. (See also EXCRETORY UROGRAPHY, Precautions.)

Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible nondiabetic patients (often elderly with preexisting renal disease) following excretory urography. Therefore, careful consideration of the potential risks should be given before performing this radiographic procedure in these patients. (See also EXCRETORY UROGRAPHY, Precautions—Preparatory Dehydration.)

Immediately following surgery, excretory urography should be used with caution in renal transplant recipients.

The possibility of an idiosyncratic reaction in susceptible patients should always be considered (see ADVERSE REACTIONS—General). The susceptible population includes patients with a history of a previous reaction to a contrast media, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity: bronchial asthma, hay fever, and food allergies.

The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to injection of any contrast media, may be more accurate than pretesting in predicting potential adverse reactions.

A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent, where a diagnostic procedure is thought essential, but caution should be exercised (see ADVERSE REACTIONS—General). Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

Due to the transitory increase in the circulatory osmotic load, injections of urographic agents should be used with caution in patients with congestive heart failure. Such patients should be observed for several hours following the procedure to detect delayed hemodynamic disturbances.

General anesthesia may be indicated in the performance of some procedures in young or uncooperative children and in selected adult patients; however, a higher incidence of adverse reactions has been reported in these patients, and may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia which can reduce cardiac output and increase the duration of exposure to the contrast agent.

Seizure activity is rare (about 0.01%) on intravenous injection of ionic contrast media. However, in the higher doses used for CT in patients with brain metastases the incidence can be much higher (1% to 10%). In these patients prophylactic use of a small parenteral dose of a diazepam is suggested immediately before injection when extra high dose CT regimens are employed.

In addition to the general precautions already described, excretory urography, angiography, and other uses also have hazards associated with the particular techniques employed. (See INDIVIDUAL INDICATIONS AND USAGE section.)

INFORMATION FOR PATIENTS

Patients receiving injectable radiopaque diagnostic agents should be instructed to:

1. Inform the physician if they are pregnant (see CLINICAL PHARMACOLOGY).


2. Inform the physician if they are diabetic or if they have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disorder (see WARNINGS—General).


3. Inform the physician if they are allergic to any drugs, food, or if they have had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS—General).


4. Inform the physician about any other medications they are currently taking, including nonprescription drugs, before they are administered this drug.

DRUG INTERACTIONS

Renal toxicity has been reported in a few patients with liver dysfunction who were given oral cholecystographic agents followed by urographic agents. Administration of intravascular urographic agents should therefore be postponed in any patient with a known or suspected hepatic or biliary disorder who has recently received a cholecystographic contrast agent.

Addition of an inotropic agent to contrast agents may produce a paradoxical depressant response which can be deleterious to the ischemic myocardium.

Diphenhydramine hydrochloride may cause precipitation when mixed in the same syringe with HYPAQUE sodium 50%.

Under certain circumstances (pH, temperature, concentrations, time), diatrizoate solutions are incompatible with promethazine hydrochloride, diphenhydramine hydrochloride, brompheniramine maleate, or papaverine hydrochloride solutions.

Do not prefill plastic syringes with HYPAQUE sodium 50% for prolonged periods (ie, for several hours or longer) before use.

DRUG/LABORATORY TEST INTERACTIONS

If any of these studies, which might be affected by contrast media are indicated, it is recommended that they be performed prior to administration of the contrast medium or two or more days afterwards.

Diatrizoate salts interfere with several laboratory urine and blood tests.

BLOOD TESTS

Coagulation: Diatrizoate salts significantly inhibit all stages of coagulation. The fibrinogen concentration, Factors V, VII, and VIII are decreased. Prothrombin time and thromboplastin time are increased.

Platelet aggregation: High levels of plasma diatrizoates inhibit platelet aggregation.

Serum calcium: Diatrizoate salts may decrease serum calcium levels. However, this depletion of serum calcium may also be the result of the addition of chelating agents (edetate disodium) in the preparation of certain contrast media.

Red cell counts: Transitory decreases in red cell counts. Technetium-99m—RBC labeling interference.

Leukocyte counts: Decrease.

Urea nitrogen (BUN): Transitory increase (see CLINICAL PHARMACOLOGY).

Serum creatinine: Transitory increase.

URINE TESTS

Contrast media which are excreted in the urine, may interfere with some laboratory determinations eg, proteinuria, specific gravity, osmolality, or bacterial cultures.

THYROID FUNCTION TESTS

Protein-bound iodine (PBI) and total serum organic iodine: Transient increase of both tests following urography have been noticed. The results of PBI and radioactive iodine uptake studies which depend on iodine estimations will not accurately reflect thyroid function for up to 16 days following administration of iodinated urographic media. However, thyroid function tests not depending on iodine estimations, eg, T3 resin uptake or free thyroxine assays are not affected.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term studies in animals have not been performed in order to evaluate carcinogenic potential, mutagenesis, or whether HYPAQUE sodium 50 percent can affect fertility in males or females.

PREGNANCY CATEGORY C

Animal reproduction studies have not been conducted with HYPAQUE sodium 50 percent. It is also not known whether HYPAQUE sodium 50 percent can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HYPAQUE sodium 50 percent should be given to a pregnant woman only if clearly needed.

LABOR AND DELIVERY

It is not known whether use of these contrast agents during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

NURSING MOTHERS

Diatrizoate salts are excreted unchanged in human milk. Because of the potential adverse reactions, although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when these contrast media are administered to a nursing woman.

PEDIATRIC USE

Infants and small children should not have any fluid restriction prior to excretory urography or any other procedures (see PRECAUTIONS—General). Guidelines for pediatric dosages are presented in DOSAGE AND ADMINISTRATION—General.

ADVERSE REACTIONS—General

Approximately 95 percent of adverse reactions accompanying the intravascular use of diatrizoate salts are of mild to moderate severity. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred.

Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions.

Chemotoxic reactions result from the physicochemical properties of the contrast media, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category.

Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of dose injected, the speed of injection, the mode of injection, and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.

The reported incidence of adverse reactions to contrast media in patients with a history of allergy are twice that of the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations.

Most adverse reactions to injectable contrast media appear within one to three minutes after the start of injection, but delayed reactions may occur.

Adverse reactions are grouped by organ system and listed below by decreasing order of occurrence and with an approximate incidence of occurrence. Significantly more severe reactions are listed before the other reactions regardless of frequency.

GREATER THAN 1 IN 100 PATIENTS

Body as a Whole: Reported incidences of death range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock following urography are found in the literature. The incidence of shock is estimated to occur in 1 out of 20,000 (0.005 percent) patients.

Cardiovascular System: The most frequent adverse reaction to diatrizoate salts is vasodilation (feeling of warmth). The estimated incidence is 49 percent.

Digestive System: Nausea 6 percent, vomiting 3 percent.

Nervous System: Paresthesia 6 percent, dizziness 5 percent.

Respiratory System: Rhinitis 1 percent, increased cough 2 percent.

Skin and Appendages: Urticaria 1 percent.

Pain at the injection site is estimated to occur in about 12 percent of the patients undergoing urography. Pain is usually due to extravasation.

Painful hot erythematous swelling above the venipuncture site was estimated to occur in more than one percent of the patients undergoing phlebography.

Special Senses: Perversion of taste 11 percent.

Urogenital System: Osmotic nephrosis of the proximal tubular cells is estimated to occur in 23 percent of patients following excretory urography.

LESS THAN 1 IN 100 PATIENTS

Other infrequently reported reactions without accompanying incidence rates are listed below, grouped by organ system.

Body as a Whole: Malaria relapse, uremia high creatinine and BUN (see PRECAUTIONS—General, Drug/Laboratory Test Interactions), thrombocytopenia, leukopenia, and anemia.

Cardiovascular System: Cerebral hematomas, hemodynamic disturbances, sinus bradycardia, transient electrocardiographic abnormalities, ventricular fibrillation, petechiae, chest pain, cardiac arrest, tachycardia, hypertension, hypotension, and vascular collapse.

Digestive System: Severe unilateral or bilateral swelling of the parotid and submaxillary glands.

Nervous System: Convulsions, paralysis, coma, memory loss. ( See PRECAUTIONS—General.)

Respiratory System: Asthma, dyspnea, laryngeal edema, pulmonary edema, and bronchospasm.

Skin and Appendages: Extravasation necrosis, urticaria with or without pruritus, mucocutaneous edema, and angioneurotic edema.

Special Senses: Bilateral ocular irritation, lacrimation, itching, conjunctival chemosis, infection, and conjunctivitis.

Urogenital: Renal failure, pain.

Overdosage

At dosage levels of diatrizoate sodium above a level containing 45 g of iodine, the incidence of unpleasant side effects increases. At total dosage equivalent to 80 gI or 90 gI administered over a short period of time (eg, 30 minutes), clinical signs of systemic intolerance appear (mostly related to hyperosmolar effects) and are manifest as tremors, irritability, and tachycardia. Above these maximal tolerated dosage levels in otherwise healthy adults, an increasing incidence and severity of dyspnea and pulmonary edema should be expected.

Four cases of overdosage in infants, during urography, are reported. Three of the infants died within 19 hours of the injection. The overdose ranged from slightly above the recommended pediatric dosage to a dose exceeding 19 g/kg. The symptoms of overdosage appeared between 10 minutes to several hours after injection of the contrast medium. Adverse effects were life-threatening, affecting mainly the pulmonary and cardiovascular systems. The symptoms included: cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma, and cardiac arrest. All infants showed a poor visualization of the kidneys and a diffuse opacification of all the tissues and vasculature. Autopsy findings showed acute pulmonary damage and/or edema of subcutaneous tissues. Treatment of an overdose of injectable radiopaque contrast media is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.

The acute intravenous LD50 of diatrizoate sodium in mice is equivalent in iodine content of 5.3 gI/kg to 8.0 gI/kg and seem to be directly proportional to the rate of injection.

Diatrizoate sodium is dialyzable.

DOSAGE AND ADMINISTRATION—General

Preparation of the patient will vary with preference of the radiologist and the type of radiological procedure performed. Specific radiologic procedures used will depend on the state of the patient and the diagnostic indications. Individual doses should be tailored according to age, body size, and indication for examination. (See INDIVIDUAL INDICATIONS AND USAGE section for specific Dosage and Administration.)

Solutions of radiopaque diagnostic agents for intravascular use should be at body temperature when injected and may need to be warmed before use. In the event that crystallization occurs, the solution may be clarified by placing the vial in a water bath at 40 ° C to 5O ° C and shaking gently for two to three minutes or until the solids redissolve. If particles still persist, do not use this vial but discard it. The solution should be protected from light and any unused portion remaining in the container should be discarded.

Dilution and withdrawal of the, contrast agents should be accomplished under aseptic conditions with sterile syringes.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Avoid contaminating catheters, syringes, needles, and contrast media with glove powder or cotton fibers.

PEDIATRIC DOSAGE

Pediatric doses of injectable radiopaque diagnostic agents are generally determined on a weight basis and should be calculated for each patient individually. (See INDIVIDUAL INDICATIONS AND USAGE section.)

DRUG INCOMPATIBILITIES

Diatrizoate salts are incompatible in vitro with some antihistamines and many other drugs. It is believed that one of the chief causes of in vitro incompatibility is an alteration of pH. Turbidity of solutions of intravascular contrast medium occurs between pH 2.5 and 4.1. Another cause is chemical interaction; therefore, other pharmaceuticals should not be mixed with contrast agents in the same syringe.

INDIVIDUAL INDICATIONS AND USAGE

THE FOLLOWING SECTIONS FOR INDIVIDUAL INDICATIONS AND USAGE CONTAIN CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, AND DOSAGE AND ADMINISTRATION SECTIONS RELATED TO THE SPECIFIC PROCEDURES. HOWEVER, IT SHOULD BE UNDERSTOOD THAT THE INFORMATION IN THE GENERAL SECTIONS IS ALSO LIKELY TO APPLY TO ALL OF THESE SPECIFIC USES.

Hydration—With the possible exception of urography, patients should be fully hydrated prior to the following procedures.

EXCRETORY UROGRAPHY

Dehydration (fluid deprivation for 12 to 15 hours) improves urographic contrast especially at lower dosage level (see PRECAUTIONS—General). A preparatory laxative at bedtime to reduce gas and feces is often employed.

Diatrizoate salts are used in small, medium, and large dose urography. (See Dosage and Administration—EXCRETORY UROGRAPHY.) Visualization of the urinary tract can be achieved by either direct intravenous bolus injection, intravenous drip infusion, or sometimes by intramuscular or subcutaneous injections, or incidentally following intra-arterial procedure.

In infants less than 1 month only visualization of the urinary tract is delayed, therefore the number of roentgen exposures during the early part of the examination should be limited.

In patients with substantially impaired renal function and in patients with urinary tract obstruction, optimal visualization may be delayed for as long as 60 minutes or more. In such patients large doses may be required for adequate urograms.

For distribution and excretion of diatrizoates, see CLINICAL PHARMACOLOGY.

CONTRAINDICATION

Urography is contraindicated in patients with anuria.

PRECAUTIONS

See PRECAUTIONS—General. Some clinicians consider multiple myeloma a contraindication to excretory urography because of the great possibility of producing transient to fatal renal failure. Others believe that the risk of causing anuria is definite but small. If excretory urography is performed in the presence of multiple myeloma, dehydration should be avoided since it favors protein precipitation in renal tubules.

Although azotemia is not considered a contraindication, care is required in patients with advanced renal failure. The usual preparatory dehydration should be omitted, and urinary output should be observed for one to two days in these patients. Adequate visualization may be difficult or impossible to attain in patients with severely impaired renal and/or hepatic function. Use with extreme caution in patients with concomitant hepatorenal disease.

Preparatory Dehydration

Preparatory dehydration is dangerous in infants, young children, the elderly, and azotemic patients (especially those with polyuria, oliguria, diabetes, advanced vascular disease, or preexisting dehydration). The undesirable dehydration in these patients may be accentuated by the osmotic diuretic action of the medium.

Dehydration may improve image quality in patients with adequate renal function particularly if a low dose is used. Dehydration, however, will not improve contrast quality in patients with substantial renal insufficiencies and will increase risk of contrast induced renal damage. Dehydration in these patients is therefore contraindicated.

ADVERSE REACTIONS

See ADVERSE REACTIONS—General.

DOSAGE AND ADMINISTRATION

INTRAVENOUS DOSAGE

Adults. A dose of 30 mL of the 50 percent solution administered intravenously with or without compression produces diagnostic shadows in the majority of adults subjected to partial dehydration and to effective purgation. If the administration of 30 mL does not provide satisfactory visualization, this dose may be repeated in 15 to 30 minutes. In persons of slight build 20 mL may produce adequate shadows.

Larger doses ranging from 50 mL to 60 mL of the 50 percent solution may be used for routine excretory urography in adults. The increased dosage offers better and more complete visualization of the urinary tract. This technique requires neither compression nor dehydration and is more effective in obese patients. Adverse reactions to the larger dose are similar to those encountered with lower doses without an increase in incidence, severity, or type of reactions. Voiding cystourethrograms may be obtained when desired. For the best results and minimal side effects, it is advisable to inject the total amount of solution intravenously in one to three minutes.

Children. The dosage of the 50 percent solution for children under 6 months of age is 5 mL; for children 6 to 12 months of age, 6 mL to 8 mL; for children 1 to 2 years of age, 8 mL to 10 mL; for children 2 to 5 years of age, 10 mL to 12 mL; for children 5 to 7 years of age, 12 mL to 15 mL; for children 7 to 11 years of age, 15 mL to 18 mL, and for children 11 to 15 years of age, 18 mL to 20mL.

Subcutaneous or Intramuscular Urography

HYPAQUE sodium 50 percent may be used for excretory urography via intramuscular injection, undiluted or diluted; or subcutaneously diluted with equal quantities of sterile water for injection.

The intramuscular injection site generally used is the gluteal muscles in two separate, equal doses. Used subcutaneously the medium is generally injected in divided equal doses over each scapula.

In both locations the contrast medium is rapidly absorbed providing urograms beginning variously 5 to 10 minutes following intramuscular injection; subsequent exposures being made according to degree of pyelographic contrast.

Radiographs with subcutaneous injection are usually exposed at 10, 20, and 30 minutes. The urograms achieved with either methods will be almost equal to that following intravenous injection.

The usual intramuscular or subcutaneous (diluted) dose of HYPAQUE sodium 50 percent in adults and older children is about 20 mL to 30 mL. For infants and young children, the dose ranges from 5 mL to 16 mL.

Roentgenography

A plain film is often made prior to IVP. A nephrogram effect is available in 30 to 60 seconds. Its duration is dose dependent.

Urograms may be available as early as two minutes.However, urograms of optimal density are usually made at 5, 10, or 15 minutes following injection.

Ureteric films are usually made between 10 and 20 minutes, and cystograms at 30 minutes. In impaired renal function, delayed films may be required.

ANGIOGRAPHY

Angiography should be avoided whenever possible in patients with homocystinuria, because of the risk of inducing thrombosis and embolism.

CEREBRAL ANGIOGRAPHY

HYPAQUE sodium 50 percent may be administered for visualization of the cerebral vessels. In as much as cerebral angiography is a highly specialized procedure requiring the use of special techniques, it is recommended that HYPAQUE sodium 50 percent be used for this purpose only by persons skilled and experienced in carrying out the procedure.

CONTRAINDICATION

Carotid angiography during the progressive period of a stroke should be avoided, particularly on the left side because of the increased risk of cerebral complications.

PRECAUTIONS

See PRECAUTIONS—General. Patients in whom cerebral angiography is to be performed should be selected with care.

Although cerebral angiography has been considered contraindicated in patients who have recently experienced cerebral embolism or thrombosis (stroke syndrome), many experts now believe that the diagnostic value of the procedure, when employed early as an aid in locating lesions amenable to operation, outweighs any added risk to the patient. Furthermore, a small number of postangiographic fatalities have been reported, including progressive thrombosis already clinically evident before angiography, in which the procedure did not appear to play any direct role. Patients with severe cerebrovascular disease should be examined primarily by indirect methods of angiography.

In cerebral angiography, every precaution must be taken to prevent untoward reactions. Reactions may vary directly with the concentration of the substance, the amount used, the speed and frequency of injections, and the interval between injections.

In subarachnoid hemorrhage, angiography is expected to be hazardous. In migraine, the procedure can be hazardous because of ischemic complications, particularly if performed during or soon after an attack.

ADVERSE REACTIONS

See ADVERSE REACTIONS—General. With any contrast medium introduced into the cerebral vasculature, neurologic complications, including neuromuscular disorders, seizures, loss of consciousness, hemiplegia, unilateral dysesthesias, visual field defects, language disorders (aphasia), amnesia, and respiratory difficulties may occur, particularly when the extent of the intrinsic lesion is unknown. Such untoward reactions are for the most part temporary, although permanent visual field defects have been reported. Some investigators who are experienced in angiographic procedure emphasize the fact that they tend to occur after repeated injections or higher doses of the contrast medium. Other clinicians find that they occur most frequently in elderly patients. In as much as the procedure itself is attended by technical difficulties regardless of the risk the patient presents (eg, mechanical catheter obstruction of the vertebral artery can cause transient blindness), the more experienced the radiologic team, the fewer the complications of any degree that are apt to arise.

Amaurosis can occur following carotid or especially selective vertebral arteriography. It is almost always transitory (4 to 48 hours).

DOSAGE AND ADMINISTRATION

A dose of 8 mL to 12 mL injected at a rate not exceeding the normal flow in the carotid artery (about 5 mL per second) is suggested. The dose may be repeated as indicated; however, an increased risk attends each repeat injection. In the retrograde brachial or catheter method (aortic arch), a single injection of 35 mL to 50 mL is generally used. Children require a smaller dose in proportion to weight. Light anesthesia may be required in these procedures.

PERIPHERAL ANGIOGRAPHY

HYPAQUE sodium 50 percent may be administered for peripheral arteriography and for venography.

PRECAUTIONS

See PRECAUTIONS—General. Extreme caution is advised in considering peripheral arteriography in patients suspected of having thromboangiitis obliterans (Buerger’s disease) since any procedure (even insertion of a needle or catheter) may induce a severe arterial or venous spasm. Caution is also advisable in patients with severe ischemia associated with ascending infection.

ADVERSE REACTIONS

See ADVERSE REACTIONS—General. Soreness in extremities has also been reported.

Adverse reactions observed during peripheral arteriography may sometimes be due to arterial trauma during the procedure (ie, insertion of needle or catheter, subintimal injection, perforation) as well as to the hypertonicity or effect of the medium. Reported adverse reactions include transient arterial spasm, extravasation, hemorrhage, hematoma formation with tamponade, injury to nerves in close proximity to artery, thrombosis, dissecting aneurysm, arteriovenous fistula (eg, with accidental perforation of femoral artery and vein during the needing), and transient leg pain from contraction of calf muscles in femoral arteriography. Transient hypotension has been reported after intra-arterial (brachial) injection of the medium. Also, brachial plexu