Fluconazole in Dextrose

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Overview

What is Fluconazole in Dextrose?

Fluconazole, the first of a new subclass of synthetic triazole antifungal agents, is available as a sterile solution for intravenous use in flexible plastic containers.

Fluconazole is designated chemically as 2,4-difluoro-α,α-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of CHFNO and molecular weight of 306.3. The structural formula is:

Fluconazole is a white crystalline solid which is slightly soluble in water and saline.

Fluconazole in Dextrose Injection, USP is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a dextrose diluent. Each mL contains 2 mg of fluconazole and 56 mg of dextrose, hydrous. The pH ranges from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are packaged in flexible plastic containers.

The flexible plastic container is fabricated from a specially formulated polyvinyl chloride. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

What does Fluconazole in Dextrose look like?

What are the available doses of Fluconazole in Dextrose?

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What should I talk to my health care provider before I take Fluconazole in Dextrose?

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How should I use Fluconazole in Dextrose?

Fluconazole is indicated for the treatment of:

What interacts with Fluconazole in Dextrose?

Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg/day or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See and )

What are the warnings of Fluconazole in Dextrose?

Hepatic Injury: Fluconazole should be administered with caution to patients with liver dysfunction. 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 the patient has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole.

Anaphylaxis:

Dermatologic:

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What are the precautions of Fluconazole in Dextrose?

General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. (See ) During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life threatening ventricular arrhythmias and torsade de pointes.

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

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided.

Fluconazole should be administered with caution to patients with renal dysfunction.

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 metabolized through CYP2C9 and CYP3A4 should be monitored.

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

Drug Interactions

(See and ) Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19, 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, CYP2C19, and CYP3A4 coadministered 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 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed. These are described in greater detail below:

Oral hypoglycemicsCoumarin-type anticoagulantsPhenytoinCyclosporineRifampinTheophyllineVoriconazoleTofacitinibOral ContraceptivesHydrochlorothiazideAmitriptyline, nortriptylineAzithromycinCalcium Channel BlockersCyclophosphamide

QuinidineHalofantrineLosartanNon-steroidal anti-inflammatory drugsSaquinavirVinca AlkaloidsZidovudineTerfenadineCisaprideAstemizoleRifabutinTacrolimusShort-acting benzodiazepines

TriazolamPimozideAlfentanilAmiodaroneAmphotericin BCarbamazepineCelecoxibFentanylHMG-CoA reductase inhibitorsMethadonePrednisoneSirolimusVitamin A

Oral Hypoglycemics

Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When fluconazole is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary. (See )

Coumarin-type Anticoagulants

Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. 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. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See )

Phenytoin

Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended. (See )

Cyclosporine

Fluconazole significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine. (See ) This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration.

Rifampin

Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of fluconazole when it is administered with rifampin. (See )

Theophylline

Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving fluconazole and theophylline is recommended. (See )

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/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 and ) The coadministration of fluconazole at doses lower than 400 mg/day with terfenadine should be carefully monitored.

Cisapride

There have been reports of cardiac events, including torsade de pointes, in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant treatment with fluconazole 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. The combined use of fluconazole with cisapride is contraindicated. (See and )

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.

Rifabutin

There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See )

Voriconazole

Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is recommended; especially, if voriconazole is started within 24 h after the last dose of fluconazole. (See )

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. (See )

Short-acting Benzodiazepines

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 short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (See )

Tofacitinib

Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once daily as instructed in the XELJANZ [tofacitinib] label). (See )

Triazolam

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

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.

Pimozide

Although not studied or 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.

Quinidine

Although not studied or , concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and quinidine is contraindicated. (See )

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.

Alfentanil

A study observed a reduction in clearance and distribution volume as well as prolongation of t 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.

Amiodarone

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

Amitriptyline, Nortriptyline

Fluconazole increases the effect of amitriptyline and nortriptyline. 5-Nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after 1 week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin 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 no interaction in intracranial infection with , and antagonism of the two drugs in systemic infection with The clinical significance of results obtained in these studies is unknown.

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.

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 calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, 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 C and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

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 12 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 metabolized 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 C and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were 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 non-steroidal anti-inflammatory drugs (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.

Prednisone

There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a 3 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.

Saquinavir

Fluconazole increases the AUC of saquinavir by approximately 50%, C by approximately 55%, and decreases the clearance of saquinavir by 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.

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, central nervous system (CNS) related undesirable effects have developed in the form of pseudotumor 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 the C and AUC of zidovudine by 84% and 74%, respectively, due to an approximately 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.

Physicians should be aware that interaction studies with medications other than those listed in the section have not been conducted, but such interactions may occur.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2 to 7 times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of , and in the mouse lymphoma L5178Y system. Cytogenetic studies (murine bone marrow cells, following oral administration of fluconazole) and (human lymphocytes exposed to fluconazole at 1000 mcg/mL) showed no evidence of chromosomal mutations.

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5 mg/kg, 10 mg/kg, or 20 mg/kg or with parenteral doses of 5 mg/kg, 25 mg/kg, or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5 mg/kg, 20 mg/kg, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5 to 15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still born pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific estrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole. (See )

Pregnancy

Nursing Mothers

Fluconazole is secreted in human milk at concentrations similar to maternal plasma concentrations. Caution should be exercised when fluconazole is administered to a nursing woman.

Pediatric Use

An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See )

The use of fluconazole in children with cryptococcal meningitis, esophagitis, or systemic infections is supported by the efficacy shown for these indications in adults and by the results from several small noncomparative pediatric clinical studies. In addition, pharmacokinetic studies in children (See ) have established a dose proportionality between children and adults. (See )

In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of fluconazole was similar to that reported for the treatment of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days, respectively, following cessation of therapy.

The efficacy of fluconazole for the suppression of cryptococcal meningitis was successful in 4 of 5 children treated in a compassionate-use study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children.

The safety profile of fluconazole in children has been studied in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See )

Efficacy of fluconazole has not been established in infants less than 6 months of age. (See ) A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with fluconazole.

Geriatric Use

In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 65 and older (9%, n = 339) than for younger patients (14%, n = 2240). However, there was no consistent difference between the older and younger patients with respect to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and diarrhea occurred in greater proportions of older patients. Similar proportions of older patients (2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In post-marketing experience, spontaneous reports of anemia and acute renal failure were more frequent among patients 65 years of age or older than in those between 12 and 65 years of age. Because of the voluntary nature of the reports and the natural increase in the incidence of anemia and renal failure in the elderly, it is however not possible to establish a casual relationship to drug exposure.

Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65 and older to evaluate whether they respond differently from younger patients in each indication. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, care should be taken to adjust dose based on creatinine clearance. It may be useful to monitor renal function. (See and )

What are the side effects of Fluconazole in Dextrose?

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 have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

In Patients Receiving Multiple Doses for Other Infections

Sixteen percent of over 4,000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.

Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%).

The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4,048 patients receiving fluconazole for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.

In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with fluconazole. (See ) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of fluconazole.

In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.

Post-Marketing Experience

In addition, the following adverse events have occurred during post-marketing experience:

Immunologic:

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Adverse Reactions in Children

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

In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase.

**Percentage of Patients with Treatment-related Side Effects**
	Fluconazole(N = 577)	Comparative Agents(N = 451)
With any side effect	13.0	9.3
Vomiting	5.4	5.1
Abdominal pain	2.8	1.6
Nausea	2.3	1.6
Diarrhea	2.1	2.2

What should I look out for while using Fluconazole in Dextrose?

Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg/day or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See and )

What might happen if I take too much Fluconazole in Dextrose?

There have been reports of overdose with fluconazole accompanied by hallucination and paranoid behavior.

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if clinically indicated) should be instituted.

Fluconazole is largely excreted in urine. A 3-hour hemodialysis session decreases plasma levels by approximately 50%.

In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.

How should I store and handle Fluconazole in Dextrose?

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing.Product: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLEProduct: 71335-0114NDC: 71335-0114-1 30 TABLET in a BOTTLENDC: 71335-0114-3 60 TABLET in a BOTTLENDC: 71335-0114-4 90 TABLET in a BOTTLENDC: 71335-0114-5 120 TABLET in a BOTTLENDC: 71335-0114-6 100 TABLET in a BOTTLENDC: 71335-0114-7 180 TABLET in a BOTTLENDC: 71335-0114-8 25 TABLET in a BOTTLEProduct: 71335-0127NDC: 71335-0127-1 100 TABLET in a BOTTLENDC: 71335-0127-2 30 TABLET in a BOTTLENDC: 71335-0127-3 60 TABLET in a BOTTLENDC: 71335-0127-4 90 TABLET in a BOTTLENDC: 71335-0127-5 180 TABLET in a BOTTLE

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Clinical Information

Chemical Structure

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Clinical Pharmacology

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (C) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50 to 400 mg, fluconazole plasma concentrations and area under the plasma concentration-time curve (AUC) are dose proportional.

Administration of a single oral 150 mg tablet of fluconazole to ten lactating women resulted in a mean C of 2.61 mcg/mL (range: 1.57 to 3.65 mcg/mL).

Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on Day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11 to 12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see ). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid (CSF) are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue: plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid: plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.

The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. (See ) A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.

In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the adrenocorticotropic hormone (ACTH)-stimulated cortisol response.

Non-Clinical Toxicology

Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg/day or higher based upon results of a multiple dose interaction study. Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole. (See and )

(See and ) Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19, 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, CYP2C19, and CYP3A4 coadministered 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 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed. These are described in greater detail below:

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. (See ) During post-marketing surveillance, there have been rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Most of these reports involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life threatening ventricular arrhythmias and torsade de pointes.

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

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. This combination should be avoided.

Fluconazole should be administered with caution to patients with renal dysfunction.

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 metabolized through CYP2C9 and CYP3A4 should be monitored.

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

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 have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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