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Diflucan (Fluconazole) - Warnings and Precautions

 
 



WARNINGS

(1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy should be monitored for the development of more severe hepatic injury. DIFLUCAN should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to DIFLUCAN.

(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.

(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions progress.

(4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400–800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus (See PRECAUTIONS, Pregnancy.)

PRECAUTIONS

General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. 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.

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.

DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.

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

Single Dose

The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the treatment of vaginal yeast infections should be weighed against the acceptability of a higher incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.)

Drug Interactions

(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and CONTRAINDICATIONS.) DIFLUCAN 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 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 4–5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below:

Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Triazolam
Oral Contraceptives
Pimozide
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
Vitamin A
Zidovudine

Oral hypoglycemics

Clinically significant hypoglycemia may be precipitated by the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When DIFLUCAN 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 CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Coumarin-type anticoagulants

Prothrombin time may be increased in patients receiving concomitant DIFLUCAN 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 DIFLUCAN and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Phenytoin

DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Cyclosporine

DIFLUCAN may significantly increase cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Rifampin

Rifampin enhances the metabolism of concurrently administered DIFLUCAN. Depending on clinical circumstances, consideration should be given to increasing the dose of DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Theophylline

DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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 DIFLUCAN 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 CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.) 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 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 CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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 CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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 CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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 CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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 CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20–32%, and increases t½ by 25–50 % 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 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.

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 T½ 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-amitriptyline may be measured at initiation of the combination therapy and after one 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 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.

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 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.

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 Cmax and AUC of flurbiprofen were 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] 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 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 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.

Saquinavir

Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55%, and decreases 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, 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 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 CLINICAL PHARMACOLOGY 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 2–7× 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 4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 µg/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, 10, or 20 mg/kg or with parenteral doses of 5, 25, 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, 20, and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg (approximately 5–15× 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 CLINICAL PHARMACOLOGY.)

Pregnancy

Teratogenic Effects

Pregnancy Category C

Single 150 mg tablet use for Vaginal Candidiasis

There are no adequate and well-controlled studies of Diflucan in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg.

Pregnancy Category D

All other indications

A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400–800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.)

Human Data

Several published epidemiologic studies do not suggest an increased risk of congenital anomalies associated with low dose exposure to fluconazole in pregnancy (most subjects received a single oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400–800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies.

Animal Data

Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose based on BSA); no adverse fetal effects were observed.

In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition

Nursing Mothers

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

Pediatric Use

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

The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or systemic Candida 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 CLINICAL PHARMACOLOGY) have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)

In a noncomparative study of children with serious systemic fungal infections, most of which were candidemia, the effectiveness of DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN 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 ADVERSE REACTIONS.)

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

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 CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Page last updated: 2012-05-22

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