MYCOZAN

Fluconazole, commonly known as Diflucan, is an antifungal drug used for the treatment of both systemic and superficial fungal infections in a variety of tissues.

It was initially approved by the

FDA in 1990.

This drug is an azole antifungal, in the same drug family as ketoconazole and itraconazole.

Fluconazole has many advantages over the other antifungal drugs including the option of oral administration.

The side effect profile of this drug is minimal.

It has been demonstrated as an efficacious treatment for vaginal yeast infections in one single dose.

Fluconazole can be administered in the treatment of the following fungal infections 27: 1) Vaginal yeast infections caused by Candida Peritonitis (inflammation of the peritoneum) caused by Candida A note on fungal infection prophylaxis Patients receiving bone marrow transplantation who are treated with cytotoxic chemotherapy and/or radiation therapy may be predisposed to candida infections, and may receive fluconazole as prophylactic therapy.

A note on laboratory testing

Obtaining specimens for fungal culture and other important laboratory studies such as serology or pathology is advised before starting fluconazole therapy in order to isolate the organisms to be eliminated through treatment.

It is permissible to start therapy before the results are available, however, adjusting the therapy once laboratory results confirm the causative organism may be necessary.

Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections 27: Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth as well as cell adhesion, thereby treating fungal infections and their symptoms. 27, 2, 5 The fungistatic activity of fluconazole has also been shown in normal and immunocompromised animal models with both systemic and intracranial fungal infections caused by Cryptococcus neoformans and for systemic infections caused by Candida albicans.

It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole. 11, 12, 13 This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy. 14, 20 A note on steroidal effects of fluconazole There has been some concern that fluconazole may interfere with and inactivate human steroids/hormones due to the inhibition of hepatic cytochrome enzymes.

Fluconazole has demonstrated to be more selective for fungal cytochrome P-450 enzymes than for a variety of mammalian cytochrome P-450 enzymes.

Fluconazole 50 mg administered daily for up to 28 days in individuals of reproductive age has been show to have no effect on testosterone plasma concentrations of males and plasma concentrations of steroids in females.

A 200-400 mg dose of fluconazole showed no clinically relevant effect on steroid levels or on ACTH-stimulated steroid response in healthy males, in one clinical study mentioned on the European Medicines Agency label.

Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data. 10, 18.

The pharmacokinetic properties of fluconazole are comparable after administration by the intravenous (Intravenous) and oral (Oral) routes.

In healthy volunteers, the bioavailability of Oral administered fluconazole is measured to be above 90%.

It is extensively absorbed in the gastrointestinal tract when an oral dose is taken.

Oral absorption is not affected by food intake with fluconazole but may increase the time until the maximum concentration is reached. 26, 21 Tmax (or the time taken to achieve the maximum concentration) in one clinical study of healthy patients receiving 50 mg/kg of fluconazole was 3 hours.

Peak plasma concentrations (Cmax) in fasting and healthy volunteers occur between 1-2 hours post-dose.

Steady-state concentrations are achieved within 5-10 days after oral doses of 50-400 mg administered once daily.

Administration of a loading dose on the first day of fluconazole treatment, or twice the usual daily dose, leads to plasma concentrations close to steady-state by the second day.

AUC (area under the curve) was 20.3 in healthy volunteers receiving 25 mg of fluconazole.

A note on the capsule and powder form and malabsorption syndromes The capsule forms of fluconazole often contain lactose and should not be administered with hereditary galactose intolerance, Lapp lactase enzyme deficiency, or malabsorption of glucose/galactose.

The powder form, used for the oral suspension, lists sucrose as an ingredient and should not be used in patients who have been diagnosed with fructose, glucose/galactose malabsorption, and sucrase-isomaltase enzyme deficiency.

The apparent volume of distribution is said to be similar to the volume of distribution of total body water.

One clinical study of healthy volunteers administered 50 mg/kg of fluconazole was 39 L, based on a body weight of 60 kg.

Fluconazole shows substantial penetration in many body fluids, which is a property that renders it an ideal treatment for systemic fungal infections, especially when administered over a longer time. 21, 27 Fluconazole is found in high concentrations in the stratum corneum and dermis-epidermis of skin, in addition to eccrine sweat.

Fluconazole is found to accumulate especially well in the stratum corneum, which is beneficial in superficial fungal infections.

Saliva and sputum concentrations of fluconazole are found to be similar to the plasma concentrations.

In patients diagnosed with fungal meningitis, fluconazole CSF (cerebrospinal fluid) levels are measured to be about 80% of the corresponding plasma levels.

Therefore, fluconazole crosses the blood-brain barrier.

The meninges are increasingly permeable to fluconazole in states of inflammation, facilitating treatment in meningitis.

Fluconazole is metabolized minimally in the liver.

Fluconazole is an inhibitor of

CYP2C9, CYP3A4 and CYP2C19. 26, 27 Two metabolites were detected in the urine of healthy volunteers taking a 50 mg radiolabeled dose of fluconazole; a glucuronidated metabolite on the hydroxyl moiety (6.5%) and a fluconazole N-oxide metabolite (2%).

The same study indicated that no signs of metabolic cleavage of fluconazole were observed, suggesting a difference in metabolism when compared to other agents in the same drug class, which are heavily metabolized in the liver. 23, 24 Hover over products below to view reaction partners Fluconazole O-Glucuronidated metabolite, Fluconazole Fluconazole N-oxide.

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

About 11% of the dose is excreted in the urine as metabolites. 27.

A study of a 50 mg radiolabeled dose of fluconazole revealed that 93.3% of the dose was found excreted in the urine.

A note on renal failure

The pharmacokinetics of fluconazole are significantly affected by renal dysfunction.

The dose of fluconazole may need to be reduced in patients with decreased renal function.

A 3-hour hemodialysis treatment lowers plasma fluconazole concentrations by about 50%.

The terminal elimination half-life in the plasma is approximately 30 hours (range: 20-50 hours) after oral administration.

The long plasma elimination half-life supports a single-dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.

Patients with renal failure may require dosage adjustment, and half-life can be significantly increased in these patients.

This drug is mainly eliminated by the kidneys and the mean body clearance in adults is reported to be 0.23 mL/min/kg.

One clinical study of healthy subjects showed total clearance of 19.5 ± 4.7 mL/min and renal clearance of 14.7 ± 3.7 mL/min (1.17 ± 0.28 and 0.88 ± 0.22 L/h).

Clearance in the pediatric population varies according to age, as does clearance in patients with renal failure.

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Acute oral toxicity (LD50) : 1271 mg/kg (rat) MSDS Overdose information Fluconazole overdoses have been associated with hallucination and paranoia, sometimes in combination.

In cases of overdose, employ supportive treatment.

Gastric lavage may be necessary.

Other modalities such as forced diuresis or hemodialysis may also be used.

A note on liver toxicity The

FDA label warns that this drug carries a risk of hepatotoxicity.

Rare but serious cases of serious hepatic toxicity have been reported, especially in patients with serious underlying medical conditions using fluconazole.

This group of patients has an increased risk of fatality when using fluconazole.

In patients with existing liver dysfunction, use caution during fluconazole therapy.

Those who are found to have abnormal liver function tests during therapy should be carefully monitored for the development of increasingly severe injury to the liver.

Fluconazole should be stopped if its use is likely to be the underlying cause of liver injury, and medical attention should be sought. 27, 25 Fluconazole induced hepatotoxicity is usually reversible.

Carcinogenesis, mutagenesis, and impairment of fertility Fluconazole demonstrated no evidence of carcinogenic risk in mice and rats treated Oral for 24 months at doses equivalent to approximately 2-7 time the recommended human dose).

Male rats given fluconazole at doses equivalent to supratherapeutic human doses showed an increased incidence of hepatocellular adenomas.

Cytogenetic studies in vivo and in vitro demonstrated no sign of chromosomal mutation.

The significance of these findings for humans is unknown.

Use in pregnancy

There are no sufficient and well-controlled studies of fluconazole use in pregnant women.

Available human data do not show an increased risk of congenital anomalies after pregnant women were treated with standard doses (<200 mg/day) of fluconazole, either in a single dose or multiple doses in the first trimester did not appear to impact the fetus negatively.

Several case reports describe rare but striking congenital anomalies observed in infants who were exposed to fluconazole at high doses reaching 400-800 mg/day, primarily in the first trimester of pregnancy.

Similar findings were observed in animal studies.

If this drug is administered during pregnancy, or if the patient becomes pregnant while taking fluconazole, the risk should be discussed thoroughly.

Use in nursing

Fluconazole is secreted in breastmilk at high concentrations.

Exercise caution if this drug is used during nursing.

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.

In rare cases, anaphylaxis has been reported.

Exfoliative skin disorders during treatment with fluconazole have been reported.

Fatal outcomes have been reported in patients with serious underlying diseases.

Patients with deep seated fungal infections who develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress.

Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole.

Potential for fetal harm

There are no adequate and well-controlled clinical trials of fluconazole in pregnant women.

Case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester.

These reported anomalies are similar to those seen in animal studies.

If fluconazole 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.

Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with fluconazole to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.

Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

Fluconazole tablets are 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 tablets to patients with hypersensitivity to other azoles.

Coadministration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as erythromycin, pimozide, and quinidine are contraindicated in patients receiving fluconazole.

Single Dose Vaginal candidiasis: The recommended dosage of fluconazole for vaginal candidiasis is 150 mg as a single oral dose.

Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL AND INTRAVENOUS ADMINISTRATION.

In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy.

The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy.

Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided.

An inadequate period of treatment may lead to recurrence of active infection.

Patients with

AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.

Oropharyngeal candidiasis

The recommended dosage of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily.

Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.

Esophageal candidiasis

The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily.

Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy.

Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.

Systemic Candida infections

For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established.

In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used.

Urinary tract infections and peritonitis

For the treatment of Candida urinary tract infections and peritonitis, daily doses of to 200 mg have been used in open, noncomparative studies of small numbers of patients.

Cryptococcal meningitis

The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily.

A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy.

The recommended duration of treatment for initial therapy of cryptococcal meningitis is to 12 weeks after the cerebrospinal fluid becomes culture negative.

The recommended dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily.

Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily.

Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils cells/mm 3 ) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells/mm 3.

The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults * Some older children may have clearances similar to that of adults.

Absolute doses exceeding 600 mg/day are not recommended. 3 mg/kg 100 mg 6 mg/kg 200 mg 12 * mg/kg 400 mg Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns.

Based on the prolonged half-life seen in premature newborns (gestational age to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours.

After the first two weeks, these children should be dosed once daily.

No information regarding fluconazole pharmacokinetics in full-term newborns is available.

The recommended dosage of fluconazole for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily.

Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.

For the treatment of esophageal candidiasis, the recommended dosage of fluconazole in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily.

Doses up to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.

Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.

For the treatment of candidemia and disseminated Candida infections, daily doses of to 12 mg/kg/day have been used in an open, noncomparative study of a small number of children.

For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily.

A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy.

For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.

Dosage In Patients With Impaired Renal Function: Fluconazole is cleared primarily by renal excretion as unchanged drug.

There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function.

In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 mg to 400 mg should be given.

After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (mL/min) Recommended Dose (%) >50 100 ≤50 (no dialysis) 50 Hemodialysis 100% after each hemodialysis Patients on hemodialysis should receive 100% of the recommended dose after each hemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.

These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses.

Further adjustment may be needed depending upon clinical condition.

When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) x (140 - age) ————————————— 72 x serum creatinine (mg/100 mL) Females: 0.85 × above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults.

The following formula may be used to estimate creatinine clearance in children: K x linear length or height (cm) ————————————— serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants). Administration Fluconazole tablets are administered orally.

Fluconazole tablets can be taken with or without food.

USP, 150 mg are pink mottled, biconvex, capsule shaped uncoated tablets with “C” debossed on one side and “10” debossed on other side.

Unit dose package of 1 NDC68071-3474-1 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

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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.

A few published case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester.

These reported anomalies are similar to those seen in animal studies.

Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with fluconazole to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.

If fluconazole 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.

Spontaneous abortions and congenital abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies.

There are no adequate and well-controlled studies of fluconazole in pregnant women. See WARNINGS: Potential for Fetal Harm. Human Data Case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400 to 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.

Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg and at 5 mg/kg, 25 mg/kg, 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 body surface area [BSA] comparison), 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 mg/kg or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 mg/kg and 50 mg/kg and higher doses.

At doses ranging from to 320 mg/kg (approximately 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 craniofacial 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.

Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose, based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued breastfeeding 5 days to 19 months postpartum.

The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours post-dose) was 0.39 mg/kg/day, which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis. (Labeled pediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose is 13% of 3 mg/kg/day maintenance dose).

There are no data on fluconazole levels in milk after repeated use or after high-dose fluconazole.

A published survey of 96 breastfeeding women who were treated with fluconazole 150 mg every other day (average of 7.3 capsules [range to 29 capsules]) for lactation-associated candida of the breasts reported no serious adverse reactions in infants.

Caution should be exercised when fluconazole is administered to a nursing woman.

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.

The use of fluconazole 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 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 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 and 18 days, respectively, following cessation of therapy.

The efficacy of fluconazole for the suppression of cryptococcal meningitis was successful in 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 to 15 mg/kg/day for to 1,616 days. See ADVERSE REACTIONS. Efficacy of fluconazole has not been established in infants less than 6 months of age.

A small number of patients ranging in age from 1 day to 6 months have been treated safely with fluconazole.

In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in fewer patients aged 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 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 causal relationship to drug exposure.

Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 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.