CYTORX Tablets (Flucytosine)

Table of Content

Fungal infections are a global health issue, affecting millions of patients every year.   The treatment of invasive fungal infections (IFIs) is often complicated by low tolerability, narrow spectrum of activity, low penetration at various sites of infection, toxicities, major drug interactions, or resistance of antifungals such as azoles, echinocandins and amphotericin B.

Each tablet of CYTORX contains 500 mg of flucytosine. Flucytosine is a prodrug which is converted to 5-fluorouracil. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis or interfere with the biosynthesis of fungal DNA.

The advantages of flucytosine include its rapid absorption by the digestive tract at a rate of 90%. It penetrates and achieves good levels in heart, lung, liver, spleen, kidney tissues, including the cerebrospinal, vitreous fluids and urine.

CYTORX is indicated in the treatment of serious infections caused by susceptible strains of Candida (such as septicemia, endocarditis and urinary system infections) and/or Cryptococcus (such as meningitis and pulmonary infections).

Flucytosine is usually administered in combination with amphotericin B as it is synergistic and in some cases, it allows dose reduction and reduces the risk of the emergence of secondary resistance to flucytosine.

The combination of amphotericin B with flucytosine has shown to be the most rapidly fungicidal regimen and leading to more rapid sterilization of the cerebrospinal fluid in patients with HIV and non-HIV associated cryptococcal meningitis.

In patients with invasive candidiasis such as urinary tract infections, candidemia, endocarditis, especially caused by non-albicans Candida species, which often have either reduced susceptibility or resistance to fluconazole, addition of flucytosine to amphotericin B should be strongly considered as it has shown improved clinical outcomes. Limited data is also available against candidiasis and cryptococcosis for flucytosine in combination with azoles.

Dosage of CYTORX ranges from 50 to 150 mg/kg per day, depending on the nature of the infection, its site and sensitivity of the causative agent. The daily dosage must be divided into three or four oral doses.

Composition

CYTORX

Each uncoated tablet contains:

Flucytosine IP……………500 mg

Excipients………………...q.s.

Dosage Form

Oral (uncoated) tablets.

Pharmacology

Pharmacodynamics

Mechanism of Action

Flucytosine is 5-fluorocytosine (5‐FC), a fluorinated pyrimidine, which is related to fluorouracil and floxuridine. Flucytosine is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal ribonucleic acid (RNA) or interfere with the biosynthesis of fungal deoxyribonucleic acid (DNA) through the inhibition of the enzyme thymidylate synthetase.

Mechanism of Resistance

Flucytosine resistance may arise from a mutation of an enzyme necessary for the cellular uptake or metabolism of flucytosine or from an increased synthesis of pyrimidines, which compete with the active metabolites of flucytosine (fluorinated antimetabolites). Resistance to flucytosine has been shown to develop during monotherapy after prolonged exposure to the drug.

Candida krusei should be considered to be resistant to flucytosine.

Microbiology

Flucytosine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections:

Candida albicans

Cryptococcus neoformans

The following in vitro data are available, but their clinical significance is unknown.

Flucytosine exhibits in vitro minimum inhibitory concentrations (MIC values) of 4 mcg/mL, or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of flucytosine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Candida dubliniensis

Candida glabrata

Candida guilliermondii

Candida lusitaniae

Candida parapsilosis

Candida tropicalis

Candida krusei should be considered to be resistant to flucytosine.

In vitro activity of flucytosine is affected by the test conditions. It is essential to follow the approved standard method guidelines.

Strains initially susceptible to flucytosine may acquire resistance during treatment. It is therefore recommended that the sensitivity of these strains be evaluated before and also during treatment. Use of 5‐FC discs is recommended.

For some pathogen species, synergy has been demonstrated in vitro and in vivo with a combination of flucytosine and amphotericin B, which is particularly pronounced in the case of organisms with reduced susceptibility to flucytosine.

Drug Combination

Flucytosine is usually administered in combination with amphotericin B due to lack of cross-resistance and reported synergistic activity of both drugs.

Pharmacokinetics

Absorption

When administered orally, this treatment is absorbed by the digestive tract at a rate of 90% and produces the same concentrations as those observed following short‐term intravenous (IV) infusion with an identical dose. After single IV administration, peak serum concentrations are approximately equivalent, in micrograms/mL, to the dose administered in mg/kg.

Distribution

The volume of distribution is between 0.5 and 1 L/kg. This medicinal product is diffused throughout the body, including in the cerebrospinal fluid (CSF), as a result of very low binding (<5%) to plasma proteins. Urinary concentrations of this medicinal product are always higher than plasma concentrations in patients with normal renal function.

Metabolism

More than 90% of the flucytosine dose is recovered in unchanged form in the urine. Flucytosine is metabolized (probably by intestinal bacteria) to 5‐fluorouracil (5‐FU). The 5‐FU/5‐FC plasma concentration ratio is low.

Excretion

The plasma half‐life is 3 to 6 hours. Elimination is rapid via the kidneys, mainly by glomerular filtration, in unchanged form. In patients with renal impairment, the plasma half‐life is prolonged; the dosage must therefore be adjusted to creatinine clearance. Flucytosine is dialyzable.

Indications

Flucytosine is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus.

Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine.

Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported.

Flucytosine should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to flucytosine.

Dosage and Administration

Dosages range from 50 to 150 mg/kg per day, depending on the nature of the infection, its site and sensitivity of the causative agent. The daily dosage must be divided into three or four oral doses.

Combination with Other Antifungals

The flucytosine/amphotericin B combination is synergistic: in some cases, it allows a dose reduction and reduces the risk of the emergence of secondary resistance to flucytosine.

There does not seem to be antagonism with imidazole derivatives.

Special Populations

Renal Impairment

Doses must be administered at longer intervals, according to the following dosing regimen:

Table 1: Flucytosine Dosage Adjustment for Patients with Renal Impairment

Creatinine Clearance

Single dose

Interval

≥40 mL/min

25–50 mg/kg

6 hours

20–40 mL/min

25–50 mg/kg

12 hours

10–20 mL/min

25–50 mg/kg

24 hours

<10 mL/min

Single dose of 25 mg/kg, then plasma monitoring for 12 hours after the initial dose, before repeating the dose.

Patients on Dialysis

Since  flucytosine  is  dialysable,  the  dose  of  this  medicinal  product  must  be  repeated  after  each blood‐cleansing session.

Contraindications

Flucytosine is contraindicated in the following:

  • In patients with known hypersensitivity to flucytosine or to any of the excipients.
  • In combination with certain antiviral nucleosides such as brivudine, sorivudine and their analogs . 
  • In breastfeeding women.

Warnings and Precautions

General

Treatment with this medicinal product should be administered after identification of the strain and an assessment with regard to flucytosine susceptibility, due to possible primary resistance. It should be maintained under regular medical surveillance.

Flucytosine must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they 1) have a hematologic disease; 2) are being treated with radiation or drugs that depress bone marrow; or, 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.

Before therapy with flucytosine is instituted, electrolytes (because of hypokalemia) and the hematologic and renal status of the patient should be determined. Close monitoring of the patient during therapy is essential.

Drug Interactions

Combinations Requiring Precautions for Use

Zidovudine

Increased hematological toxicity (additive myelotoxic effects). More frequent monitoring of blood counts is recommended.

Drugs with Bone Marrow or Renal Toxicity

In combination with a medicinal product with bone marrow or renal toxicity, more frequent monitoring of blood counts is recommended throughout the entire treatment, in view of the increased risk of hematological disorders.

Cytosine Arabinoside

Cytosine arabinoside, a cytostatic agent, has been reported to inactivate the antifungal activity of flucytosine by competitive inhibition. Drugs that impair glomerular filtration may prolong the biological half-life of flucytosine.

Laboratory Tests

Since renal impairment can cause progressive accumulation of the drug, blood concentrations and kidney function should be monitored during therapy. Hematologic status (leukocyte and thrombocyte count) and liver function (alkaline phosphatase, serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase ) should be determined at frequent intervals during treatment as indicated.

It is recommended that blood counts and liver function tests be performed (alanine aminotransferase , aspartate aminotransferase , alkaline phosphatases) along with regular monitoring, especially at the start of treatment.

Drug/Laboratory Test Interactions

Measurement of serum creatinine levels should be determined by the Jaffé reaction, since flucytosine does not interfere with the determination of creatinine values by this method. Most automated equipment for measurement of creatinine makes use of the Jaffé reaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Flucytosine has not undergone adequate animal testing to evaluate carcinogenic potential. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of S. typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes.

Flucytosine was non-mutagenic in three different repair assay systems (i.e., rec, uvr and pol). There have been no adequate trials in animals on the effects of flucytosine on fertility or reproductive performance. The fertility and reproductive performance of the offspring (F generation) of mice treated with 100 mg/kg/day (345 mg/m2/day or 0.059 times the human dose), 200 mg/kg/day (690 mg/m2/day or 0.118 times the human dose) or 400 mg/kg/day (1,380 mg/m2/day or 0.236 times the human dose) of flucytosine on days 7 to 13 of gestation was studied; the in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring.

Influence on Diagnostic Tests

Flucytosine may interfere in the enzymatic (2‐step) creatinine assay by causing an artificial elevation of the values observed.

Contraception in Men and Women

Flucytosine is partially metabolized to 5‐fluorouracil, which is genotoxic and considered to be potentially teratogenic in humans. Women of childbearing potential have to use effective contraception during treatment and up to 1 month after discontinuation of treatment. Male patients (or their female partners of childbearing potential) have to use effective contraception during treatment and up to 3 months after discontinuation of treatment.

Renal Impairment

Flucytosine must be given with extreme caution to patients with impaired renal function. Since flucytosine is excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. Flucytosine serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.

As elimination of this medicinal product is exclusively renal, creatinine clearance must be regularly monitored in patients with renal impairment or in combination with a nephrotoxic agent likely to alter renal function, and the dosage must be adjusted according to this clearance.

Almost 65 to 75% of flucytosine present in the body is removed by hemodialysis. Therefore, in patients on dialysis, administration of this medicinal product must be repeated after each dialysis or blood‐cleansing session.

Pregnancy

Studies  in  animals  have  shown  reproductive  toxicity  for  flucytosine  and  one  of  its  metabolites (5‐fluorouracil) (teratogenicity and embryotoxicity). In humans, flucytosine crosses the placenta.

There are very limited data from the use of flucytosine in pregnant women.  Embryonic or foetal toxicity cannot be excluded, especially in the event of exposure during the first trimester. Therefore, flucytosine must not be used during pregnancy and in women of childbearing potential without effective contraception, unless absolutely necessary in case of life‐threatening infections and in the absence of an effective therapeutic alternative.

If flucytosine is administered during pregnancy, the patient must be advised of the teratogenic risk with flucytosine and careful prenatal and postnatal monitoring must be performed. Furthermore, if administered up until delivery and in view of the safety profile of flucytosine, neonatal surveillance (hematological and hepatic) must be performed.

Lactation

There are no data on the excretion of flucytosine in human milk. Breastfeeding is contraindicated during treatment with flucytosine.

Pediatric Use

Flucytosine tablets are not suitable for children under 6 years of age, who often have difficulty swallowing them due to their size. In this case, the tablets can be crushed to facilitate administration.

Undesirable Effects

  • Gastrointestinal disorders such as nausea, diarrhea and, more rarely, vomiting.
  • Hematological disorders: (leukopenia, thrombocytopenia), mainly moderate and transient and more common in patients with renal impairment or when serum flucytosine levels exceed 100 μg/mL. More severe disorders (aplasia, agranulocytosis), potentially irreversible and possibly fatal in exception cases, have sometimes been observed; mainly, however, in patients undergoing treatment with bone marrow toxicity.
  • Hepatic disorders: elevated transaminase levels (ASAT, ALAT), alkaline phosphatases, resolving upon discontinuation of treatment, as well as rare acute cases of hepatitis, have sometimes been observed.
  • Cardiac disorders in exceptional cases, usually ischemic in nature.
  • Allergic manifestations: rare cases of skin rash and exceptional cases of Lyell’s syndrome.

Given below are the adverse reactions that have occurred during treatment with flucytosine capsules and are grouped according to the organ system affected:

  • Cardiovascular: Cardiac arrest, myocardial toxicity, ventricular dysfunction.
  • Respiratory: Respiratory arrest, chest pain, dyspnea.
  • Dermatologic: Rash, pruritus, urticaria, photosensitivity.
  • Gastrointestinal: Nausea, emesis, abdominal pain, diarrhea, anorexia, dry mouth, duodenal ulcer, gastrointestinal hemorrhage, acute hepatic injury, including hepatic necrosis with possible fatal outcome in debilitated patients, hepatic dysfunction, jaundice, ulcerative colitis, enterocolitis, bilirubin elevation, increased hepatic enzymes.
  • Genitourinary: Azotemia, creatinine and blood urea nitrogen (BUN) elevation, crystalluria, renal failure.
  • Hematologic: Anemia, agranulocytosis, aplastic anemia, eosinophilia, leukopenia, pancytopenia, thrombocytopenia, and fatal cases of bone marrow aplasia.
  • Neurologic: Ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, pyrexia, vertigo, sedation, convulsions.
  • Psychiatric: Confusion, hallucinations, psychosis.
  • Miscellaneous: Fatigue, hypoglycemia, hypokalemia, weakness, allergic reactions, Lyell’s syndrome.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@Cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PVPI on 1800 180 3024.

By reporting side effects, you can help provide more information on the safety of this product.

Overdosage

In the event of overdose, which may result from impaired renal function in particular, exaggerated adverse reactions, especially hematological, can be expected. Blood counts must, therefore, be very closely monitored.

There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 mcg/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis).

In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended.

Adequate fluid intake should be maintained, by the IV route if necessary. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted.

Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage.

Incompatibility

Not applicable.

Storage and Handling Instructions

Store below 25°C, excursion permitted between 15°C to 30°C. Protect from light. Keep all medicines out of reach of children.     

Packaging Information

CYTORX: 10 tablets are packed in one blister, one such blister is packed in carton along with pack insert.

Last Reviewed: February 2019

Last Updated: February 2019