Flucytosine - Indication, Dosage, Precautions, and Pharmacological Aspects

Overview:

Flucytosine was first created in 1957, and the FDA (Food and Drug Administration) approved it in 1971 for treating severe Candida and Cryptococcus infections. It does not impact mammalian cells and only exerts its pharmacologic effects in the presence of fungal cells. Since there is a significant chance that using Flucytosine alone will result in the development of drug resistance, monotherapy is normally not advised. It is used more frequently in combination with other antifungal drugs. Flucytosine can be used in place of a second medicine for non-systemic, non-life-threatening fungal infections, such as Candida infections of the vagina and lower urinary tract. Flucytosine and Amphotericin B are frequently used together in the treatment of systemic infections like endophthalmitis, meningitis, peritonitis, endocarditis, cystitis, and systemic infections such as Cryptococcal meningitis and candidiasis.

It is crucial to remember that each person's medical situation should be considered when using Flucytosine, particularly their renal function. Flucytosine does not go through much metabolism in the human body, and between 85 percent and 95 percent of the medication is eliminated through the urine in its pure form after 24 hours of administration. This means that selecting the right dosage and frequency of delivery for this drug depends critically on renal function.

Drug Group: Flucytosine (5-fluorocytosine) is a systemic antifungal medication that acts as an antimetabolite agent.

Available Doses and Dosage Forms: Flucytosine is available in capsules. These capsules are available in two strengths, each containing 250 mg (milligrams) or 500 mg of Flucytosine. It is often given orally every six hours in separate doses between 50 and 150 mg per kilogram of the patient's weight (50 to 150 mg/kg/day). To reduce the risk of nausea or vomiting, a few capsules should be taken at a time for 15 minutes.

For Patients:

What Are Fungal Diseases?

Any illness or condition brought on by a fungus is a fungal infection. They often impact the skin, hair, nails, or mucous membranes but can also spread to other body parts, including the lungs. A compromised immune system puts a person at a greater risk for fungal infections. Usually, fungal infections are treated with antifungal drugs.

How Does Flucytosine Work?

Flucytosine enters the fungal cell with the help of cytosine permease, where it is converted to 5-Fluorouracil in fungi. Fungal RNA contains large amounts of 5-Fluorouracil, which prevents the creation of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). The fungus dies as a result of its imbalanced growth.

What Is the Dosage of Flucytosine?

• Oral - An oral dosage of 50 mg to 150 mg/kg/day (milligram per kilogram per day) administered every six hours might be used to begin treatment with the drug. The medicine is bioavailable between 75 and 90 percent after being taken orally.

• Suspension - Flucytosine in suspension is 2.5 gm/250 ml (grams per milliliter).

• Intravenous - Flucytosine administered intravenously needs to keep concentrations at 50 mg/L (milligrams per liter).

• Intrathecal - For intrathecal administration, the FDA has not yet approved Flucytosine.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Any prescription and over-the-counter medications, vitamins, nutritional supplements, and herbal products that a patient is taking or wants to take must be disclosed to the doctor and pharmacist.

• If a patient using Flucytosine is expecting a child, intends to become pregnant, or is currently nursing a child, the doctor should be notified immediately.

• Inform the physician of any medical condition a patient had in the past or is having currently. They should be particular about any kidney issues, decreased bone marrow function (low white, red, or platelet blood counts), a specific metabolic disorder (DPD enzyme deficiency), liver issues, mineral imbalance (such as low blood potassium levels), and radiation therapy.

• The doctor should also be informed about any allergy or allergic reaction the patient has or might have encountered.

• Flucytosine may increase the risk of contracting an illness or worsen an existing one. Avoid contact with someone with an infection that can spread quickly, such as the flu, chicken pox, COVID-19, and measles. If a person has been exposed to an infection, they should consult the doctor.

• Patients must inform their healthcare provider regarding their use of Flucytosine before receiving any vaccinations or immunizations. Avoid interacting with anyone who has just received a live vaccine, such as a nasal flu shot.

How Is Flucytosine Administered?

Flucytosine should be taken as the doctor advises, every six hours or four times a day. Do not swallow the entire amount of capsules of one dose at once, as it can cause stomach upset or distress. One entire dose should be swallowed slowly within 15 minutes of the period. The patient’s weight, medical history, and treatment response determine the dosage. When the level of the drug in the body is maintained at a steady level, Flucytosine performs at its best. Take this medication at regular intervals. Take it simultaneously every day for the best results and to avoid missing the dose. It is always advised to complete the entire dosing of the drug as advised by the doctor and not to leave the dosing schedule incomplete in between. This may reactivate the fungal infection.

What Are the Side Effects of Flucytosine?

• Flucytosine frequently causes gastrointestinal side effects such as:

  • Nausea.

  • Vomiting.

  • Abdominal pain.

  • Diarrhea.

• Adverse effects that can affect the skin are rashes and itching.

• Acute hepatitis.

• Nephrotoxicity (loss of kidney function).

• More serious hematologic side effects, including bone marrow suppression, pancytopenia (a decrease in the count for the three types of blood cells), aplastic anemia (a disorder brought on by the body's insufficient production of new blood cells), and agranulocytosis (a disease where there are less than 100 neutrophils per microliter of blood (absolute neutrophil count, or ANC), have occasionally been documented.

• Flucytosine use has also, though infrequently, been linked to serious gastrointestinal side effects like colon perforation and inflammatory bowel diseases like ulcerative colitis.

Dietary Considerations: No specific dietary modification unless instructed by the doctor.

Missed Dose: If possible, one should take a missed dose as soon as they remember it. If the next dose timing is approaching, it is advisable to skip the missed dose and go back to the regular dosing plan. Refrain from doubling the dose to make up for a missing dose, as this is not advised. Careful adherence to the suggested dosing schedule is essential for the medication's effectiveness and safety.

Overdose: Overdosing should be reported to the nearest healthcare center and the doctor immediately.

Storage:

The medications should be safely fastened, out of the reach of children, and in their original package. This approach is essential for the safety of the children and other family members. Medication should not be kept in the bathroom because the high humidity can worsen it. For best preservation, keep them at room temperature. Additionally, never flush or dispose of drugs in the trash because doing that can endanger animals, especially stray animals. Instead, enroll in government disposal standards or a take-back scheme. When in doubt, seek advice from the pharmacist. Setting these rules as a top priority encourages responsible medication use and makes the environment safer for people and animals.

For Doctors:

Indication:

• Only severe infections caused by drug-susceptible Candida or Cryptococcus strains are indicated for Flucytosine treatment. When necessary or other treatment choices are ineffective or inappropriate, Flucytosine is utilized specifically for these infections.

• Candida - Flucytosine has been successfully used to treat septicemia, endocarditis, and urinary system infections. Few studies support Flucytosine's utility in lung infections.

• Cryptococcus - Flucytosine is a successful treatment for Cryptococcus infections, especially when used to treat meningitis and pulmonary infections, where its efficacy is well-established. Even though there may not be much information on its effectiveness in treating septicemias and urinary tract infections brought on by Cryptococcus, studies indicate that it has succeeded in such situations.

• Due to the development of Flucytosine resistance, it should be used in conjunction with Amphotericin B to treat systemic candidiasis and cryptococcosis.

Dose: 50 to 150 mg/kg/day (milligrams per kilogram per day) as a separate dose after every six hours.

Dosing Considerations:

• The usual daily dose of Flucytosine is between 50 and 150 mg per kilogram of the patient's weight per day ( 50 to 150 mg/kg/day), administered in separate doses every six hours. A few capsules should be administered over 15 minutes to reduce the possibility of nausea or vomiting. It is a good idea to start with the lower end of the dosage range if there is any evidence of renal impairment, such as high BUN (blood urea nitrogen) serum creatinine levels or other kidney disorders.

• Due to the development of Flucytosine resistance, it should be taken together with Amphotericin B to treat systemic candidiasis and cryptococcosis.

What Are the Pharmacological Aspects of Flucytosine?

• Physical Properties of the Drug:

  • Color - White to off-white.

  • Drug Group - Antifungal.

  • Chemical Name - Flucytosine is a fluorinated pyrimidine that is related to Fluorouracil and Floxuridine chemically, and its chemical name is 5-Fluorocytosine.

  • Molecular Weight - 129.09.

  • Components of the Drug - The active component is Flucytosine, and the inactive components are talc, corn starch, and lactose. In addition, it also contains titanium, gelatin, and iron oxide.

• Clinical Pharmacology and Pharmacokinetics:

  • Absorption - Oral administration of the drug Flucytosine results in excellent absorption. It is predicted that the oral dose is absorbed by the body between 78 percent and 89 percent more effectively than intravenous delivery. A two-gram oral dose usually results in the drug's blood levels reaching their peak in two hours. The half-life, which measures how long it takes for a drug's concentration to reduce by half, typically falls between 2.4 and 4.8 hours in healthy people.

  • Elimination - Over 90 percent of the dose injected is recovered in the urine in its unmodified form, indicating that the medication is primarily eliminated through the kidneys. The conversion of Flucytosine Into the metabolite 5-Fluorouracil, which has a blood ratio of 4 percent, is possibly caused by gut bacteria. The medication is partially excreted in the stool.

  • Bioavailability - Flucytosine has low levels of protein binding in the blood, ranging from 2.9 percent to 4 percent. Significantly, the medication can cross the blood-brain barrier and reach clinically useful amounts in cerebrospinal fluid. Treatment for specific fungi infections that impact the central nervous system can benefit from this feature.

• Mechanism of Action: The enzyme cytosine permease is used by fungi to absorb Flucytosine. The enzyme cytosine deaminase quickly transforms Flucytosine into Fluorouracil inside the fungus cell. Fluorouracil works as an antifungal agent by converting into several active metabolites that either prevent the biosynthesis of fungal DNA (deoxyribonucleic acid) by inhibiting the enzyme thymidylate synthetase or prevent protein synthesis by mistakenly incorporating it into fungal RNA (ribonucleic acid).

• Pharmacokinetics in Pediatric Patients: Little evidence is available regarding the drug's physiological actions in neonatal patients receiving Flucytosine for systemic candidiasis. It is important to carefully evaluate and modify the treatment for each baby because how these medications function in infants differs from how they do in adults.

Toxicity:

• Carcinogenic - Flucytosine's ability to cause cancer (carcinogenic potential) has not been thoroughly tested on animals.

• Mutagenic - Studies on the mutagenic potential of five distinct Salmonella typhimurium mutants were done utilizing Ames-type evaluation. Regardless of the presence or absence of activating enzymes, these studies showed no proof that Flucytosine is mutagenic. Flucytosine was also found to be non-mutagenic in three other repair test systems, specifically rec, uvr, and pol.

• These results imply that Flucytosine does not display mutagenic qualities under the examined settings. Still, it is crucial to note that animal carcinogenic potential has yet to be thoroughly studied.

• Teratogenic - Research on pregnant rats shows that intraperitoneal injection of Flucytosine can cross the placental barrier. When administered to rats, Flucytosine was demonstrated to produce teratogenic effects.

Drug Resistance:

Flucytosine resistance can be caused by a variety of mechanisms, such as mutations in the enzymes needed for Flucytosine uptake or metabolism in cells, as well as increased production of pyrimidines, which compete with Flucytosine's active metabolites (fluorinated antimetabolites). It is significant to remember that Flucytosine resistance has been seen to emerge when the medication is used as monotherapy for an extended period.

Clinical Studies:

Fluconazole's effectiveness was compared with a combination of Amphotericin B and Flucytosine in research including 40 surgical patients with deep-seated mycoses. Regarding age, sex, and underlying illnesses, both groups were similar. In comparison to Fluconazole (median 8.5 days), the combination therapy (Amphotericin B/5-FC) resulted in a quicker eradication of microorganisms (median 5.5 days). The most common fungus found was Candida albicans, and the cure rates for both regimens were comparable. Throughout the trial, six patients in the Fluconazole group and five in the combination group passed away. Only the combo group experienced side effects that required a therapy modification. Overall, postoperative patients with deep-seated candida mycoses showed faster pathogen clearance with combination therapy, showing cure rates that were comparable to those of Fluconazole.

What Are the Contraindications of Flucytosine?

Patients who have previously experienced an adverse or hypersensitive reaction to Flucytosine should not take them.

Warnings and Precautions:

• Extreme caution is suggested when giving Flucytosine to patients with compromised renal function. Flucytosine is largely removed through the kidneys; hence, renal dysfunction can lead to drug buildup. Regularly monitoring Flucytosine serum concentrations is crucial to evaluate renal elimination efficiency in these patients. To avoid the increasing buildup of active medication, appropriate dosage changes should be performed for people with renal insufficiency.

• Patients who run the risk of developing bone marrow depression should receive Flucytosine with extreme caution. These patients consist of individuals who:

  • Having a hematologic illness.

  • A person receiving radiation therapy or taking drugs that have bone marrow-depressing effects.

  • Have a history of getting radiation or medicines that are known to inhibit bone marrow function.

It is significant to stress that, under these circumstances, bone marrow damage can be fatal and irreversible, especially in immunosuppressed individuals. Throughout therapy, it is essential to regularly and thoroughly monitor both the hematopoietic (blood-forming system) and hepatic (liver) systems to identify and handle any side effects.

• Before beginning Flucytosine therapy, it is crucial to monitor the patient's hematologic and renal state and electrolyte levels, especially given the possibility of hypokalemia (low potassium levels). Following the start of treatment, the patient must be continuously watched over with care. Close observation enables rapid detection and management of any potential side effects or complications, ensuring the patient's safety and efficacy of the drug.

What Are the Drug Interactions of Flucytosine?

A cytostatic substance called cytosine arabinoside is known to disrupt Flucytosine’s antifungal action through competitive inhibition. The biological half-life of Flucytosine may also be extended by medications that block glomerular filtration.

Specific Considerations:

• Pregnancy -

  • When Flucytosine is given to rats in dosages of 40 mg/kg/day (milligrams per kilogram per day), which is roughly 0.051 times the human dose, on days seven to thirteen of gestation, it has been discovered that the drug had teratogenic effects resulting in vertebral fusion. Additional birth abnormalities such as cleft lip and palate and micrognathia were seen at greater dosages (700 mg/kg/day, or around 0.89 times the human dose) given on days nine to 12 of gestation.

  • Flucytosine, when given to rabbits from days six to 18 of gestation, did not have teratogenic effects at dosages up to 100 mg/kg/day, roughly 0.243 times the human dose.

  • According to research carried out on pregnant rats, Flucytosine can pass the placental barrier when injected intraperitoneally. To give conclusive information on its effects during human pregnancy, there is not any well-controlled research on pregnant women. The use of Flucytosine during pregnancy should only be considered if the possible advantages to the mother outweigh the potential dangers to the fetus, given the potential concerns revealed in animal studies. Healthcare professionals must carefully consider each patient's unique situation and consult with pregnant patients before prescribing this medicine.

• Nursing Mothers - Flucytosine's excretion in human breast milk is yet unknown. A choice should be carefully reviewed because many medications are known to be excreted in human milk. Since Flucytosine exposure can have major negative effects on breastfeeding infants, the potential hazards to the nursing infant should be considered along with the importance of the drug's advantages for the mother.

• Pediatric Population - Pediatric patients have yet to be the subject of in-depth research on the safety and efficacy of Flucytosine. Flucytosine, alone or in combination with Amphotericin B, has been used to treat systemic candidiasis in a few newborns. The doses ranged from 25 to 200 mg/kg/day. Notably, there were no unexpected adverse effects recorded in these young children. However, it is important to emphasize that particular adverse occurrences were noted in some situations. In one case, a patient who had Flucytosine and Amphotericin B together suffered acidemia and hypokalemia.

• Another instance was a patient who received only Flucytosine and experienced anemia. Two additional patients, one receiving Amphotericin B concurrently, also demonstrated temporary thrombocytopenia. These results highlight the need for caution while administering Flucytosine to young children, especially when considering potential side effects. More thorough research is required to understand the safety and effectiveness of this medicine in the pediatric population.