Flucytosine (flucytosine)

Because prolonged serum flucytosine concentrations exceeding 100 mcg/mL may be associated with an increased risk of toxicity (e.g., adverse hematologic, GI, and hepatic effects), flucytosine dosage usually should be adjusted to ensure that peak serum concentrations of the drug remain below 100 mcg/mL. However, optimal target serum concentrations have not been identified, and a variety of target ranges have been recommended. The American Academy of Pediatrics (AAP), US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), and others generally recommend target serum flucytosine concentrations of 30-80 mcg/mL.

Some clinicians suggest that serum flucytosine concentrations should be measured beginning 3-5 days after initiation of the drug (or beginning after 3-5 doses) and then once or twice weekly during treatment and whenever there is evidence of toxicity or a change in renal function. Peak serum concentrations usually are measured using blood samples taken 2 hours after an oral dose.

In patients with impaired renal function, doses and/or frequency of administration of flucytosine must be modified in response to the degree of impairment and serum concentrations of the drug. Several methods of calculating flucytosine dosage for patients with impaired renal function have been proposed; however, for greater accuracy, dosage in these patients should be based on actual serum concentrations of the drug. Precise dosing is limited, since flucytosine is commercially available only as 250- and 500-mg capsules.

Some clinicians recommend that adults with creatinine clearances of 20-40 mL/minute receive 25 mg/kg of flucytosine every 12 hours and that those with creatinine clearances of 10-20 mL/minute receive 25 mg/kg once daily. In those with creatinine clearances less than 10 mL/minute, these clinicians recommend a flucytosine dosage of 25 mg/kg once every 48 hours.

Other clinicians recommend that the usual individual dose of flucytosine (12.5-37.5 mg/kg) be administered every 12 hours in patients with creatinine clearances of 20-40 mL/minute, every 24 hours in those with creatinine clearances of 10-20 mL/minute, and every 24-48 hours or longer (as determined by serum drug concentrations) in those with creatinine clearances less than 10 mL/minute. Alternatively, other clinicians have recommended that flucytosine doses of 12-35 mg/kg be administered at intervals equal to twice the half-life of the drug.

In patients undergoing hemodialysis, some clinicians recommend that flucytosine doses of 20-50 mg/kg be given once every 48-72 hours and that the doses be administered after dialysis.

Flucytosine is administered orally. The manufacturer suggests that nausea and vomiting associated with oral flucytosine may be reduced or avoided if each dose is administered by ingesting the capsules a few at a time over a 15-minute period.

Flucytosine has been administered IV; however, a parenteral dosage form of the drug is not commercially available in the US. Flucytosine also has been administered topically as a cream, but topical preparations of the drug are not commercially available in the US.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

There are no moderate interactions for this drug.

There is no enhanced messaging for this drug.

• Lactation

• Aplastic anemia secondary to drugs
• Bone marrow depression
• Granulocytopenic disorder
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Thrombocytopenic disorder

• Disease of liver
• Hypokalemia

There is no enhanced messaging for this drug.

More Frequent

• Allergic dermatitis
• Anemia
• Hepatitis
• Jaundice
• Leukopenia
• Pruritus of skin
• Skin rash
• Thrombocytopenic disorder

Less Frequent

• Acute cognitive impairment
• Hallucinations

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Acute respiratory distress syndrome
• Agranulocytosis
• Chest pain
• Duodenal ulcer
• Dyspnea
• Enterocolitis
• Eosinophilia
• Gastrointestinal hemorrhage
• Hepatic necrosis
• Hyperbilirubinemia
• Hypokalemia
• Hypoplastic anemia
• Neutropenic disorder
• Pancytopenia
• Parkinsonism
• Pure red cell aplasia
• Renal failure
• Seizure disorder
• Toxic epidermal necrolysis
• Ulcerative colitis
• Urticaria
• Ventricular arrhythmias

More Frequent

• Acute abdominal pain
• Anorexia
• Diarrhea
• Headache disorder
• Nausea
• Vomiting

Less Frequent

• Fatigue
• Fever
• Sedation
• Skin photosensitivity

Rare or Very Rare

• Ataxia
• Crystalluria
• Drug-induced psychosis
• Hearing loss
• Hypoglycemic disorder
• Paresthesia
• Peripheral neuropathy
• Stomatitis
• Vertigo
• Xerostomia

No enhanced messaging available.

No enhanced messaging available.

Flucytosine was shown to be teratogenic in rats. When flucytosine was given to rats in a dosage of 40 mg/kg daily (0.051 times the human dosage) on days 7-13 of gestation, vertebral fusions occurred; at a dosage of 700 mg/kg daily (0.89 times the human dosage) on days 9-12 of gestation, cleft lip and palate and micrognathia were reported. In mice, flucytosine dosage of 400 mg/kg daily (0.236 times the human dosage) on days 7-13 of gestation was associated with a low incidence of cleft palate that was not statistically significant. Flucytosine was not teratogenic in rabbits when given in dosages up to 100 mg/kg daily (0.243 times the human dosage) on days 6-18 of gestation.

There are no adequate or controlled studies to date using flucytosine in pregnant women, and the drug should be used during pregnancy only when potential benefits justify possible risks to the fetus.

It is not known whether flucytosine is distributed into human milk.

Because many drugs are distributed into human milk and because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.

No enhanced messaging available.