Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

FLUTAMIDE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Flutamide is a nonsteroidal nonhormonal antiandrogenic drug which has been demonstrated to block the action of dihydrotestosterone (DHT) on prostatic tissue androgen receptors resulting in involution of the prostate gland. It does not possess androgenic, adrenocortical, antiestrogenic, estrogenic, progestational, antilibido, antifertility, or gonadotropin-inhibiting actions.

Specific Substances

    1) Niftholide
    2) Niftolide
    3) Propanamide, 2-methyl-n-(4-nitro-3-(trifluoromethyl)-phenyl)
    4) SCH 13521
    5) a,a,a-Trifluoro-2-methyl-4-nitro-m-propionotoluidide
    6) CAS 13311-84-7
    7) Molecular Formula: C11-H11-F3-N2-O3

Available Forms Sources

    A) FORMS
    1) Flutamide is available in 125 mg capsules (Prod Info flutamide oral capsules, 2009).
    B) USES
    1) Flutamide is approved for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate in combination with either a luteinizing hormone-releasing hormone analogue or orchiectomy (Prod Info flutamide oral capsules, 2009).

Overview

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent diarrhea with antidiarrheals and treat nausea and/or vomiting with several antiemetics of different classes. Ensure adequate hydration and correct electrolyte abnormalities.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe nausea and vomiting may respond to a combination of agents from different drug classes. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Neutropenia has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and the airway can be protected.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and the airway can be protected.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a minor exposure. Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress.
    E) ANTIDOTE
    1) None.
    F) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    G) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    H) ENHANCED ELIMINATION
    1) Because flutamide is so highly protein-bound, it is UNLIKELY that hemodialysis would be of any clinical benefit in removal of drug in overdose cases.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative.
    K) PHARMACOKINETICS
    1) Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Protein binding: 92% to 96%. Metabolism: Flutamide is metabolized to at least 10 different metabolites, the major metabolite being 2-hydroxyflutamide which is an alpha-hydroxylated derivative that is biologically active. Excretion: Primarily through the kidneys, with 28% of a 200-mg dose excreted in the urine in 24 hours. After 3 days, 98% of the drug was excreted as parent compound plus metabolites in urine or feces (4%). Elimination half-life: 5 to 6 hours for biologically active alpha-hydroxylated metabolite.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hepatotoxicity or myelosuppression.

Range Of Toxicity

    A) TOXICITY: The range of toxicity of flutamide has not yet been established; however, one patient survived without sequelae after a single ingestion of more than 5 g. Gynecomastia, breast tenderness, and elevated serum SGOT were observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted.
    B) THERAPEUTIC DOSE: ADULT: 250 mg (two 125 mg capsules) three times daily at 8-hr intervals. MAX DOSE: 750 mg daily. PEDIATRIC: Safety and efficacy in the pediatric population have not been established.

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Flutamide is approved for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate in combination with either a luteinizing hormone-releasing hormone analogue or orchiectomy.
    B) PHARMACOLOGY: Flutamide is an acetanilid and nonsteroidal antiandrogen. It inhibits the uptake of androgen and its nuclear binding in target tissues.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Serious adverse events with flutamide overdoses are uncommon. The following adverse effects have been reported in patients receiving flutamide: Hypertension, photosensitivity and rash, gynecomastia, galactorrhea, nausea, vomiting, diarrhea, transient elevations of BUN and creatinine, anemia, neutropenia, thrombocytopenia, jaundice, hepatitis, elevated liver enzymes, CNS depression. Myocardial ischemia has been reported in patients with preexisting cardiac disease. Flutamide has induced methemoglobinemia following chronic therapeutic therapy in humans.
    E) WITH POISONING/EXPOSURE
    1) In animal studies, signs of overdose of flutamide included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, vomiting, and methemoglobinemia. Gynecomastia, breast tenderness, and elevated serum SGOT were observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted.
    0.2.20) REPRODUCTIVE
    A) Flutamide is classified as FDA pregnancy category D and is not indicated for use in women. Animal data have indicated that decreased survival time for offspring and feminization of male fetuses have occurred with larger doses. Skin changes have also been seen in rat fetuses. Increased testicular interstitial cell adenomas at doses 4-fold the human dose have also been noted. Flutamide resulted in adverse effects on fertility, including failure to mate, abnormal sexual behavior, and decreased conception rates, in animal studies.
    0.2.21) CARCINOGENICITY
    A) Malignant breast neoplasms have been rarely reported in men treated with flutamide capsules.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    D) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    E) Obtain an ECG, and institute continuous cardiac monitoring.

Clinical Effects

Summary Of Exposure

    A) USES: Flutamide is approved for the management of locally confined Stage B2-C and Stage D2 metastatic carcinoma of the prostate in combination with either a luteinizing hormone-releasing hormone analogue or orchiectomy.
    B) PHARMACOLOGY: Flutamide is an acetanilid and nonsteroidal antiandrogen. It inhibits the uptake of androgen and its nuclear binding in target tissues.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Serious adverse events with flutamide overdoses are uncommon. The following adverse effects have been reported in patients receiving flutamide: Hypertension, photosensitivity and rash, gynecomastia, galactorrhea, nausea, vomiting, diarrhea, transient elevations of BUN and creatinine, anemia, neutropenia, thrombocytopenia, jaundice, hepatitis, elevated liver enzymes, CNS depression. Myocardial ischemia has been reported in patients with preexisting cardiac disease. Flutamide has induced methemoglobinemia following chronic therapeutic therapy in humans.
    E) WITH POISONING/EXPOSURE
    1) In animal studies, signs of overdose of flutamide included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, vomiting, and methemoglobinemia. Gynecomastia, breast tenderness, and elevated serum SGOT were observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted.

Heent

    3.4.3) EYES
    A) ANIMAL STUDIES: Increased lacrimation has been reported to occur in animal studies of flutamide toxicity (Prod Info flutamide oral capsules, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension is reported in approximately 1% of patients following therapeutic doses of flutamide (Prod Info flutamide oral capsules, 2011).
    B) MYOCARDIAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) Two patients had evidence of myocardial ischemia while taking therapeutic doses of flutamide, but both had preexisting cardiac conditions that may have influenced the development of myocardial infarction (Sogani & Whitmore, 1979).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Interstitial pneumonia occurred in a 88-year-old man with prostate cancer 3 weeks after starting flutamide 375 mg/day. He developed dyspnea and bilateral pulmonary interstitial infiltrates. He improved 4 days later after the withdrawal of flutamide and steroid therapy (Nomura et al, 2004).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOVENTILATION
    a) ANIMAL STUDIES: Decreased respirations have been observed in animal toxicity studies (Prod Info flutamide oral capsules, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Approximately 1% of patients taking therapeutic doses of flutamide exhibit signs of CNS depression, including drowsiness, confusion, and depression, which may be preceded by anxiety and nervousness (Prod Info flutamide oral capsules, 2011).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) ANIMAL STUDIES: Signs of CNS depression, including hypoactivity, ataxia, and somnolence, have been reported in animal studies of flutamide overdose effects (Prod Info flutamide oral capsules, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Up to 12% of patients taking therapeutic doses of flutamide will exhibit nausea, vomiting, or diarrhea as an adverse event (Fossa et al, 2001; Prod Info Eulexin(R), flutamide, 2000; Prod Info Euflex(R), 1986; Narayana et al, 1981). Other gastrointestinal effects occurring in 6% of patients have included increased appetite, dyspepsia, constipation, anorexia, and abdominal pain (Prod Info Euflex(R), 1986). These patients were also receiving a luteinizing hormone-releasing hormone (LHRH) agonist concomitantly.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) VOMITING
    a) ANIMAL STUDIES: Anorexia and vomiting were seen in animal studies of flutamide toxicity (Prod Info flutamide oral capsules, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Jaundice and hepatitis have been reported to occur in 1% to 5% of patients following therapeutic doses of flutamide, and slight elevations of serum aminotransferases may commonly occur (Prod Info Eulexin(R), flutamide, 2000; Gomez et al, 1992). Generally, the liver disorders are reversible on discontinuation of flutamide. Flutamide-induced hepatitis may involve an immunological mechanism (Pontiroli et al, 1998).
    1) In a case series (n=9) of flutamide-induced hepatotoxicity, none developed hypersensitivity features. Active alcoholism was ruled out in all cases. Two of the cases resulted in fulminant hepatic failure. These authors speculated that flutamide-induced severe acute hepatitis is due to an idiosyncratic metabolic mechanism (Cortes et al, 2001).
    b) Two case reports described fulminant hepatitis following 6 to 8 weeks of therapeutic flutamide therapy. Hepatic encephalopathy and a marked prolongation of prothrombin time resulted following continuation of flutamide. Extensive hepatic necrosis was demonstrated. One patient died of acute liver failure and the other recovered following an extensive hospitalization (Dourakis et al, 1994).
    c) One case report described hepatocellular necrosis which resolved following discontinuation of flutamide (Pontiroli et al, 1998).
    d) LACK OF EFFECT: There was no evidence of hepatotoxicity in 190 hyperandrogenic girls and young women receiving low or ultra-low doses (250 to 62.5 mg/day) of flutamide for up to 54 months (Ibanez et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) Elevated serum SGOT was observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted (Prod Info flutamide oral capsules, 2011).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Due to postmarketing reports of rare deaths due to liver failure in patients taking flutamide, the manufacturer has revised its labeling to include a contraindication for flutamide use in patients with preexisting liver dysfunction. Hepatic injury appears to be reversible in some patients after discontinuation of flutamide. In about 50% of patients, liver injury occurs within the first 3 months of flutamide therapy (Prod Info Eulexin(R), flutamide, 2000; (Anon, 1999)).
    b) Incidence of severe hepatotoxicity was reported to be 9% (2/22 patients) in a study of frequency of flutamide-induced hepatotoxicity in prostate carcinoma patients. One patient died due to fulminant liver failure and the other patient experienced an improvement in liver function tests after stopping flutamide therapy (Cetin et al, 1999).
    c) Two case reports described liver failure secondary to therapeutic flutamide combined with goserelin for prostate cancer. One patient developed jaundice, ascites, and hepatic coma and the other became jaundiced with a pattern consistent with cholestatic disease. Following the discontinuation of flutamide, but continuing goserelin, liver function improved in both patients (Moller et al, 1990).
    d) A case of cholestatic hepatitis was reported in a 72-year-old male after 6 weeks of therapeutic flutamide therapy. On admission to the emergency department the patient was jaundiced with dark urine, light-colored stools, and pruritus. History was notable for heavy ethanol use 13 years prior to admission, but no recent ingestions. Liver biopsy showed severe cholestasis. The patient's clinical symptoms slowly resolved following discontinuation of flutamide (Rosman et al, 1993).
    1) A case report described cholestatic hepatitis in a 79-year-old male with no history of previous liver disease who received no other drugs with flutamide. All liver function tests returned to normal following discontinuation of flutamide (Hart & Stricker, 1989).
    e) Near fatal liver dysfunction is reported in a 66-year-old male after 2 months of flutamide therapy with no history of predisposing liver diseases. Jaundice with markedly elevated liver function tests were noted, and the flutamide was discontinued. Screens for hepatitis A and B were negative. Liver function returned to normal over the next 6 weeks (Dankoff, 1992).
    f) A case report described fulminant liver failure in a 14-year-old girl who had taken flutamide (250 mg twice daily) for 3 months for hirsutism. Her medical history was unremarkable. Liver transplantation was done 9 days post-admission, and the explanted liver was remarkable for massive necrosis (Andrade et al, 1999).
    g) In a review of published cases of liver injury thought to be secondary to antiandrogens, hepatitis was the most commonly reported type of hepatotoxicity, occurring with all antiandrogens. This adverse reaction was not dependent upon the patient's age, therapeutic indication or the dose of medication prescribed. A longer latency period was noted with cyproterone acetate than with flutamide. Significantly higher transaminase levels were observed with flutamide than with cyproterone acetate; however, the evolution was no worse in the cases reported for flutamide (Thole et al, 2004).
    h) The pathogenesis of flutamide-induced cholestatic hepatitis, focusing on the bile salt export pump, was investigated in a study. The study suggests that flutamide itself and not its metabolite may cause cholestasis by inhibiting bile salt excretion (Iwanaga et al, 2007).
    C) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) Hepatic necrosis, as seen on liver biopsy, has been reported in a patient taking flutamide with no concomitant medications. Following discontinuation of flutamide, clinical signs and symptoms improved and liver function returned to normal within 3 months (Chu et al, 1998). One case report described massive hepatic necrosis in a patient following flutamide therapy (Cortes et al, 2001).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Transient elevations of BUN and creatinine have occasionally been observed following therapeutic doses of flutamide (Prod Info flutamide oral capsules, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been reported as an adverse event in approximately 6% of patients following therapeutic doses of flutamide (Prod Info flutamide oral capsules, 2011).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported to occur in approximately 3% of patients taking therapeutic doses of flutamide (Prod Info flutamide oral capsules, 2011).
    b) Neutropenia was reported in a 75-year-old man receiving flutamide 250 mg 3 times daily for prostate cancer. Absolute neutrophil count dropped from 2.58 to 0.28 billion cells/L after 6 months of therapy (McDonnell & Livingston, 1994).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported to occur in approximately 1% of patients taking therapeutic doses of flutamide (Prod Info flutamide oral capsules, 2011).
    D) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Thrombophlebitis and pulmonary embolism have rarely occurred following therapeutic flutamide doses (Kassem & Neri, 1982; Prod Info Euflex(R), 1986); the majority of patients experiencing these events had been previously treated with estrogens (Kassem & Neri, 1982).
    E) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) A case report described flutamide-induced methemoglobinemia in a man occurring one year after initiation of flutamide therapy. No other regular drug use or chemical exposures were reported. Laboratory investigation revealed a methemoglobin concentration equivalent to 16.2% of the total hemoglobin (normal value less than 1%). Upon discontinuation of flutamide and treatment with ascorbic acid, methemoglobin levels returned to normal (Schott et al, 1991).
    b) A case report described methemoglobinemia induced by flutamide therapy in an 82-year-old man. After 2 months of therapy, an arterial blood gas showed a methemoglobin content of 4.5% (normal 0.4% to 1.5%). Following discontinuation of flutamide, methemoglobin levels returned to normal. Re-challenge with flutamide resulted in a return of elevated methemoglobin levels within one week (Khan et al, 1997).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) METHEMOGLOBINEMIA
    a) ANIMAL STUDIES: Methemoglobinemia has been reported following flutamide toxicity in animal studies (Prod Info flutamide oral capsules, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Rare photosensitivity reactions may occur following flutamide therapy, with erythema and vesiculo-erosive necrolytic lesions.
    b) A case report described a flutamide-induced photoallergic reaction to therapeutic doses. Positive photopatch tests were obtained with flutamide. The patient developed pruritic, papulovesicular erythema on sun-exposed areas (Moraillon et al, 1991).
    c) A case report described a 67-year-old man diagnosed with flutamide photosensitivity following 3 to 4 months therapy. Exposed skin demonstrated erythema, vesicular lesions and pruritus. After flutamide withdrawal and treatment with topical corticosteroids, his lesions cleared after 10 days (Vilaplana et al, 1998).
    d) A case report described a 72-year-old man who developed vitiliginous lesions after receiving flutamide for photosensitive dermatitis. Five months after discontinuing flutamide, repigmentation had not occurred (Swoboda et al, 2007).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash may occur rarely from therapeutic doses of flutamide (Prod Info flutamide oral capsules, 2011).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) Gynecomastia, galactorrhea, and breast tenderness are reported with high frequency in patients receiving therapeutic flutamide (Prod Info flutamide oral capsules, 2011; Kassem & Neri, 1982; Airhart et al, 1978; Sarfaty et al, 1984; Sogani & Whitmore, 1979).
    2) WITH POISONING/EXPOSURE
    a) Gynecomastia, breast tenderness, and elevated serum SGOT were observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted (Prod Info flutamide oral capsules, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Flutamide is classified as FDA pregnancy category D and is not indicated for use in women. Animal data have indicated that decreased survival time for offspring and feminization of male fetuses have occurred with larger doses. Skin changes have also been seen in rat fetuses. Increased testicular interstitial cell adenomas at doses 4-fold the human dose have also been noted. Flutamide resulted in adverse effects on fertility, including failure to mate, abnormal sexual behavior, and decreased conception rates, in animal studies.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by most practitioners as the most critical for abnormal fetal development (Glantz, 1994).
    B) ANIMAL STUDIES
    1) RATS: The effects of flutamide on skin development in rat fetuses was reported. Pregnant rats were given flutamide (10 mg/100 g) daily for 10 days during pregnancy. A penile skin biopsy was taken from offspring at 3 months after birth. Atrophic epidermis and dermal adnexa were seen on histological examination. It was speculated that flutamide interfered with epidermal growth factor metabolism (Inaloz & Ketani, 2000).
    2) RATS: When subQ flutamide was administered to female rats at doses of 3, 10, or 30 mg/kg during gestational days 16 to 21, a significant and dose-dependent decrease in anogenital distance was observed in male offspring in all dosing groups compared with controls. At the 30 mg/kg dose, there were significant delays in preputial separation in males. At doses of 10 mg/kg or greater, cryptorchidism and absence of the prostate gland and seminal vesicles were found and at 30 mg/kg and testicular hypoplasia was observed. Hypospadias was noted in all dose groups. The effects on the testes themselves were mild, although effects on accessory reproductive organs were severe. Necropsy findings included hypospermatogenesis, degeneration of the seminiferous tubules, and hypoplasia and inflammation of the seminal vesicles and prostate (Goto et al, 2004).
    3) RATS: Ano-genital distance was shorter in pregnant rats treated with flutamide compared with control groups (Yamasaki et al, 2005).
    4) MICE: Perturbation of spermatogenesis was observed when flutamide was injected directly into the seminiferous tubules of live mice (Nagaosa et al, 2007).
    5) MINNOWS: When flutamide was given to flathead minnows, it was shown to effect the reproductive endocrine function consistent with its antiandrogenic mode-of-action (Jensen et al, 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified flutamide as FDA pregnancy category D (Prod Info Eulexin(R), flutamide, 2000).
    B) ANIMAL STUDIES
    1) RATS: Data from rat studies indicate a decreased 24-hr survival time in offspring at maternal doses of 30, 100, or 200 mg/kg/day (3, 9, and 19 times the recommended human dose). Feminization of male fetuses was also reported at the two highest doses (Prod Info flutamide oral capsules, 2009). The number of stillborns in rats were significantly higher in those treated with flutamide than control groups (Yamasaki et al, 2005).
    2) RABBITS: There was a reduced survival rate when pregnant rabbits were given flutamide at the highest dose of 15 mg/kg/day (1.4 times the recommended human dose) (Prod Info flutamide oral capsules, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS, DOGS: There were no adverse effects on estrous cycles or interference with the mating behavior of males and females when rats were given doses at 25 and 75 mg/kg/day prior to mating. When male rats were treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose), they failed to mate; however, mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Spermatogenesis was suppressed when rats were given flutamide for 52 weeks at approximately 3, 8, or 17 times the human dose and when dogs were given flutamide for 78 weeks at 1.4, 2.3, and 3.7 times the human dose (Prod Info flutamide oral capsules, 2009).
    2) RATS: When subQ flutamide was administered to female rats at doses of 3, 10, or 30 mg/kg during gestational days 16 to 20, male offspring showed impairments of sexual behavior as adults in a dose-dependent manner. In all treated groups, the number and frequency of mounts and intromissions was markedly decreased, compared with controls. Abnormalities of the external genitalia were closely associated with changes in sexual behavior. Serum testosterone, luteinized hormone, and follicle-stimulating hormone were comparable between the treated group and controls; therefore, the reproductive dysfunction in the treated animals could not be attributed to abnormal sex hormone levels during maturation (Goto et al, 2004).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Malignant breast neoplasms have been rarely reported in men treated with flutamide capsules.
    3.21.3) HUMAN STUDIES
    A) MALIGNANT BREAST NEOPLASMS
    1) Rare cases of malignant breast neoplasms have been reported in men who were administered flutamide capsules (Prod Info flutamide oral capsules, 2009).
    3.21.4) ANIMAL STUDIES
    A) TESTICULAR ADENOMAS
    1) MALE RATS: Interstitial cell adenomas of the testes were reported in 49% to 75% of all rats exposed to flutamide doses of 10, 30, and 50 mg/kg/day (plasma Cmax values of 1, 2, 3, and 4-fold, respectively, those associated with therapeutic doses in humans) in a 1-year dietary study. Tumors were observed in 43% to 47% of male rats after a 1-year drug-free period following 1 year of similar dosing. In a 2-year study with the same daily doses, testicular interstitial cell adenomas were observed in 91% to 95% of all treated rats compared with 11% of untreated control rats. There were also increased frequencies of mammary adenomas, adenocarcinomas, and fibroadenomas in treated male rats at exposure levels that were 1 to 4-fold those observed with a human therapeutic dose (Prod Info flutamide oral capsules, 2009).

Genotoxicity

    A) DNA modifying activity was not demonstrated with flutamide in the Ames Salmonella/microsome Mutagenesis Assay. In rats, dominant lethal tests were negative (Prod Info flutamide oral capsules, 2009).
    B) In an evaluation of flutamide genotoxicity in rats and in primary human hepatocytes, negative responses were found in all of the in vivo assays as well as in an in vitro assay. Comet assay tests were negative for DNA fragmentation in primary cultures of human hepatocytes and DNA repair synthesis was absent. The authors concluded that flutamide is a non-genotoxic drug (Martelli et al, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    D) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    E) Obtain an ECG, and institute continuous cardiac monitoring.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest x-ray in patients with severe respiratory or CNS depression.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Flutamide and its metabolites have been measured in plasma by mass spectrometry (Katchen et al, 1976), gas chromatography (Schulz et al, 1988), and high pressure liquid chromatography (Belanger et al, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    D) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    E) Obtain an ECG, and institute continuous cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Treat persistent diarrhea with antidiarrheals and treat nausea and/or vomiting with several antiemetics of different classes. Ensure adequate hydration and correct electrolyte abnormalities.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Severe nausea and vomiting may respond to a combination of agents from different drug classes. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Neutropenia has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status in symptomatic patients.
    3) Monitor serum electrolytes in patients with significant diarrhea and/or vomiting.
    4) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    5) Obtain an ECG, and institute continuous cardiac monitoring.
    C) VOMITING
    1) SUMMARY
    a) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING
    1) Treat patients with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
    2) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adults: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
    3) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). Chlorpromazine: Children: greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
    4) SEROTONIN 5-HT3 ANTAGONISTS: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
    5) BENZODIAZEPINES: Lorazepam: Adults: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
    6) STEROIDS: Dexamethasone: Adults: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
    7) ANTIPSYCHOTICS: Haloperidol: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).
    D) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    9) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    10) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    11) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    12) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    13) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    14) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    15) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    E) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    F) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Because flutamide is so highly protein-bound, it is UNLIKELY that hemodialysis would be of any clinical benefit in removal of drug in overdose cases.

Range Of Toxicity

Summary

    A) TOXICITY: The range of toxicity of flutamide has not yet been established; however, one patient survived without sequelae after a single ingestion of more than 5 g. Gynecomastia, breast tenderness, and elevated serum SGOT were observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted.
    B) THERAPEUTIC DOSE: ADULT: 250 mg (two 125 mg capsules) three times daily at 8-hr intervals. MAX DOSE: 750 mg daily. PEDIATRIC: Safety and efficacy in the pediatric population have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Recommended dose is 250 mg (two 125 mg capsules) three times daily at 8-hr intervals. MAX DOSE: 750 mg daily (Prod Info flutamide oral capsules, 2011).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric population have not been established (Prod Info flutamide oral capsules, 2011).

Maximum Tolerated Exposure

    A) The range of toxicity of flutamide has not yet been established. However, one patient survived without sequelae after a single ingestion of more than 5 g (Prod Info Euflex(R), 1986).
    B) Flutamide doses of up to 1.5 g/day have been effective without evidence of increased toxicity (Kassem et al, 1981; Airhart et al, 1978).
    C) Gynecomastia, breast tenderness, and elevated serum SGOT were observed when patients received flutamide doses up to 1500 mg/day for periods up to 36 weeks, but no serious adverse effects were noted (Prod Info flutamide oral capsules, 2011).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)RAT:
    a) 289 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)RAT:
    a) 787 mg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Flutamide is a nonsteroidal nonhormonal antiandrogenic drug which has been demonstrated to block the action of dihydrotestosterone (DHT) on prostatic tissue androgen receptors resulting in involution of the prostate gland. It has been reported to produce clinical remission in patients with prostate cancer. Animal studies have shown that flutamide lacks androgenic, adrenocortical, antiestrogenic, estrogenic, progestational, anti-libido, antifertility, and gonadotropin-inhibiting actions (Neri et al, 1972).
    B) Flutamide has been shown to interfere with the binding of testosterone and dihydrotesterone (DHT) to target tissues, such as the prostate. Flutamide does not inhibit gonadotropin secretion or suppress testosterone (Neri & Monahan, 1972; Neri et al, 1972; Petts et al, 1973; Liao et al, 1974; Mainwaring et al, 1974).
    C) Laboratory and clinical studies have demonstrated that flutamide produces alterations in the metabolism of testosterone (Hellman et al, 1977), estradiol (Zumoff et al, 1979), and cortisol (Fukushima et al, 1978). Flutamide therapy in 11 males with prostatic cancer regularly produced alterations in peripheral testosterone metabolism; testosterone conversion to androsterone markedly increased, while conversion to etiocholanolone decreased (Hellman et al, 1977). In another study, flutamide resulted in marked decreases in the conversion of estradiol to 2-hydroxyestrone and 2-methoxyestrone in 5 patients with advanced prostatic cancer (Zumoff et al, 1979).
    D) Cortisol metabolism was altered after flutamide therapy in 8 patients with prostatic cancer. Although the mean 24-hour plasma cortisol concentration did not change, cortisol production rate decreased by an average of 53%. Cortisol half-life was shown to increase from 80 to 108 minutes, and the volume of distribution decreased from 17.8 to 13.8 liters. Flutamide also significantly decreased formation of the 5-beta metabolites (THE and THF) and increased the formation of the 5-alpha metabolite (ATHF) (Fukushima et al, 1978).
    1) Although flutamide produces multiple alterations of steroid metabolism, these changes are seen in patients regardless of clinical response (Zumoff et al, 1979; Fukushima et al, 1978) and it does not appear that the effects of flutamide on steroid metabolism contribute to the therapeutic effects of the drug.

References

General Bibliography

    1) Airhart RA, Barnett TF, & Sullivan JW: Flutamide therapy for carcinoma of the prostate. South Med J 1978; 71:798-801.
    2) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    3) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    4) Andrade RJ, Lucena MI, & Fernandez MC: Fulminant liver failure associated with flutamide therapy for hirsutism (letter). Lancet 1999; 353:983.
    5) Anon: Important prescribing information (flutamide). U.S. Food and Drug Administration. Rockville, MD, USA. 1999. Available from URL: http://www.fda.gov/medwatch/safety/1999/eulexi.htm. As accessed Accessed September 28, 1999.
    6) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    7) Belanger A, Labrie F, & Dupont A: Endocrine effects of combined treatment with a LHRH agonist in association with flutamide in metastic prostatic carcinoma. Clin & Invest Med 1988; 11:321-326.
    8) Cetin M, Demirci D, & Unal A: Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma. Hum Experiment Toxicol 1999; 18:137-140.
    9) Chu CW, Hwang SJ, & Luo JC: Flutamide-induced liver injury: a case report. Chin Med J (Taipei) 1998; 61:678-682.
    10) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    11) Cortes MG, Andrade RJ, & Lucena MI: Flutamide-induced hepatotoxicity: report of a case series. Rev Esp Enferm Dig 2001; 93:428-432.
    12) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    13) Dankoff JS: Near fatal liver dysfunction secondary to administration of flutamide for prostate cancer. J Urol 1992; 148:1914.
    14) Dourakis SP, Alexopoulou AA, & Hadziyannis SJ: Fulminant hepatitis after flutamide treatment. J Hepatology 1994; 20:350-353.
    15) Dunipace AJ, Beaven R, Noblitt T, et al: Mutagenic potential of toluidine blue evaluated in the Ames test. Mutat Res 1992; 279(4):255-259.
    16) Dupuis LL & Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 2003; 5(9):597-613.
    17) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    18) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    19) Fossa SD, Slee PHT, & Brausi M: Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer Genitourinary Group. J Clin Oncol 2001; 19:62-71.
    20) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
    21) Fukushima DK, Levin J, Kream J, et al: Effect of flutamide on cortisol metabolism. J Clin Endocrinol Metab 1978; 47:788-791.
    22) Glantz JC: Reproductive toxicology of alkylating agents. Obstet Gynecol 1994; 49:709-715.
    23) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    24) Gomez JL, Dupont A, & Cusan L: Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients. Am J Med 1992; 92:465-470.
    25) Goto K, Koizumi K, Takaori H, et al: Effects of flutamide on sex maturation and behavior of offspring born to female rats treated during late pregnancy. J Toxicol Sci 2004; 29(5):517-534.
    26) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    27) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    28) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    29) Hart W & Stricker BHC: Flutamide and hepatitis (letter). Ann Intern Med 1989; 110:943-944.
    30) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    31) Hellman L, Bradlow HL, Freed S, et al: The effect of flutamide on testosterone metabolism and the plasma levels of androgens and gonadotropins. J Clin Endocrinol Metab 1977; 45:1224-1229.
    32) Herman MI, Chyka PA, & Butlse AY: Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med 1999; 33:111-113.
    33) Hix WR & Wilson WR: Toluidine blue staining of the esophagus: a useful adjunct in the panendoscopic evaluation of patients with squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1987; 113(8):864-865.
    34) Hjelt K, Lund JT, Scherling B, et al: Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84(4):365-370.
    35) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    36) Ibanez L, Jaramillo A, Ferrer A, et al: Absence of hepatotoxicity after long-term, low-dose flutamide in hyperandrogenic girls and young women. Hum Reprod 2005; 20(7):1833-1836.
    37) Ilbawi MN, Idriss FS, DeLeon SY, et al: Hemodynamic effects of intravenous nitroglycerin in pediatric patients after heart surgery. Circulation 1985; 72(3 Pt 2):II101-II107.
    38) Inaloz HS & Ketani MA: The effects of sialoadenectomy & flutamide on skin development. Clin Exp Obstet Gynecol 2000; 27:231-234.
    39) Iwanaga T, Nakakariya M, Yabuuchi H, et al: Involvement of bile salt export pump in flutamide-induced cholestatic hepatitis. Biol Pharm Bull 2007; 30(4):739-744.
    40) Jensen KM, Kahl MD, Makynen EA, et al: Characterization of responses to the antiandrogen flutamide in a short-term reproduction assay with the fathead minnow. Aquat.Toxicol 2004; 70(2):99-110.
    41) Kassem NY & Neri RO: Flutamide in advanced cancer of the prostate (abstract). Clin Pharmacol Ther 1982; 31:238.
    42) Kassem NY, Neri RO, & Munroe JS: Effect of flutamide, an antiandrogen, on stage D cancer of the prostate. Clin Pharmacol Ther 1981; 29:256.
    43) Katchen B & Buxbaum S: Disposition of a new, nonsteroid, antiandrogen, a,a,a- trifluoro-2-methyl-4'-nitro-m-propionotoluidide (flutamide), in men following a single oral 200m mg dose. J Clin Endocrinol Metab 1975; 41:373-379.
    44) Katchen B, Dancik S, & Millington G: Percutaneous penetration and metabolism of topical (14 C) flutamide in men. J Invest Dermatol 1976; 66:379-382.
    45) Khan AM, Singh NT, & Bilgrami S: Flutamide induced methemoglobinemia. J Urol 1997; 157:1363.
    46) Kiese M , Lorcher W , Weger N , et al: Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog. Eur J Clin Pharmacol 1972; 4(2):115-118.
    47) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    48) Koch-Weser J: Hypertensive emergencies. N Engl J Med 1974; 290:211.
    49) Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
    50) Laitinen P, Happonen JM, Sairanen H, et al: Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth 1997; 11(7):870-874.
    51) Liao S, Howell DK, & Chang TM: Action of a nonsteroidal antiandrogen, flutamide on the receptor binding and nuclear retention of 5-ox-dihydrotestosterone in rat ventral prostate. Endocrinology 1974; 94:1205.
    52) Lindenmann J, Matzi V, Kaufmann P, et al: Hyperbaric oxygenation in the treatment of life-threatening isobutyl nitrite-induced methemoglobinemia--a case report. Inhal Toxicol 2006; 18(13):1047-1049.
    53) Mainwaring WIP, Mangan FR, Feherty PA, et al: An investigation into the antiandrogenic properties of the nonsteroidal compound, SCH 13521 (4'-nitro-3'-trifluoromethylisobutyranilide). Mol Cell Endocrinol 1974; 1:113.
    54) Marquez A & Todd M: Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract 1959; 10:1548-1550.
    55) Martelli A, Campart GB, & Carrozzino R: Evaluation of flutamide genotoxicity in rats and in primary human hepatocytes. Pharmacol Toxicol 2000; 86:129-134.
    56) McDonnell ND & Livingston RB: Severe reversible neutropenia following treatment of prostate cancer with flutamide. J Urol 1994; 151:1353-1354.
    57) McMillian WD, Trombley BJ, Charash WE, et al: Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm 2011; 68(2):130-134.
    58) Moller S, Iversen P, & Franzmann MB: Flutamide-induced liver failure. J Hepat 1990; 10:346-349.
    59) Moraillon I, Jeanmougin M, & Manciet JR: Photoallergic reaction induced by flutamide. Photodermatol Photoimmunol Photomed 1991; 8:264-265.
    60) Nagaosa K, Kishimoto A, Kizu R, et al: Perturbation of spermatogenesis by androgen antagonists directly injected into seminiferous tubules of live mice. Reproduction 2007; 133(1):21-27.
    61) Nam YT, Shin T, & Yoshitake J: Induced hypotension for surgical repair of congenital dislocation of the hip in children. J Anesth 1989; 3(1):58-64.
    62) Narayana AS, Loening SA, & Culp DA: Flutamide in the treatment of metastatic carcinoma of the prostate. Br J Urol 1981; 53:152-153.
    63) Nemec K: Antidotes in acute poisoning. Eur J Hosp Pharm Sci Pract 2011; 17(4):53-55.
    64) Neri R, Florance K, Koziol P, et al: A biological profile of a nonsteroid antiandrogen, SCH 13521 (4'-nitro-3'-trifluoromethylisobutyranilide). Endocrinology 1972; 91:427.
    65) Neri RO & Monahan M: Effects of a novel nonsteroidal antiandrogen and canine prostatic hyperplasia. Invest Urol 1972; 10:123.
    66) Nomura M, Sato H, Fujimoto N, et al: Interstitial pneumonitis related to flutamide monotherapy for prostate cancer. Int J Urol 2004; 11(9):798-800.
    67) None Listed: ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 1999; 56(8):729-764.
    68) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    69) Petts E, Henson F, Neri R, et al: Effects of nonsteroidal antiandrogen SCH 13521 on testosterone disposition in rats. Fed Proc 1973; 32:759.
    70) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    71) Pontiroli L, Sartori M, & Pittau S: Flutamide-induced acute hepatitis: investigation on the role of immunoallergic mechanisms. Ital J Gastroenterol Hepatol 1998; 30:310-314.
    72) Product Information: COMPAZINE(R) tablets, injection, suppositories, syrup, prochlorperazine tablets, injection, suppositories, syrup. GlaxoSmithKline, Research Triangle Park, NC, 2004.
    73) Product Information: Compazine(R), prochlorperazine maleate spansule. GlaxoSmithKline, Research Triangle Park, NC, 2002.
    74) Product Information: Euflex(R). Schering Corporation, Kenilworth, NJ, 1986.
    75) Product Information: Eulexin(R), flutamide. Schering Corporation, Kenilworth, NJ, 2000.
    76) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    77) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    78) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    79) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    80) Product Information: PROVAYBLUE(TM) intravenous injection, methylene blue intravenous injection. American Regent (per FDA), Shirley, NY, 2016.
    81) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    82) Product Information: flutamide oral capsules, flutamide oral capsules. PAR PHARMACEUTICAL COMPANIES, INC, Spring Valley, NY, 2009.
    83) Product Information: flutamide oral capsules, flutamide oral capsules. Watson Pharma, Inc. (per DailyMed), Corona, CA, 2011.
    84) Product Information: methylene blue 1% IV injection, methylene blue 1% IV injection. American Regent, Inc (per manufacturer), Shirley, NY, 2011.
    85) Product Information: methylene blue 1% intravenous injection, methylene blue 1% intravenous injection. Akorn, Inc. (per manufacturer), Lake Forest, IL, 2011.
    86) Product Information: promethazine hcl rectal suppositories, promethazine hcl rectal suppositories. Perrigo, Allegan, MI, 2007.
    87) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 8/31/2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    88) Rasch DK & Lancaster L: Successful use of nitroglycerin to treat postoperative pulmonary hypertension. Crit Care Med 1987; 15(6):616-617.
    89) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    90) Rhoney D & Peacock WF: Intravenous therapy for hypertensive emergencies, part 1. Am J Health Syst Pharm 2009; 66(15):1343-1352.
    91) Rosman AS, Frissora-Rodeo C, & Marshall AT: Cholestatic hepatitis following flutamide. Digestive Diseases & Sci 1993; 38:1756-1759.
    92) Sarfaty GA, Alder SJ, & McLean RG: A pilot study of flutamide, a new agent in the treatment of advanced prostatic cancer. Med J Aust 1984; 140:219-221.
    93) Schott AM, Vial T, & Gozzo I: Flutamide-induced methemoglobinemia. DICP Ann Pharmacother 1991; 25:600-601.
    94) Schulz M, Schmeldt A, & Donn F: The pharmacokinetics of flutamide and its major metabolites after a single oral dose and during chronic treatment. Eur J Clin Pharm 1988; 34:633-636.
    95) Shepherd G & Keyes DC: Methylene blue. In: Dart,RC, ed. Medical Toxicology, 3rd ed. 3rd ed, Philadelphia, PA, 2004, pp -.
    96) Singh D, Akingbola O, Yosypiv I, et al: Emergency management of hypertension in children. Int J Nephrol 2012; 2012:420247.
    97) Sogani PC & Whitmore WF Jr: Experience with flutamide in previously untreated patients with advanced prostatic cancer. J Urol 1979; 122:640-643.
    98) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    99) Stanford SC , Stanford BJ , & Gillman PK : Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24(10):1433-1438.
    100) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    101) Swoboda A, Kasche A, Baumstark J, et al: Vitiliginous lesions after photosensitive dermatitis due to flutamide. J Eur Acad Dermatol Venereol 2007; 21(5):681-682.
    102) Teunis BS, Leftwich EI, & Pierce LE: Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101:527-531.
    103) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    104) Thole Z, Manzo G, Salgueiro E, et al: Hepatoxicity inducted by antiandrogens: a review of the literature. Urol Int 2004; 73:410-419.
    105) U.S. Department of Health and Human Services; National Institutes of Health; and National Heart, Lung, and Blood Institute: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. U.S. Department of Health and Human Services. Washington, DC. 2004. Available from URL: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. As accessed 2012-06-20.
    106) U.S. Food and Drug Administration: FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. U.S. Food and Drug Administration. Silver Spring, MD. 2011. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. As accessed 2011-07-26.
    107) Vilaplana J, Romaguera C, & Azon A: Flutamide photosensitivity - residual vitiliginous lesions. Contact Derm 1998; 38:68-70.
    108) Winek CL, Collom WD, & Martineau P: Toluidine blue intoxication. Clin Toxicol 1969; 2:1-3.
    109) Yamasaki K, Noda S, Muroi T, et al: Effects of in utero and lactational exposure to flutamide in SD rats: comparison of the effects of administration periods. Toxicology 2005; 209(1):47-54.
    110) Zumoff B, Fishman J, Freed S, et al: Effect of flutamide on estradiol metabolism. J Clin Endocrinol Metab 1979; 49:467-468.
    111) do Nascimento TS, Pereira RO, de Mello HL, et al: Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol 2008; 58(6):651-664.