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NITISINONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitisinone is a member of the triketone class of compounds. It is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase, and is used in the treatment of hereditary tyrosinemia type 1 (HT-1). It inhibits the catabolism of tyrosine. Nitisinone is in the drug class of metabolic enzymes, and is an orphan drug product. As a triketone derivative, it also has herbicidal activity, and has been used investigationally as an agricultural herbicide.

Specific Substances

    A) SYNONYMS
    1) 1,3-Cyclohexanedione, 2-(2-nitro-4-
    2) (trifluoromethyl)benzoyl)-
    3) 2-(2-Nitro-4-trifluoromethylbenzoyl)cyclohexane-
    4) 1,3-dione
    5) NTBC
    6) Orfadin
    7) Molecular Formula: C14-H10-F3-NO5
    8) CAS 104206-65-7

Available Forms Sources

    A) FORMS
    1) Nitisinone is available as 2 mg, 5 mg, or 10 mg capsules (Prod Info ORFADIN(R) oral capsules, 2010).
    B) USES
    1) Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1) (Prod Info ORFADIN(R) oral capsules, 2010).
    2) Nitisinone had been investigated as an agricultural herbicide (RTECS , 2002). Members of the triketone family have been shown to have herbicidal activity and have been used as broad-spectrum, bleaching herbicides, active both pre- and post-emergence on grass and broadleaf weeds. Development of nitisinone as an herbicide was discontinued (Lock et al, 1998).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).
    B) PHARMACOLOGY: Nitisinone inhibits normal catabolism of tyrosine in individuals with HT-1 and prevents accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In the presence of HT-1, these catabolic intermediates are converted to toxic metabolites (ie, succinylacetone and succinylacetoacetate), which may cause hepatotoxicity, renal toxicity, or porphyric crises.
    C) TOXICOLOGY: There have been no reports of nitisinone overdose; however, overdose effects are anticipated to be an exaggeration of the adverse effects associated with therapeutic doses.
    D) EPIDEMIOLOGY: There are no reports of overdose in humans.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include hepatic neoplasm, liver failure, conjunctivitis, corneal opacities, keratitis, photophobia, blepharitis, eye pain, cataracts, thrombocytopenia, leukopenia, granulocytopenia, porphyria, epistaxis, pruritis, exfoliative dermatitis, dry skin, maculopapular rash, alopecia
    2) LESS FREQUENT: Although causality has not been established, other adverse effects that have been reported less frequently (less than 1%) include seizure, brain tumor, encephalopathy, somnolence, nervousness, headache, hyperkinesia, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, amenorrhea, pathologic fracture, tooth discoloration, hepatic dysfunction, elevated hepatic enzymes, hepatomegaly, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, bronchitis, respiratory insufficiency, cyanosis, and death.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There have been no reports of nitisinone overdose; however, in testing, one individual maintaining a regular diet (no tyrosine and phenylalanine restrictions) experienced sensitivity to sunlight after exposure to nitisinone. Ingestion of nitisinone by individuals eating normal diets may cause elevated blood tyrosine levels.
    0.2.20) REPRODUCTIVE
    A) In animal studies, oral administration of nitisinone during organogenesis resulted in incomplete skeletal ossification of fetal bones, decreased pup survival, and increased gestational length in mice as well as incomplete skeletal ossification in rabbit fetuses. It appears that nitisinone is excreted into the milk of lactating rats due to the presence of ocular toxicity and lower body weight being observed in drug-naive nursing pups. Reduced litter size, decreased pup birthweight, and decreased pup survival were seen in a fertility study of rats.
    0.2.21) CARCINOGENICITY
    A) Studies in animals to assess carcinogenicity are limited. Human information is not available (Prod Info Orfadin(R), nitisinone, 2002).

Laboratory Monitoring

    A) Assays for plasma nitisinone concentrations are not routinely available. There is no correlation between nitisinone plasma levels and toxicity.
    B) Monitor plasma tyrosine and phenylalanine levels in symptomatic patients. Normal range of phenylalanine is 35 to 100 mcmol/L. Tyrosine levels should not exceed 500 mcmol/L.
    C) Monitor platelet and white-cell counts with differential.
    D) Monitor liver enzymes as indicated in symptomatic patients.
    E) Ophthalmologic examination including slit-lamp examination should be performed in patients developing ocular symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Inadvertent or intentional ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. Chronic tyrosinemia may be associated with eye, skin and nervous system toxicity. Restriction of tyrosine and phenylalanine in the diet should limit toxicity associated with tyrosinemia. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported with therapeutic doses. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia, bleeding. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is generally not necessary.
    2) HOSPITAL: GI decontamination is generally not necessary. Administer activated charcoal if the overdose is very large, recent, the patient is not vomiting, and is able to maintain airway.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION
    1) Information on the distribution and excretion of nitisinone in humans is not available and the effectiveness of hemodialysis is not known.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients who have inadvertently ingested a single extra dose can be monitored at home.
    2) OBSERVATION CRITERIA: Any patient with symptoms ore deliberate overdose should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with severe neutropenia, acute alterations in mental or neurologic status, respiratory distress, profuse diarrhea, severe abdominal pain, dehydration, or tyrosinemia should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) Early symptoms of overdose may be delayed or not evident, particularly myelosuppression, so reliable follow-up is imperative.
    H) PHARMACOKINETICS
    1) The median time for maximum plasma concentration was 3 hours for the capsule and 15 minutes for the liquid following administration of a single oral dose of 1 mg/kg of body weight. The mean terminal plasma half-life of nitisinone is 54 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression, hepatotoxicity, or elevated tyrosine levels.

Range Of Toxicity

    A) TOXICITY: No cases of human overdose have been reported. A specific minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN AGES BIRTH TO 17 YEARS: ORAL: 1 to 2 mg/kg/day divided into 2 daily doses.

Clinical Effects

Summary Of Exposure

    A) USES: Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).
    B) PHARMACOLOGY: Nitisinone inhibits normal catabolism of tyrosine in individuals with HT-1 and prevents accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In the presence of HT-1, these catabolic intermediates are converted to toxic metabolites (ie, succinylacetone and succinylacetoacetate), which may cause hepatotoxicity, renal toxicity, or porphyric crises.
    C) TOXICOLOGY: There have been no reports of nitisinone overdose; however, overdose effects are anticipated to be an exaggeration of the adverse effects associated with therapeutic doses.
    D) EPIDEMIOLOGY: There are no reports of overdose in humans.
    E) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include hepatic neoplasm, liver failure, conjunctivitis, corneal opacities, keratitis, photophobia, blepharitis, eye pain, cataracts, thrombocytopenia, leukopenia, granulocytopenia, porphyria, epistaxis, pruritis, exfoliative dermatitis, dry skin, maculopapular rash, alopecia
    2) LESS FREQUENT: Although causality has not been established, other adverse effects that have been reported less frequently (less than 1%) include seizure, brain tumor, encephalopathy, somnolence, nervousness, headache, hyperkinesia, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, amenorrhea, pathologic fracture, tooth discoloration, hepatic dysfunction, elevated hepatic enzymes, hepatomegaly, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, bronchitis, respiratory insufficiency, cyanosis, and death.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There have been no reports of nitisinone overdose; however, in testing, one individual maintaining a regular diet (no tyrosine and phenylalanine restrictions) experienced sensitivity to sunlight after exposure to nitisinone. Ingestion of nitisinone by individuals eating normal diets may cause elevated blood tyrosine levels.

Heent

    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) Tooth discoloration was reported rarely (less than 1%) in a clinical study of nitisinone (median treatment duration 22 months) involving 207 patients with hereditary tyrosinemia type 1; however, a direct causal relationship to the drug has not been established (Prod Info ORFADIN(R) oral capsules, 2010).
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Ocular complications during therapy of hereditary tyrosinemia type 1 have included photophobia, conjunctivitis, keratitis, pruritus, burning/eye pain, corneal opacities, cataracts, and blepharitis (Prod Info ORFADIN(R) oral capsules, 2010; Holme & Lindstedt, 1998). These effects are not related to a direct toxic effect of nitisinone itself, but rather to elevated ocular tyrosine levels from sustained inhibition of 4-hydroxyphenylpyruvate dioxygenase by this agent (Holme & Lindstedt, 2000; Wilson et al, 2000; Lock et al, 1998a). Corneal crystals were observed in one patient (Holme & Lindstedt, 1998).
    a) Ocular symptoms are not frequent (less than 3% of patients) and are usually transient, persisting for several days; however, recurrence on several occasions during therapy has been observed, and prolonged episodes (16 to 672 days) have been reported in a few patients (Prod Info ORFADIN(R) oral capsules, 2010; Holme & Lindstedt, 2000).
    b) In clinical studies, tyrosine plasma levels tended to be higher in patients developing ocular symptoms, although there was no clear plasma level-effect correlation (Holme & Lindstedt, 2000; Holme & Lindstedt, 1998). The manufacturer recommends maintaining tyrosine levels below 500 micromols/L (Prod Info ORFADIN(R) oral capsules, 2010), although this may not prevent ocular complications in all patients.
    B) ANIMAL STUDIES
    1) RAT STUDIES: Corneal lesions were noted in rats when ocular tyrosinemia was prolonged and sustained. When nitisinone was fed in the diet, it produced a time- and dose-dependent tyrosinemia in plasma and aqueous humor; corneal lesions occurred within one week (Lock et al, 1998; Lock et al, 1998a; Lock et al, 1996). Corneal lesions were reversible on discontinuation of the drug.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Diarrhea, abdominal pain, gastroenteritis, gastrointestinal hemorrhage, melena, and enanthema were reported rarely (less than 1%) in a clinical study of nitisinone (median treatment duration 22 months) involving 207 patients with hereditary tyrosinemia type 1; a clear relationship to the drug was not established (Prod Info ORFADIN(R) oral capsules, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) NEOPLASM OF LIVER
    1) WITH THERAPEUTIC USE
    a) In an uncontrolled open-label study of nitisinone in patients with hereditary tyrosinemia type 1 (n=207), 5% of patients developed malignant hepatic neoplasms and 3% developed benign hepatic neoplasms during therapy (median treatment duration 22 months). However, individuals with hereditary tyrosinemia type 1 (HT-1) have an increased risk for developing hepatic neoplasms as a complication of HT-1 (Prod Info ORFADIN(R) oral capsules, 2010).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) In an uncontrolled open-label study of nitisinone in patients with hereditary tyrosinemia type 1 (n=207), 7% of patients developed liver failure and 13% required liver transplantation during therapy (median treatment duration 22 months). However, individuals with hereditary tyrosinemia type 1 (HT-1) have an increased risk for developing liver failure requiring transplantation as a complication of HT-1. Elevated liver enzymes and hepatomegaly, and death were observed in less than 1% of patients in the same study (Prod Info ORFADIN(R) oral capsules, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Leukopenia and/or thrombocytopenia were reported in 3% and granulocytopenia in 1% of patients (n=207) with hereditary tyrosinemia type 1 (HT-1) treated with nitisinone in clinical trials (median treatment duration 22 months). Three patients had platelet counts less than or equal to 30,000/mcL (Prod Info ORFADIN(R) oral capsules, 2010; Holme & Lindstedt, 2000; Holme & Lindstedt, 1998). An improvement in blood counts has been observed after dose-lowering, although the majority of patients can continue therapy in the absence of dose modification, with slow normalization of platelet/white-cell counts.
    b) In 4 patients developing thrombocytopenia in clinical studies (n=207), platelet counts returned to normal without decreasing the dose. In 2 patients with thrombocytopenia, nitisinone was discontinued and platelet counts gradually returned to normal within 2 weeks to 5 months. One patient who developed leukopenia and thrombocytopenia showed improvement after the nitisinone dose was decreased (Prod Info ORFADIN(R) oral capsules, 2010).
    B) PORPHYRIA
    1) WITH THERAPEUTIC USE
    a) In an uncontrolled open-label study of nitisinone in 207 patients with hereditary tyrosinemia type 1, 1% of patients developed porphyria during therapy (median treatment duration 22 months). However, individuals with hereditary tyrosinemia type 1 (HT-1) have an increased risk for porphyric crises as a complication of HT-1 (Prod Info ORFADIN(R) oral capsules, 2010).
    C) EPISTAXIS
    1) WITH THERAPEUTIC USE
    a) In an uncontrolled open-label study of nitisinone in 207 patients with hereditary tyrosinemia type 1, 1% of patients experienced epistaxis during therapy (median treatment duration 22 months) (Prod Info ORFADIN(R) oral capsules, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) In an uncontrolled open-label study of nitisinone in patients with hereditary tyrosinemia type 1 (n=207), exfoliative dermatitis, dry skin, cutaneous pruritus, alopecia, and maculopapular rashes were each reported at some point during therapy (median, 22 months) in 1% of patients. Hyperkeratotic plaques on the hands and feet may occur with excessive tyrosinemia (Prod Info ORFADIN(R) oral capsules, 2010). It is unclear if cutaneous adverse effects reported in clinical studies with nitisinone are secondary to high tyrosine levels.

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DISORDER OF ENDOCRINE SYSTEM
    1) WITH THERAPEUTIC USE
    a) Dehydration, thirst, hypoglycemia, and amenorrhea were reported rarely (less than 1%) in a clinical study of nitisinone (median treatment duration 22 months) involving 207 patients with hereditary tyrosinemia type 1; however, a direct causal relationship to the drug has not been established (Prod Info ORFADIN(R) oral capsules, 2010).

Reproductive

    3.20.1) SUMMARY
    A) In animal studies, oral administration of nitisinone during organogenesis resulted in incomplete skeletal ossification of fetal bones, decreased pup survival, and increased gestational length in mice as well as incomplete skeletal ossification in rabbit fetuses. It appears that nitisinone is excreted into the milk of lactating rats due to the presence of ocular toxicity and lower body weight being observed in drug-naive nursing pups. Reduced litter size, decreased pup birthweight, and decreased pup survival were seen in a fertility study of rats.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).
    B) ANIMAL STUDIES
    1) Oral administration in mice during organogenesis resulted in incomplete skeletal ossification of the fetal bones and decreased pup survival at 0.4 times the recommended human dose as well as increased gestational length at 4 times the recommended human dose. Oral nitisinone in rabbits during organogenesis caused incompleted skeletal ossification of the fetal bones and maternal toxicity at doses 1.6 times the recommended human dose based on body surface area (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    B) RISK SUMMARY
    1) There are no adequate and well-controlled studies of nitisinone in pregnant women. In animal studies, oral administration in mice during organogenesis resulted in incomplete skeletal ossification of the fetal bones and decreased pup survival at 0.4 times the recommended human dose and increased gestational length at 4 times the recommended human dose. Oral nitisinone administration to rabbits during organogenesis caused incompleted skeletal ossification of the fetal bones and maternal toxicity at doses 1.6 times the recommended human dose based on body surface area (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    C) ANIMAL STUDIES
    1) Oral administration in mice during organogenesis resulted in decreased pup survival at 0.4 times the recommended human dose (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) RISK SUMMARY
    1) It is not known whether nitisinone is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. However, it appears that nitisinone is excreted into the milk of lactating rats due to signs of ocular toxicity and lower body weight being observed in drug-naive nursing pups (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    B) BREAST MILK
    1) It is not known whether nitisinone is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. However, it appears that nitisinone is excreted into the milk of lactating rats due to signs of ocular toxicity and lower body weight being observed in drug-naive nursing pups. Discontinue treatment or discontinue nursing taking into account the importance of the drug to the mother (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    B) ANIMAL STUDIES
    1) Reduced litter size, decreased pup birthweight, and decreased pup survival were seen in a study of rats given a single nitisinone dose 12 times the recommended human doses based on body surface area (Prod Info ORFADIN(R) oral capsules, suspension, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Studies in animals to assess carcinogenicity are limited. Human information is not available (Prod Info Orfadin(R), nitisinone, 2002).
    3.21.4) ANIMAL STUDIES
    A) HEPATIC CARCINOMA
    1) In a murine model study, using mice with fumarylacetoacetate hydrolase deficiency, Al-Dhalimy et al (2002) demonstrated that nitisinone did not prevent the development of hepatic carcinoma in a 2-year follow-up, although it abolished acute liver failure when given in conjunction with a restricted tyrosine diet. It should be noted that in human patients with hereditary tyrosinemia, acute hepatic failure and chronic liver disease with cirrhosis and liver carcinoma frequently develop when no treatment is given.

Genotoxicity

    A) In the Ames test, nitisinone was not mutagenic (Prod Info Orfadin(R), nitisinone, 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Assays for plasma nitisinone concentrations are not routinely available. There is no correlation between nitisinone plasma levels and toxicity.
    B) Monitor plasma tyrosine and phenylalanine levels in symptomatic patients. Normal range of phenylalanine is 35 to 100 mcmol/L. Tyrosine levels should not exceed 500 mcmol/L.
    C) Monitor platelet and white-cell counts with differential.
    D) Monitor liver enzymes as indicated in symptomatic patients.
    E) Ophthalmologic examination including slit-lamp examination should be performed in patients developing ocular symptoms.

Methods

    A) CHROMATOGRAPHY
    1) Nitisinone plasma levels have been quantified by direct injection into a coupled column liquid chromatographic system, with UV detection. The efficiency on the analytical column was higher at a low pH, as well as on a base-deactivated column compared to a reversed-phase column. A limit of quantitation of approximately 0.3 mM, using 20 mcL of plasma, was reported (Bielenstein et al, 1999).
    2) Hall et al (2001) described a reverse phase liquid chromatography method with UV detection for determining the concentration of nitisinone in human plasma. The lower limit of quantification was 20 ng/mL.
    3) Tyrosine in plasma or aqueous humor is most often measured as a determination of nitisinone toxicity. Concentrations have been determined using a fluorometric assay or high performance liquid chromatography (HPLC) analysis (Lock et al, 1998a; Lock et al, 1996). Hall et al (2001) described a reverse phase liquid chromatographic method with UV detection for determination of tyrosine in plasma.

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 neutropenia, acute alterations in mental or neurologic status, respiratory distress, profuse diarrhea, severe abdominal pain, dehydration, or tyrosinemia should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients who have inadvertently ingested a single extra dose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a 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) Any patient with symptoms or a deliberate overdose should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Assays for plasma nitisinone concentrations are not routinely available. There is no correlation between nitisinone plasma levels and toxicity.
    B) Monitor plasma tyrosine and phenylalanine levels in symptomatic patients. Normal range of phenylalanine is 35 to 100 mcmol/L. Tyrosine levels should not exceed 500 mcmol/L.
    C) Monitor platelet and white-cell counts with differential.
    D) Monitor liver enzymes as indicated in symptomatic patients.
    E) Ophthalmologic examination including slit-lamp examination should be performed in patients developing ocular symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) It is not known if activated charcoal will be useful in treating ingestions. Decontamination is recommended in symptomatic patients and those with significant coingestants.
    B) 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) SUMMARY
    1) GI decontamination is generally not necessary. Activated charcoal is recommended in patients with very large, recent ingestions and those with significant coingestants.
    B) 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) Treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor CBC, platelet and white-cell counts with differential.
    2) Monitor liver enzymes as indicated in symptomatic patients.
    3) Ophthalmologic examination including slit-lamp examination should be performed in patients developing ocular symptoms.
    4) Assays for plasma nitisinone concentrations are not routinely available. There is no correlation between nitisinone plasma levels and toxicity.
    5) Monitor plasma tyrosine and phenylalanine levels in symptomatic patients. Normal range of phenylalanine is 35 to 100 mcmol/L. Tyrosine levels should not exceed 500 mcmol/L.
    C) 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.
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) SUMMARY
    1) The use of extracorporeal elimination techniques for toxicity with this agent have not been investigated.

Range Of Toxicity

Summary

    A) TOXICITY: No cases of human overdose have been reported. A specific minimum toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN AGES BIRTH TO 17 YEARS: ORAL: 1 to 2 mg/kg/day divided into 2 daily doses.

Therapeutic Dose

    7.2.1) ADULT
    A) HEREDITARY TYROSINEMIA TYPE 1
    1) Initial Dose: 0.5 mg/kg orally twice daily. Maximum dose: 1 mg/kg orally twice daily (Prod Info ORFADIN(R) oral capsules, suspension, 2016).
    7.2.2) PEDIATRIC
    A) HEREDITARY TYROSINEMIA TYPE 1
    1) Initial Dose: 0.5 mg/kg orally twice daily. Maximum dose: 1 mg/kg orally twice daily (Prod Info ORFADIN(R) oral capsules, suspension, 2016).

Maximum Tolerated Exposure

    A) A specific minimum toxic dose has not been established.
    B) ANIMAL DATA
    1) RATS: After the administration of a single oral dose of nitisinone (0.5 up to 160 milligrams/kilogram), a marked tyrosinemia (dose- and time-dependent) in the plasma and aqueous humor was noted. At the higher doses, duration of the effect was markedly longer (Lock et al, 1996).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Following single oral doses of 1 mg/kg in healthy subjects, the mean peak plasma concentration was 7.8 mcg/mL (Hall et al, 2001).
    b) Following single oral doses of 1 mg/kg as a solution in healthy subjects, the mean peak plasma concentration was 8.2 mcg/mL (Hall et al, 2001).
    c) TIME TO PEAK CONCENTRATION: The median time for maximum plasma concentration was 3 hours for the capsule and 15 minutes for the liquid following administration of a single oral dose of 1 mg/kg of body weight (Prod Info ORFADIN(R) oral capsules, 2010).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ROUTE OF EXPOSURE
    a) ORAL: In clinical studies, tyrosine plasma levels tended to be higher in patients developing ocular symptoms, although there was no clear plasma level-effect correlation (Holme & Lindstedt, 2000; Holme & Lindstedt, 1998). The manufacturer recommends maintaining tyrosine levels below 500 micromol/L (Prod Info ORFADIN(R) oral capsules, 2010), although this may not limit ocular toxicity in some patients.
    1) In clinical studies, most patients with tyrosine levels above 1000 micromol/L have not developed ocular symptoms (Holme & Lindstedt, 2000; Holme & Lindstedt, 1998).
    2) Ingestion of 1 mg/kg in healthy volunteers resulted in maximum tyrosine levels of 1200 micromol/L from 48 to 120 hours after dosing. The mean plasma tyrosine level was 808 micromoles/liter after a 14-day washout period (Prod Info ORFADIN(R) oral capsules, 2010).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nitisinone (NTBC) is a triketone derivative with herbicidal activity (Holme & Lindstedt, 2000; Hall et al, 2001; Lock et al, 1998). In patients with hereditary tyrosinemia type 1 (HT-1), nitisinone competitively inhibits 4-hydroxyphenylpyruvate dioxygenase (HPPA), the second enzyme in the pathway of tyrosine catabolism. It is a time-dependent (tight-binding) and reversible inhibitor of HPPD (Holme & Lindstedt, 2000; Russo et al, 2001; Lock et al, 1998)(Ellis et al, 1995). This prevents accumulation of the catabolic intermediates, maleylacetoacetate and fumarylacetoacetate, and the subsequent conversion of these intermediates to the toxic metabolites succinylacetone and succinylacetoacetate; these latter metabolites are considered responsible for hepatic and renal injury in HT-1 (Holme & Lindstedt, 1998; Prod Info Orfadin(R), nitisinone, 2002; Mohan et al, 1999; Pitkanen et al, 2000). Accumulation of succinylacetone in HT-1 results in inhibition of porphobilinogen synthase and accumulation 5- aminolevulinic acid, a heme precursor responsible for porphyria-like crises (Pitkanen et al, 2000; Gibbs et al, 1993).
    1) Nitisinone is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, with a concentration of 5 nmol/L producing 50% inhibition of the pure human liver enzyme in vitro (Holme & Lindstedt, 2000). Tyrosine concentrations increase during nitisinone administration, and restricted intake of phenylalanine and tyrosine is indicated during therapy (Prod Info ORFADIN(R) oral capsules, 2010; Wilson et al, 2000; Holme & Lindstedt, 1998).
    B) Prior to nitisinone treatment, a pediatric patient was noted to have coproporphyrin (CP)-1 urinary excretion, which accounted for 94% of the total urinary CP (normal about 30%). After one week of nitisinone therapy, a pronounced and steady increase of CP-III and the CP-III/CP-I ratio was noted. It was suggested that a direct inhibitory effect of nitisinone in another enzyme of haem biosynthesis might occur, such as coproporphyrinogen oxidase and/or protoporphyrinogen oxidase. The authors concluded that patients being treated with nitisinone may develop acquired porphyria (Depetris-Boldini et al, 1999).

Physicochemical

Physical Characteristics

    A) Nitisinone is a white to yellowish-white, crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. It is soluble in methanol and in 2 M sodium hydroxide (Prod Info ORFADIN(R) oral capsules, 2010).

Ph

    A) Nitisinone is lipophilic, with weak acid properties due to the hydrogen in the first position in the cyclohexane ring (Bielenstein et al, 1999).

Molecular Weight

    A) 329.25 (RTECS , 2002)

References

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