Version May 2024
Note: Must be used in conjunction with a diet restricted in tyrosine and phenylalanine. Titrate dose as needed based on biochemical and/or clinical response. If the biochemical response is satisfactory, the dosage should be adjusted only according to body weight gain. Do not adjust dose according to plasma tyrosine concentration.
Hereditary tyrosinemia type 1 (HT-1): Oral: Initial: 0.5 mg/kg twice daily. Increase to 0.75 mg/kg twice daily if succinylacetone is detectable 4 weeks after initiation. Further increase may be needed based on the evaluation of all biochemical parameters (maximum dose: 2 mg/kg/day); dose may be administered once daily (eg, 1 to 2 mg/kg once daily) if serum and urine succinylacetone is undetectable after ≥4 weeks of therapy.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Nitisinone: Pediatric drug information")
Note: Must be used in conjunction with a diet restricted in tyrosine and phenylalanine. If using tablets, round calculated dose up to the nearest available tablet strength.
Hereditary tyrosinemia type 1 (HT-1): Infants, Children, and Adolescents: Oral: Initial: 0.5 mg/kg/dose twice daily; titrate dose individually based on biochemical markers (eg, plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein concentrations) and clinical response. If succinylacetone concentrations are still detectable after 1 month of therapy, may increase dose to 0.75 mg/kg/dose twice daily; may further increase as needed up to a maximum of 1 mg/kg/dose twice daily; maximum daily dose: 2 mg/kg/day. Once the biochemical response is satisfactory, further dosage adjustments should be only according to body weight gain; in patients ≥5 years using capsules or oral suspension, daily dose may be transitioned to once daily (eg, 1 to 2 mg/kg/dose once daily) if serum and urine succinylacetone is undetectable after ≥4 weeks of stable therapy.
There are no dosage adjustments provided in the manufacturer's labeling. The effect of renal dysfunction on the pharmacokinetics of nitisinone has not been studied.
There are no dosage adjustments provided in the manufacturer's labeling. The effect of hepatic dysfunction on the pharmacokinetics of nitisinone has not been studied.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in pediatric patients and adults.
>10%: Endocrine & metabolic: Increased plasma tyrosine
1% to 10%:
Dermatologic: Alopecia (1%), exfoliative dermatitis (1%), maculopapular rash (1%), pruritus (1%), xeroderma (1%)
Endocrine & metabolic: Porphyria (1%)
Hematologic & oncologic: Granulocytopenia (1%), leukopenia (3%), thrombocytopenia (3%)
Hepatic: Hepatic failure (7%), hepatic neoplasm (malignant: 5%; benign: 3%)
Ophthalmic: Blepharitis (1%), cataract (1%), conjunctivitis (2%), corneal opacity (2%), eye pain (1%), keratitis (2%), photophobia (2%)
Respiratory: Epistaxis (1%)
<1%:
Dermatologic: Enanthema
Endocrine & metabolic: Hypoglycemia
Gastrointestinal: Abdominal pain, diarrhea, gastrointestinal hemorrhage, melena
Hepatic: Hepatomegaly, increased liver enzymes
Infection: Septicemia
Nervous system: Brain neoplasm, encephalopathy, seizure
Neuromuscular & skeletal: Hyperkinetic muscle activity
Respiratory: Bronchitis, cyanosis
Postmarketing:
Gastrointestinal: Gastric distress
Nervous system: Headache
Ophthalmic: Corneal ulcer
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to nitisinone or any component of the formulation; breastfeeding
Concerns related to adverse effects:
• Dermatologic effects: Failure to adequately restrict dietary tyrosine and phenylalanine may lead to hyperkeratotic plaques on the soles and palms.
• Hematologic effects: Leukopenia and/or thrombocytopenia have been reported; may improve with dose reduction. May be due to underlying liver disease rather than drug-related (McKiernan 2006). Monitor platelets and WBC regularly during therapy.
• Neurological effects: Failure to adequately restrict dietary tyrosine and phenylalanine may lead to variable degrees of intellectual disability and developmental delay; clinical laboratory assessment including tyrosine levels is recommended for any patient exhibiting abrupt changes in neurological status while on therapy.
• Ocular effects: Failure to adequately restrict dietary tyrosine and phenylalanine may lead to ocular toxicities (eg, conjunctivitis, corneal ulcers, corneal opacities, eye pain, keratitis, photophobia). Slit-lamp examination of the eyes is recommended prior to initiation of therapy and regularly thereafter, and in patients who develop photophobia, eye pain, tyrosine levels >500 mcmol/L, or signs of inflammation (eg, redness, swelling, burning of the eyes). Immediate measurement of plasma tyrosine concentration is also recommended in patients who develop ocular symptoms.
Dosage form specific issues:
• Glycerol: Oral suspension contains 500 mg/mL of glycerol; oral doses of glycerol ≥10 g may cause headache, upset stomach, and diarrhea. Patients receiving single doses >20 mL are at increased risk for these adverse reactions; consider switching patients unable to tolerate the oral suspension to nitisinone capsules.
Other warnings/precautions:
• Dietary restrictions: Must be used with dietary restriction of tyrosine and phenylalanine; inadequate restriction can result in toxic effects to the eyes, skin, and nervous system. Evaluate plasma tyrosine concentrations in patients who develop signs and symptoms of toxicity. Nutritional consultation is recommended.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Orfadin: 2 mg, 5 mg, 10 mg, 20 mg
Generic: 2 mg, 5 mg, 10 mg, 20 mg
Suspension, Oral:
Orfadin: 4 mg/mL (90 mL) [contains polysorbate 80, sodium benzoate]
Tablet, Oral:
Nityr: 2 mg, 5 mg, 10 mg
May be product dependent
Capsules (Nitisinone Oral)
2 mg (per each): $98.08
5 mg (per each): $245.21 - $245.36
10 mg (per each): $490.42
20 mg (per each): $980.87
Capsules (Orfadin Oral)
2 mg (per each): $65.39
5 mg (per each): $163.48
10 mg (per each): $326.96
20 mg (per each): $653.92
Suspension (Orfadin Oral)
4 mg/mL (per mL): $142.55
Tablets (Nityr Oral)
2 mg (per each): $107.14
5 mg (per each): $267.88
10 mg (per each): $535.74
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 2 mg, 5 mg, 10 mg, 20 mg
Suspension, Oral:
Generic: 4 mg/mL (90 mL)
Tablet, Oral:
Generic: 2 mg, 5 mg, 10 mg
Distributed by Orfadin4U comprehensive patient support program. Information regarding acquisition of product may be obtained by calling 877-473-3179. Additional information can be found at http://www.orfadin.com
Capsules: Administer at least 1 hour prior to, or 2 hours after a meal. Capsules may be opened and contents suspended in a small quantity of water, formula, or apple sauce; administer immediately.
Suspension: Administer without regards to meals. Allow suspension to warm to room temperature (30 to 60 minutes) prior to preparation.
Tablets: Administer without regards to meals. Tablets may be disintegrated in water and administered using an oral syringe or crushed and mixed with applesauce (administration with other liquids or foods is not recommended [has not been studied]). Refer to manufacturer's labeling for detailed instructions.
Applesauce administration: Add ~1 teaspoonful of applesauce to clean glass container; crush 1 tablet at a time between two teaspoons forming a fine powder (repeat if >1 tablet needed). Transfer all the powder to the applesauce; mix until well dispersed. Administer immediately or within 2 hours of mixing. Once administered, add ~1 teaspoon of applesauce to the same container and administer to ensure no powder is remaining.
Oral syringe administration: Tablet(s) must be fully disintegrated prior to administering with an oral syringe; turn oral syringe up and down for ≥30 seconds prior to administering. To ensure full administration, leave a gap between the plunger and oral syringe; after administering fill oral syringe with 2 mL of water, shake well, and administer while fully depressing the plunger (repeat if particles are still present).
Oral: Administer in divided doses in the morning and evening.
Capsules: Administer at least 1 hour prior to, or 2 hours after a meal. Capsules may be opened and contents suspended in a small quantity of water, formula, or applesauce; use immediately.
Suspension: May administer without regard to meals.
Tablets: Administer without regard to meals. Tablets may be disintegrated in water and administered using an oral syringe or crushed and mixed with applesauce (administration with other liquids or foods is not recommended [has not been studied]). Refer to manufacturer's labeling for detailed instructions.
Hereditary tyrosinemia type 1: Treatment of hereditary tyrosinemia type 1 (HT-1) as an adjunct to dietary restriction of tyrosine and phenylalanine in adult and pediatric patients.
Inhibits CYP2C9 (moderate), OAT1/3; Induces CYP2E1 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alitretinoin (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with moderate CYP2C9 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a moderate CYP2C9 inhibitor. Risk D: Consider therapy modification
Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Risk C: Monitor therapy
Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy
Celecoxib: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Celecoxib. Risk C: Monitor therapy
Clofarabine: OAT1/3 Inhibitors may increase the serum concentration of Clofarabine. Risk C: Monitor therapy
Dichlorphenamide: OAT1/3 Inhibitors may increase the serum concentration of Dichlorphenamide. Risk C: Monitor therapy
Diclofenac (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Diclofenac (Systemic). Risk C: Monitor therapy
DroNABinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of DroNABinol. Risk C: Monitor therapy
Erdafitinib: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and moderate CYP2C9 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly. Risk D: Consider therapy modification
Etravirine: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Etravirine. Risk C: Monitor therapy
Flurbiprofen (Systemic): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Flurbiprofen (Systemic). Risk C: Monitor therapy
Fluvastatin: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Fluvastatin. Management: Fluvastatin should be used at the lowest effective dose and should not exceed 20 mg twice daily when combined with moderate CYP2C9 inhibitors. Avoid coadministration of fluvastatin extended-release tablets with moderate CYP2C9 inhibitors. Risk D: Consider therapy modification
Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Lornoxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lornoxicam. Risk C: Monitor therapy
Losartan: CYP2C9 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Losartan. CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Losartan. Risk C: Monitor therapy
Meloxicam: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Meloxicam. Risk C: Monitor therapy
Methadone: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Methadone. Risk C: Monitor therapy
Nateglinide: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Nateglinide. Risk C: Monitor therapy
OAT1/3 Substrates (Clinically Relevant): Nitisinone may increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
Parecoxib: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Parecoxib. Specifically, serum concentrations of the active moiety valdecoxib may be increased. Management: Use the lowest effective dose of parecoxib and consider a dose reduction in patients taking moderate CYP2C9 inhibitors. Risk D: Consider therapy modification
Ramelteon: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Ramelteon. Risk C: Monitor therapy
Siponimod: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Siponimod. Risk C: Monitor therapy
Sulfonylureas: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy
Tetrahydrocannabinol and Cannabidiol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol. Specifically, concentrations of tetrahydrocannabinol may be increased. Risk C: Monitor therapy
Torsemide: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Torsemide. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Voriconazole: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Effect of taking nitisinone capsules with food is unknown; administration of oral suspension with a high calorie and high fat meal decreased Cmax by ~20%, but did not affect AUC. Tyrosine toxicity can occur without proper dietary restriction of tyrosine and phenylalanine. Management: Administer capsules at least 1 hour prior to, or 2 hours after a meal; administer oral suspension without regard to meals. Dietary restriction of tyrosine and phenylalanine is required.
Nitisinone crosses the placenta (Kassel 2015; Medina 2020; Vanclooster 2012).
Information related to use of nitisinone in pregnancy is limited. Dose adjustments may be needed as pregnancy progresses and again following delivery (Äärelä 2020; Kassel 2015; Medina 2020; Vanclooster 2012). Available consensus guidelines do not have recommendations related to use of nitisinone in pregnant patients. Infants exposed to nitisinone during pregnancy should be closely monitored (Chinsky 2017).
It is not known if nitisinone is present in breast milk.
Case reports of nitisinone use in patients who are breastfeeding are limited (Medina 2020). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of exposure to the infant, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Available consensus guidelines consider breastfeeding to be contraindicated if the mother is treated with nitisinone. Children diagnosed with hereditary tyrosinemia type 1 should be treated with nitisinone as soon as possible following diagnosis (Chinsky 2017).
Nitisinone capsules should be taken at least 1 hour prior to, or 2 hours after a meal. Dietary restriction of tyrosine and phenylalanine is required.
Dietary tyrosine and phenylalanine (assess dietary intake with tyrosine concentrations >500 mcmol/L); urine and/or plasma succinylacetone, liver function parameters, and alpha-fetoprotein levels; measure all biochemical markers (urine and/or plasma succinylacetone, urine 5-aminolevulinate, and erythrocyte porphobilinogen-synthase activity) at initiation, when switching from twice daily to once daily dosing, or if there is a deterioration of the patient's clinical condition; body weight; slit-lamp examination (prior to initiation of therapy and regularly thereafter, and in patients who develop symptoms of ocular toxicity or tyrosine concentrations >500 mcmol/L); plasma tyrosine (as clinically indicated with side effects; concentrations should be kept <500 mcmol/L to avoid toxicity); platelet and white blood cell counts (regularly during therapy). Detailed recommendations for monitoring developed by expert consensus are available (Chinsky 2017).
Note: Plasma succinylacetone may take up to 3 months to normalize after start of therapy (Holme 2000).
In patients with HT-1, tyrosine metabolism is interrupted due to a lack of the enzyme (fumarylacetoacetate hydrolase) needed in the last step of tyrosine degradation. Toxic metabolites of tyrosine accumulate and cause liver and kidney toxicity. Nitisinone competitively inhibits 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme present early in the tyrosine degradation pathway, thereby preventing the build-up of the toxic metabolites.
Note: Limited pharmacokinetic studies exist for children or HT-1 patients.
Vd: Healthy volunteers: 8.2 L.
Protein binding: >95%.
Metabolism: Minor metabolism possibly via CYP3A4.
Half-life elimination: Healthy volunteers: Terminal half-life: Capsule, suspension: 54 hours; Tablet: 59.3 hours.
Time to peak: Healthy volunteers:
Capsule:
Single 30 mg dose: Median: 3.5 hours (range: 0.8 to 8 hours).
Multiple 80 mg doses: Median: 4 hours (range: 0 to 16 hours).
Suspension: Single 30 mg dose: Median: 0.4 hours (range: 0.2 to 4 hours).
Tablet: Single 10 mg dose: Median: 3.5 hours (range: 1 to 4 hours).
Excretion: Healthy volunteers: Urine (3% unchanged).
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