nitisinone (Rx)

Brand and Other Names:Orfadin, Nityr
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule (Orfadin)

  • 2mg
  • 5mg
  • 10mg
  • 20mg

oral suspension (Orfadin)

  • 4mg/mL

tablet (Nityr)

  • 2mg
  • 5mg
  • 10mg

Hereditary Tyrosinemia Type 1

Indicated for hereditary tyrosinemia type 1 (HT-1) as an adjunct to dietary restriction of tyrosine and phenylalanine

Starting dose: 0.5 mg/kg PO q12hr (morning and evening); titrate dose based on biochemical and/or clinical response, as described in the full prescribing information  

Succinylacetone detectable in blood or urine 4 weeks after initiating: May increase to 0.75 mg/kg q12hr; maximum total daily dose (TDD) of 2 mg/kg may be needed based on evaluation of all biochemical parameters

Undetectable serum and urine succinylacetone concentrations after at least 4 weeks on stable dose: TDD may be given once daily (eg, 1-2 mg/kg qDay)

If satisfactory biochemical response (undetectable blood and/or urine succinylacetone), adjust dose according to body weight gain and not according to plasma tyrosine levels

Dosing Considerations

Monitoring parameters

  • Monitor plasma and/or urine succinylacetone concentrations, liver function parameters, and alpha-fetoprotein levels
  • During initiation, when switching from q12hr to qDay dosing, or if condition is deteriorating, consider closely monitoring all available biochemical parameters (ie, plasma and/or urine succinylacetone, urine 5-aminolevulinate [ALA], erythrocyte porphobilinogen [PBG]-synthase activity)
  • Maintain plasma tyrosine levels <500 mmol/L by dietary restriction of tyrosine and phenylalanine intake
  • Plasma tyrosine levels >500 micromol/L: Assess dietary tyrosine and phenylalanine intake; do not adjust dosage in order to lower plasma tyrosine concentration

Alkaptonuria (Orphan)

Treatment of alkaptonuria

Orphan indication sponsor

  • Swedish Orphan AB; Kungsgatan 37, 7th Floor; SE-111 56, Sweden

Dosage Forms & Strengths

capsule (Orfadin)

  • 2mg
  • 5mg
  • 10mg
  • 20mg

oral suspension (Orfadin)

  • 4mg/mL

tablet (Nityr)

  • 2mg
  • 5mg
  • 10mg

Hereditary Tyrosinemia Type 1

Indicated for hereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients as an adjunct to dietary restriction of tyrosine and phenylalanine

Starting dose: 0.5 mg/kg PO q12hr; titrate dose based on biochemical and/or clinical response  

Succinylacetone detectable in blood or urine 4 weeks after initiating: May increase to 0.75 mg/kg q12hr; maximum total daily dose (TDD) of 2 mg/kg may be needed based on evaluation of all biochemical parameters

Patients aged 5 years or older with undetectable serum and urine succinylacetone concentrations after at least 4 weeks on a stable dosage of nitisinone: TDD may be given once daily (eg, 1-2 mg/kg qDay)

If satisfactory biochemical response (undetectable blood and/or urine succinylacetone), adjust dose according to body weight gain and not according to plasma tyrosine levels

Dosing Considerations

Monitoring parameters

  • Monitor plasma and/or urine succinylacetone concentrations, liver function parameters, and alpha-fetoprotein levels
  • During initiation, when switching from q12hr to qDay dosing, or if condition is deteriorating, consider closely monitoring all available biochemical parameters (ie, plasma and/or urine succinylacetone, urine 5-aminolevulinate [ALA], erythrocyte porphobilinogen [PBG]-synthase activity)
  • Maintain plasma tyrosine levels <500 mmol/L by dietary restriction of tyrosine and phenylalanine intake
  • Plasma tyrosine levels >500 micromol/L: Assess dietary tyrosine and phenylalanine intake; do not adjust dosage in order to lower plasma tyrosine concentration
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Interactions

Interaction Checker

and nitisinone

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    Contraindicated

      Serious - Use Alternative

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            Adverse Effects

            >10%

            Liver transplantation (13%)

            Elevated tyrosine levels (>10%)

            1-10%

            Liver failure (7%)

            Malignant hepatic neoplasm (5%)

            Leukopenia (3%)

            Thrombocytopenia (3%)

            Conjunctivitis (2%)

            Corneal opacity (2%)

            Keratitis (2%)

            Photophobia (2%)

            Alopecia (1%)

            Blepharitis (1%)

            Cataracts (1%)

            Dry skin (1%)

            Epistaxis (1%)

            Exfoliative dermatitis (1%)

            Eye pain (1%)

            Granulocytopenia (1%)

            Maculopapular rash (1%)

            Porphyria (1%)

            Pruritus (1%)

            <1%

            Seizure

            Brain tumor

            Encephalopathy

            Hyperkinesia

            Cyanosis

            Abdominal pain

            Diarrhea

            Enanthema

            Gastrointestinal hemorrhage

            Melena

            Elevated hepatic enzymes

            Liver enlargement hypoglycemia

            Septicemia

            Bronchitis

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            Warnings

            Contraindications

            None

            Cautions

            May develop transient leukopenia, thrombocytopenia, or both; monitor CBC during therapy

            Increase tyrosine levels

            • May cause increase in plasma tyrosine levels in patient with HT-1
            • Maintain concomitant reduction in dietary tyrosine and phenylalanine during treatment
            • Inadequate restriction of tyrosine and phenylalanine may lead to elevated plasma levels of tyrosine
            • Do not adjust dosage in order to lower plasma tyrosine concentration; maintain plasma tyrosine levels below 500 micromol/L
            • In patients with HT-1 treated with dietary restrictions and receive therapy who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake
            • Tyrosine levels >500 mmol/L may lead to
              • Variable degrees of intellectual disability and developmental delay; perform a clinical assessment if abrupt changes in neurologic status occur OR
              • Painful hyperkeratotic plaques on the soles and palms OR
              • Ocular signs and symptoms (eg, corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, photophobia); rerform a baseline ophthalmologic examination including slit-lamp examination prior to initiating treatment and regularly thereafter; if photophobia, eye pain, or signs of inflammation develops or tyrosine levels are > 500 micromol/L during treatment, undergo slit-lamp reexamination and immediately measure plasma tyrosine concentration

            Glycerol content in oral suspension

            • Doses of 20 mL of oral suspension (10 g glycerol) may cause headache, upset stomach and diarrhea due to glycerol content
            • Oral suspension contains 500 mg/mL of glycerol
            • Consider switching patients who are unable to tolerate the oral suspension to the oral capsules (see Administration)

            Drug interaction overview

            Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer, and an OAT1/OAT3 inhibitor

            • Sensitive CYP2C9 substrates or CYP2C9 substrates with a narrow therapeutic index
              • Nitisinone increases exposure of CYP2C9 substrates
              • Reduce dose of coadministered CYP2C9 substrates drug by half
              • Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs; see prescribing information for those drugs
            • OAT1/OAT3 substrates
              • Nitisinone increases exposure of OAT1/OAT3 substrate Monitor for potential adverse reactions related to coadministered drug
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            Pregnancy & Lactation

            Pregnancy

            Limited data on use in pregnant women insufficiently informs a drug-associated risk of major birth defects and miscarriage

            Animal data

            • Reproduction studies were performed in mice at PO doses ~0.4, 4 and 20x the recommended human dose (1 mg/kg/day), nitisinone reported to cause incomplete skeletal ossification of fetal bones, increased gestational length at 4 and 20x the recommended human dose, and decreased pup survival at 0.4x the recommended human dose based on the body surface area
            • Studies in rabbits at PO doses ~1.6, 4, and 8x the recommended human dose based on body surface area; nitisinone caused incomplete skeletal ossification of fetal bones

            Lactation

            No data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production

            Data suggest that nitisinone may be present in rat milk due ocular toxicity and lower body weight seen in drug naïve pups; consult women of the risk versus benefits for nitisinone and any potential adverse effects on breastfed infant from nitisinone

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            4-Hydroxyphenylpyruvate dioxygenase inhibitor; inhibits catabolism of tyrosine in patients with HT-1, preventing accumulation of maleylacetoacetate & fumarylacetoacetate which are converted to toxic succinylacetone & succinylacetoacetate; succinylacetone can inhibit the porphyrin synthesis pathway, which may lead to the accumulation of the neurotoxin 5-aminolevulinate, causing the porphyric crises typical of hereditary tyrosinemia type 1

            Absorption

            Fasting

            • Peak plasma time: 3.5 hr (Orfadin capsule); 0.38 hr (Orfadin suspension); 3.5 hr (Nityr)
            • Peak plasma concentration: 10.2 micromol/L (Orfadin capsule); 9.74 micromol/L (Orfadin suspension); 1278 ng/mL (Nityr)
            • AUC: 403 micromol·hr/L (Orfadin capsule); 346 micromol·hr/L (Orfadin suspension); 77874 ng·h/mL (Nityr) (Nityr)

            Distribution

            Protein bound: >95%

            Vd: 8.2 L (Nityr)

            Metabolism

            Relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme

            Elimination

            Half-life: 54 hr; 59.3 hr (Nityr)

            Excretion: Unknown

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            Administration

            Oral Suspension Preparation (Orfadin)

            Bottle without oral syringe adapter already inserted

            • Allow bottle to warm to room temperature (30-60 minutes)
            • Shake bottle vigorously for at least 20 seconds until solid cake is completely dispersed; ensure no particles left at the bottom of the bottle; foam will form in the bottle
            • Insert bottle adapter

            Bottle with oral syringe adapter

            • Shake bottle vigorously for at least 5 seconds
            • Check that there are no particles left at the bottom of the bottle
            • Foam will form in the bottle

            Oral Suspension Preparation (Nityr)

            Prepare only 1-2 tablets per PO syringe at one time; use 5-mL PO syringe with a cap

            Remove plunger from oral syringe and insert tablet(s)

            Replace plunger and draw up 2.6 mL (1 tablet) or 5 mL (2 tablets) of room temperature water

            Cap oral syringe and leave for ≥60 minutes

            Turn syringe up and down for at least 30 seconds to suspend contents

            Administer immediately; do not administer unless tablet(s) has fully disintegrated

            If tablet(s) not fully disintegrated, leave for an additional 10 minutes and again turn syringe up and down to suspend contents; do not administer unless tablet has fully disintegrated

            Administer immediately or store suspension at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hr after adding water to the tablets; discard after 24 hr

            Uncap oral syringe and administer suspension into patient’s mouth; avoid depressing plunger to end of oral syringe (ie, leave a gap between the plunger and the oral syringe)

            Rinse oral syringe by drawing up 2 mL of water; cap syringe and shake well for 10 seconds; uncap syringe and administer remaining suspension; if particle remain in syringe, repeat this process

            Oral Administration

            Adjunct to dietary reduction of tyrosine/phenylalanine

            Orfadin

            • Suspension: May take without regard to meals
            • Capsules
              • Take at least 1 hr before or 2 hr after a meals
              • For patients who have difficulty swallowing the capsules, open contents suspend in a small amount of water, formula, or apple sauce immediately before use

            Nityr

            • Maintain dietary restriction of tyrosine and phenylalanine
            • Take with or without food
            • Patients who have difficulty swallowing intact tablets: Disintegrate tablets in water
            • Patients can swallow semi-solid foods: Crush and mix with applesauce
            • Administration with other liquids or foods not studied and not recommended

            Storage

            Orfadin

            • Capsules
              • Refrigerate between 2-8°C (36-46°F)
            • Suspension
              • Refrigerate at 2-8°C (36-46°F) prior to first use
              • Do not freeze
              • After first opening, store at room temperature (up to 25°C [77°F]) for up to 60 days; if not used within 60 days, discard unused portion

            Nityr

            • Tablets: Store at controlled room temperature of 20-25°C (68-77°F)
            • Tablets mixed in water: Store at room temperature up to 24 hr; protect from light
            • Tablets mixed in applesauce: Store at room temperature, out of direct sunlight, for up to 2 hr after adding crushed tablets to applesauce
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.