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  

If succinylacetone is still detectable after 1 month, may increase dose to 0.75 mg/kg q12hr if necessary; not to exceed 1 mg/kg PO q12hr

Once daily maintenance dose (Orfadin): May give total daily dose once daily in patients aged ≥5 years who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone

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) 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  

If succinylacetone is still detectable after 1 month, may increase dose to 0.75 mg/kg q12hr if necessary; not to exceed 1 mg/kg PO q12hr

Once daily maintenance dose (Orfadin): May give total daily dose once daily in patients aged ≥5 years who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone

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Interactions

Interaction Checker

and nitisinone

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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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

            Elevated tyrosine and phenylalanine levels may cause developmental delay and hyperkeratotic plaques; maintain plasma level of tyrosine <500 umol/L to avoid toxicity; do not adjust dosage in order to lower plasma tyrosine concentration; restrict dietary intake of tyrosine and phenylalanine

            Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels; levels > 500 micromol/L may lead to ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia; perform a baseline ophthalmologic examination including slit-lamp examination prior to initiating treatment and regularly thereafter

            Serious adverse effects include severe thrombocytopenia, and leukopenia associated with elevated tyrosine levels; monitor platelet and white blood cell counts; decreasing dose from 1 mg/kg to 0.5 mg/kg twice daily reportedly improved a patient that developed leukopenia and thrombocytopenia in clinical trials; monitor platelet and white blood cell counts

            If coadministered with drugs that are metabolized by CYP2C9, additional monitoring may be warranted because of a potential for increased systemic exposure of these drugs

            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)
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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

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            • View the formulary and any restrictions for each plan.
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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.