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
more...

Hereditary Tyrosinemia Type 1

Indicated for treatment of 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 the dose based on biochemical and/or clinical response, as described in the full prescribing information  

Titration: 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

  • 2mg
  • 5mg
  • 10mg
  • 20mg

oral suspension

  • 4mg/mL

tablet (Nityr)

  • 2mg
  • 5mg
  • 10mg
more...

Hereditary Tyrosinemia Type 1

Indicated for treatment of 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 the dose based on biochemical and/or clinical response, as described in the full prescribing information  

Titration: 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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    Interactions Found

    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 phnylalanine 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; a baseline ophthalmologic examination including slit-lamp examination should be considered prior to initiating treatment

            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 co-administered 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
            • The 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

            There is are 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·h/L (capsule); 346 micromol·h/L (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)

            Oral suspension is dispensed with an oral syringe of appropriate size and a bottle adaptor provided by the pharmacist

            Bottle without oral syringe adapter already inserted

            • Store the bottle in the refrigerator prior to first use
            • Remove the bottle from the refrigerator; calculate 60 days from when the bottle is removed from the refrigerator and write this date as the “Discard after” date on the bottle label
            • Allow the bottle to warm to room temperature (30-60 minutes)
            • Shake the bottle vigorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed; check that there are no particles left at the bottom of the bottle; foam will form in the bottle
            • Insert the bottle adapter

            Bottle with oral syringe adapter

            • Shake the 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

            Compounded oral suspension (Nityr)

            If difficulty swallowing intact tablets, Nityr can be disintegrated in water and administered via oral syringe

            Prepare only 1-2 tablets per PO syringe at one time; use 5-mL PO syringe with a cap Use only room temperature water for preparation

            Remove cap and plunger from the PO syringe and place 1 whole tablet inside PO syringe

            Draw 2.6 mL (1 tablet) or 5 mL (2 tablets) of room temperature water with PO syringe

            Pull plunger back to 3 mL; place cap on PO syringe tip Turn PO syringe up and down for 1 minute; then leave for at least 20 minutes

            After 20 minutes, turn PO syringe for 1 minute; then leave for at least 30 minutes

            Repeat turning for 1 minute; inspect syringe to ensure tablet has disintegrated prior to administration Do not administer unless tablet is fully disintegrated

            If not fully disintegrated, leave for at least 10 minutes; turn the PO syringe up and down for 1 minute

            Administer immediately; if unable to administer immediately, store PO suspension at room temperature; protect from sunlight; discard after 2 hr

            Oral Administration

            Adjunct to dietary reduction of tyrosine/phenylalanine

            Oral suspension (Orfadin): May take without regard to meals

            Oral capsules (Orfadin)

            • Take at least 1 hr before or 2 hr after a meals
            • For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use

            Unable to swallow Nityr tablet

            • If patients can swallow semisolid foods, Nityr tablets can be crushed and mixed with applesauce (other foods have not been studied and is not recommended)
            • If difficulty swallowing intact tablets, Nityr can be disintegrated in water and administered via oral syringe (see above preparation instructions)
            • Compounded Nityr suspension
              • To facilitate full administration, avoid depressing the plunger until the end of PO syringe; leave a gap between the plunger and the PO syringe
              • Rinse PO syringe with ~2 mL of water
              • Invert the PO syringe and pull the plunger to 2.6 mL; cap the PO syringe and shake well for 10 seconds to suspend any remaining particles
              • Administer the suspension into the patient’s mouth, fully depress plunger ensuring the syringe is empty

            Storage

            Oral capsules (Orfadin)

            • Store refrigerated between 2-8°C (36-46°F)
            • May store at controlled room temperature of 20-25°C (68-77°F) for up to 45 days
            • The discard after date should be noted on the bottle if stored at room temperature

            Oral suspension (Orfadin)

            • Refrigerate at 2-8°C (36-46°F) prior to first use
            • Do not freeze
            • Store bottle upright
            • After first opening, store the product at room temperature (up to 25°C [77°F]) for up to 60 days; if not used within 60 days, discard unused portion
            • The discard after date should be noted on the bottle

            Oral tablet (Nityr)

            • Store at room temperature between 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
            • Dispense in tight and light resistant container
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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.