Orfadin

Metabolic Agents, Tyrosinemia Agents

 
NOTE: To obtain or inquire about financial assistance with this drug call (800) 999-NORD in the US.

Treatment with nitisinone requires restriction of dietary intake of tyrosine and phenylalanine to prevent toxicity associated with tyrosinemia. A nutritionist specializing in managing diets of children with inborn errors of metabolism should provide information about diets low in protein and deficient in tyrosine and phenylalanine.

Capsules
Administer nitisinone capsules at least 1 hour before or 2 hours after a meal.
For patients who have difficulty swallowing, capsules may be opened and the contents suspended in a small amount of water, formula, or applesauce immediately before use.[30096]
 
Tablets
Administer nitisinone tablets without regards to meals.
For patients with difficulty swallowing tablets, nitisinone can be disintegrated in water and administered in an oral syringe. If patients can swallow semi-solid foods, tablets may be crushed and mixed with applesauce.
Mixed with applesauce: Crush tablets to form a fine powder; only crush 1 tablet at a time. Once all tablets have been crushed, the tablets may be added to a teaspoon of applesauce. Once the powder and applesauce have been mixed and are well dispersed, administer the entire nitisinone and applesauce mixture immediately. If it's not possible to administer immediately, the mixture may be stored at room temperature, out of direct sunlight, for up to 2 hours. Discard any mixture not used within 2 hours.
Mixed with water in an oral syringe: Do not prepare more than 2 tablets at once within the same oral syringe.
For 1 tablet, remove the plunger from a 5 mL oral syringe and insert a single, intact tablet. Replace the plunger and draw up 2.6 mL of room temperature water.
For 2 tablets, remove the plunger from a 5 mL oral syringe and insert 2 intact tablets. Replace the plunger and draw up 5 mL of room temperature water.
Cap the syringe and leave the oral syringe for at least 60 minutes. After 60 minutes, turn the oral syringe up and down for at least 30 seconds to suspend the material. If the tablet has fully disintegrated, it may be administered to the patient. If it is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Then turn the oral syringe up and down for 30 seconds to re-suspend the particles. Do not administer unless the tablet has fully disintegrated.
Administer immediately. If it's not possible to administer immediately, the suspension may be stored at room temperature, out of direct sunlight, for up to 24 hours after adding water to the tablets. Discard any suspension not used within 24 hours.
When administering, avoid depressing the plunger to the end of the oral syringe; a gap between the plunger and oral syringe should remain. Rinse the oral syringe by drawing up 2 mL of water. Cap the oral syringe and shake well for 10 seconds to suspend any remaining particles before administration to the patient, fully depressing the plunger to ensure complete emptying of the syringe.[62200]

Preparing a Bottle without the 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 the date as the "Discard after" date on bottle label.
Allow the bottle to warm to room temperature (30 to 60 minutes).
Shake the bottle vigorously (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.
 
Preparing a Bottle with the Adapter Already Inserted
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.
 
Measuring and Administering the Dose (once the bottle is prepared with the adapter)
Use the oral syringe to measure the dose.
Keep the bottle upright and insert the oral syringe into the adapter.
Turn the bottle upside down with the oral syringe in place; wait for the foam to rise to the top of the bottle.
Pull back on the syringe plunger to withdraw the dose.
Leave the syringe in the adapter and turn the bottle upright.
Remove the syringe from the adapter by gently twisting it out of the bottle. Do not remove the bottle adapter.
Administer the oral dose without regards to meals.
Storage: Store at room temperature (not above 25 degrees C).

hepatic failure / Delayed / 7.0-7.0
keratitis / Delayed / 2.0-2.0
corneal opacification / Delayed / 2.0-2.0
porphyria / Delayed / 1.0-1.0
exfoliative dermatitis / Delayed / 1.0-1.0

thrombocytopenia / Delayed / 3.0-3.0
leukopenia / Delayed / 3.0-3.0
conjunctivitis / Delayed / 2.0-2.0
photophobia / Early / 2.0-2.0
cataracts / Delayed / 1.0-1.0
blepharitis / Early / 1.0-1.0

ocular pain / Early / 1.0-1.0
alopecia / Delayed / 1.0-1.0
epistaxis / Delayed / 1.0-1.0
maculopapular rash / Early / 1.0-1.0
xerosis / Delayed / 1.0-1.0
pruritus / Rapid / 1.0-1.0
abdominal pain / Early / Incidence not known
diarrhea / Early / Incidence not known
headache / Early / Incidence not known

NITYR, Orfadin

Rx

Hydroxyphenyl-pyruvate dioxygenase inhibitor
Used for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine
Monitor plasma and/or urine succinylacetone concentrations, liver function parameters, alpha-fetoprotein levels, and platelet and WBC counts during therapy

0.5 mg/kg/dose PO twice daily. Treatment with nitisinone should lead to normalization of porphyrin metabolism (i.e., normal erythrocyte PBG-synthase activity, plasma succinylacetone, and urine 5-aminolevulinate). Succinylacetone should not be detected in the urine or serum. If succinylacetone is not normalized within 4 weeks of starting nitisinone therapy, increase the dosage to 0.75 mg/kg/dose PO twice daily. A maximum dose of 1 mg/kg/dose PO twice daily may be needed based on evaluation of biochemical parameters. During initiation of therapy and during acute exacerbations, it may be necessary to more closely monitor disease parameters. Maintenance therapy may be given once daily (e.g., 1 to 2 mg/kg once daily) to patients with undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable nitisinone dosage.

0.5 mg/kg/dose PO twice daily. Treatment with nitisinone should lead to normalization of porphyrin metabolism (i.e., normal erythrocyte PBG-synthase activity, plasma succinylacetone, and urine 5-aminolevulinate). Succinylacetone should not be detected in the urine or serum. If succinylacetone is not normalized within 4 weeks of starting nitisinone therapy, increase the dosage to 0.75 mg/kg/dose PO twice daily. A maximum dose of 1 mg/kg/dose PO twice daily may be needed based on evaluation of biochemical parameters. During initiation of therapy and during acute exacerbations, it may be necessary to more closely monitor disease parameters. Maintenance therapy may be given once daily (e.g., 1 to 2 mg/kg once daily) to patients 5 years of age and older with undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable nitisinone dosage.

0.5 mg/kg/dose PO twice daily. Treatment with nitisinone should lead to normalization of porphyrin metabolism (i.e., normal erythrocyte PBG-synthase activity, plasma succinylacetone, and urine 5-aminolevulinate). Succinylacetone should not be detected in the urine or serum. If succinylacetone is not normalized within 4 weeks of starting nitisinone therapy, increase the dosage to 0.75 mg/kg/dose PO twice daily. A maximum dose of 1 mg/kg/dose PO twice daily may be needed based on evaluation of biochemical parameters. During initiation of therapy and during acute exacerbations, it may be necessary to more closely monitor disease parameters.

No formal studies have been performed to assess nitisinone pharmacokinetics in patients with hepatic dysfunction.

No formal studies have been performed to assess nitisinone pharmacokinetics in patients with renal dysfunction.

Adefovir: (Moderate) Monitor for increased adefovir-related adverse effects if coadministered with nitisinone. Increased adefovir exposure is possible. Nitisinone inhibits OAT1. Adefovir is an OAT1 substrate.
Amlodipine; Celecoxib: (Major) A dosage adjustment of celecoxib may be necessary when administered with nitisinone as concurrent use may result in increased celecoxib exposure. Celecoxib is a sensitive CYP2C9 substrate; nitisinone is a moderate CYP2C9 inhibitor. Concurrent use of celecoxib with another moderate CYP2C9 inhibitor increased celecoxib exposure by 2-fold. FDA-approved labeling for nitisinone recommends reducing the dose of sensitive CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Celecoxib: (Major) A dosage adjustment of celecoxib may be necessary when administered with nitisinone as concurrent use may result in increased celecoxib exposure. Celecoxib is a sensitive CYP2C9 substrate; nitisinone is a moderate CYP2C9 inhibitor. Concurrent use of celecoxib with another moderate CYP2C9 inhibitor increased celecoxib exposure by 2-fold. FDA-approved labeling for nitisinone recommends reducing the dose of sensitive CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Celecoxib; Tramadol: (Major) A dosage adjustment of celecoxib may be necessary when administered with nitisinone as concurrent use may result in increased celecoxib exposure. Celecoxib is a sensitive CYP2C9 substrate; nitisinone is a moderate CYP2C9 inhibitor. Concurrent use of celecoxib with another moderate CYP2C9 inhibitor increased celecoxib exposure by 2-fold. FDA-approved labeling for nitisinone recommends reducing the dose of sensitive CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Cidofovir: (Moderate) Monitor for increased cidofovir-related adverse effects if coadministered with nitisinone. Increased cidofovir exposure is possible. Nitisinone inhibits OAT1. Cidofovir is an OAT1 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Food: (Major) Food and dietary interactions are a critical component of treatment with nitisinone. Foods containing tyrosine or phenylalanine should be avoided; the patient usually must adhere to a low protein diet as a result. Products containing phenylalanine include any product containing the sweetener aspartame (Nutrasweet). (Major) Food and dietary interactions are a critical component of treatment with nitisinone. Foods containing tyrosine or phenylalanine should be avoided; the patient usually must adhere to a low protein diet as a result. Products containing phenylalanine include any product containing the sweetener aspartame (Nutrasweet).
Fosphenytoin: (Moderate) Monitor serum phenytoin (the active metabolite of fosphenytoin) concentrations if fosphenytoin is coadministered with nitisinone. Consider a dose reduction of fosphenytoin if adverse reactions occur. Coadministration may increase phenytoin exposure resulting in increased adverse effects. In vitro data predicts inhibition of CYP2C9 by nitisinone. Phenytoin is a CYP2C9 substrate.
Furosemide: (Moderate) Monitor for increased furosemide-related adverse effects including excessive fluid loss or hypotension if coadministered with nitisinone. Increased furosemide exposure is possible. Nitisinone inhibits OAT3. Furosemide is an OAT3 substrate. When coadministered, the AUC of furosemide increased by 72% and Cmax increased by 12%.
Ganciclovir: (Moderate) Monitor for increased ganciclovir-related adverse effects. Coadministration may increase ganciclovir exposure resulting in increased adverse effects. Nitisinone inhibits OAT1. Ganciclovir is an OAT1 substrate.
Glimepiride: (Major) A dosage adjustment of glimepiride may be necessary when administered with nitisinone as concurrent use may result in increased glimepiride exposure which may lead to hypoglycemia. Glimepiride is a sensitive CYP2C9 substrate; nitisinone is a moderate CYP2C9 inhibitor. FDA-approved labeling for nitisinone recommends reducing the dose of sensitive CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and nitisinone; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and nitisinone is a CYP2C9 inhibitor.
Methadone: (Moderate) Monitor for increased methadone-related adverse effects including excessive sedation and somnolence if coadministered with nitisinone. Increased methadone exposure is possible. Methadone is a CYP2C9 substrate. In vitro data predicts inhibition of CYP2C9 by nitisinone potentially resulting in clinically significant interactions.
Methotrexate: (Moderate) Monitor for increased methotrexate-related adverse effects if coadministered with nitisinone. Increased methotrexate exposure is possible. Nitisinone inhibits OAT3. Methotrexate is an OAT3 substrate.
Penicillin G Benzathine: (Moderate) Monitor for increased penicillin-related adverse effects if coadministered with nitisinone. Increased penicillin exposure is possible. Nitisinone inhibits OAT3. Penicillin is an OAT3 substrate.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Monitor for increased penicillin-related adverse effects if coadministered with nitisinone. Increased penicillin exposure is possible. Nitisinone inhibits OAT3. Penicillin is an OAT3 substrate.
Penicillin G Procaine: (Moderate) Monitor for increased penicillin-related adverse effects if coadministered with nitisinone. Increased penicillin exposure is possible. Nitisinone inhibits OAT3. Penicillin is an OAT3 substrate.
Penicillin G: (Moderate) Monitor for increased penicillin-related adverse effects if coadministered with nitisinone. Increased penicillin exposure is possible. Nitisinone inhibits OAT3. Penicillin is an OAT3 substrate.
Phenytoin: (Major) Monitor phenytoin serum concentrations in patients receiving nitisinone as concurrent use may increase circulating phenytoin concentrations enhancing the risk of drug toxicity. A phenytoin dosage reduction may be necessary. Phenytoin is a CYP2C9 substrate with narrow therapeutic index (NTI); nitisinone is a moderate CYP2C9 inhibitor. FDA-approved labeling for nitisinone recommends reducing the dose of NTI CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Pioglitazone; Glimepiride: (Major) A dosage adjustment of glimepiride may be necessary when administered with nitisinone as concurrent use may result in increased glimepiride exposure which may lead to hypoglycemia. Glimepiride is a sensitive CYP2C9 substrate; nitisinone is a moderate CYP2C9 inhibitor. FDA-approved labeling for nitisinone recommends reducing the dose of sensitive CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Pravastatin: (Moderate) Monitor for increased pravastatin-related adverse effects if coadministered with nitisinone. Increased pravastatin exposure is possible. Nitisinone inhibits OAT3. Pravastatin is an OAT3 substrate.
Tenofovir Alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Tenofovir Alafenamide: (Moderate) Monitor for increased tenofovir-related adverse effects if coadministered with nitisinone. Increased tenofovir exposure is possible. Nitisinone inhibits OAT1. Tenofovir is an OAT1 substrate.
Tolbutamide: (Major) A dosage adjustment of tolbutamide may be necessary when administered with nitisinone as concurrent use may result in increased tolbutamide exposure which may lead to hypoglycemia. Tolbutamide is a sensitive CYP2C9 substrate; nitisinone is a moderate CYP2C9 inhibitor. FDA-approved labeling for nitisinone recommends reducing the dose of sensitive CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations. When co-administered, the AUC of tolbutamide increased by 131% and Cmax increased by 16%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with nitisinone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nitisinone is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

Nitisinone/Orfadin Oral Cap: 2mg, 5mg, 10mg, 20mg
NITYR Oral Tab: 2mg, 5mg, 10mg
Orfadin Oral Susp: 1mL, 4mg

2 mg/kg/day PO.

2 mg/kg/day PO.

2 mg/kg/day PO.

2 mg/kg/day PO.

2 mg/kg/day PO.

Nitisinone inhibits the normal catabolism of tyrosine in patients with hereditary tyrosinemia type I (HT-1). Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an earlier enzyme in the tyrosine catabolic pathway than fumarylacetoacetate hydrolase (FAH), the enzyme deficient in HT-1 patients. By inhibiting the normal metabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of catabolic intermediates maleylacetoacetate and fumarylacetoacetate. These intermediates are converted to toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for liver and kidney toxicity seen in patients with HT-1. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises of HT-1.

Nitisinone is administered orally. No pharmacokinetic studies of nitisinone have been conducted in children or patients with hereditary tyrosinemia type I (HT-1). There is no information regarding the metabolism of nitisinone in humans. The mean terminal half-life of nitisinone is 54 to 59 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2E1, OAT1 and 3
Nitisinone is a moderate inhibitor of CYP2C9, a weak inducer of CYP2E1, and an inhibitor of OAT1/OAT3.

In healthy volunteers, the peak plasma nitisinone concentration occurred at approximately 3.5 hours after a single dose for the capsules (30 mg) and tablets (10 mg) and 0.4 hours postdose for the oral suspension (30 mg). The Cmax (CV%) was 10.5 (26) micromol/L (capsule) and 10.1 (34) micromol/L (oral suspension) and AUC72 (CV%) was 406 (13) micromol x hour/L (capsule) and 350 (17) micromol x hour/L (oral suspension). In healthy volunteers, the peak plasma nitisinone concentration occurred at approximately 4 hours after repeated once daily 80 mg capsules, and steady-state was achieved within 14 days. The Cmax (CV%) was 120 (23) micromol/L and AUC24 (CV%) was 2,204 (18) micromol x hour/L. For nitisinone tablets, the Cmax was 1,278 (780 to 1,649) ng/mL and AUC was 77,874 (42,335 to 104,211) ng x hour/mL. For nitisinone capsules, the effect of food on absorption has not been studied. For nitisinone oral suspension, a high calorie and high fat meal did not affect total exposure (AUC72h), but decreased the Cmax by approximately 20%. For nitisinone tablets, a high calorie and high fat meal did not affect total exposure (AUC) and Cmax, but delayed the Tmax by 6 hours.

Limited data on nitisinone use in human pregnancy are not sufficient to inform any drug associated risk. Animal reproduction studies have been conducted for nitisinone. In these studies, nitisinone was administered to mice and rabbits during organogenesis with oral doses of nitisinone up to 20 and 8 times respectively, the recommended human dose. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended human dose, and increased gestational length at doses 4 times the recommended human dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended human dose. It is not known if nitisinone can cause fetal harm when given to a pregnant woman. Nitisinone should be given to a pregnant woman only if clearly needed.

According to the manufacturer, it is not known whether nitisinone is excreted in human breast milk. However, in animal studies, exposure to nitisinone via breast milk resulted in ocular toxicity and lower body weight suggesting the excretion of nitisinone in the animals' breast milk. Caution should be exercised if nitisinone is given to a woman who is breast-feeding her infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.