Dosing and uses of Orfadin (nitisinone)
Adult dosage forms and strengths
capsule
- 2mg
- 5mg
- 10mg
- 20mg
oral suspension
- 4mg/mL
Hereditary Tyrosinemia Type 1
0.5 mg/kg PO q12hr (morning and evening); after 1 month, may increase dose to 0.75 mg/kg q12hr if necessary
If needed, may further increase to 1 mg/kg q12hr
Alkaptonuria (Orphan)
Treatment of alkaptonuria
Orphan indication sponsor
- Swedish Orphan AB; Kungsgatan 37, 7th Floor; SE-111 56, Sweden
Pediatric dosage forms and strengths
capsule
- 2mg
- 5mg
- 10mg
- 20mg
oral suspension
- 4mg/mL
Hereditary Tyrosinemia Type 1
0.5 mg/kg PO q12hr (morning and evening); after 1 month, may increase to 0.75 mg/kg q12hr if necessary
If needed, may further increase (especially infants) to 1 mg/kg q12hr
Orfadin (nitisinone) adverse (side) effects
>10%
Elevated tyrosine levels
1-10%
Alopecia
Blepharitis
Cataracts
Conjunctivitis
Corneal opacity
Dry skin
Epistaxis
Exfoliative dermatitis
Eye pain
Hepatic neoplasm
Keratitis
Leukopenia
Liver failure
Maculopapular rash
Photophobia
Porphyria
Pruritus
Thrombocytopenia
Granulocytopenia
Warnings
Contraindications
None known
Cautions
Monitor urine succinylacetone, LFTs, alpha fetoprotein, serum tyrosine, and phenylalanine
Assess plasma tyrosine levels in patients with an abrupt change in neurologic status
Serious adverse effects include thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints 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 reported to improve patient that developed leukopenia and thrombocytopenia in clinical trials
Use caution in patients with preexisting myelosuppression
Restrict dietary intake of tyrosine and phenylalanine
Keep plasma level of tyrosine <500 umol/L to avoid toxicity; toxicity can result in symptoms that include intellectual disability and developmental delay or painful hyperkeratotic plaques on the soles and palms; do not adjust dosage in order to lower plasma tyrosine concentration
Perform slit lamp ophthalmologic exam of eyes before initiating treatment
May take >3 months for plasma succinylacetone to normalize
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)
Pregnancy and lactation
Pregnancy category: C
Lactation: Not known if distributed into breast milk, use caution
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.
Pharmacology of Orfadin (nitisinone)
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
Peak plasma time: 3.5 hr (capsule); 0.38 hr (suspension)
Peak plasma concentration: 10.2 micromol/L (capsule); 9.74 micromol/L (suspension)
AUC: 403 micromol·h/L (capsule); 346 micromol·h/L (suspension)
Distribution
Protein bound: >95%
Metabolism
Relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme
Elimination
Half-life: 54 hr
Excretion: Unknown
Administration
Oral Capsules
Take at least 1 hr before or 2 hr after a meals
Adjunct to dietary reduction of tyrosine/phenylalanine
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
Oral Suspension
May take without regard to meals
Preparation
- 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
Storage
Oral capsules: Store refrigerated, 2-8°C (36-46°F)
Oral suspension
- 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
