Brand and Other Names:Orfadin
- Classes: Metabolic & Endocrine, Other
Dosing & Uses
Dosage Forms & Strengths
Hereditary Tyrosinemia Type 1
If needed, may further increase to 1 mg/kg q12hr
Treatment of alkaptonuria
Orphan indication sponsor
- Swedish Orphan AB; Kungsgatan 37, 7th Floor; SE-111 56, Sweden
Serious - Use Alternative
Significant - Monitor Closely
Monitor urine succinylacetone, LFTs, alpha fetoprotein, serum tyrosine, and phenylalanine
Serious adverse effects include thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels
Restrict dietary intake of tyrosine and phenylalanine
Keep plasma level of tyrosine <500 umol/L to avoid toxicity
Perform slit lamp ophthalmologic exam of eyes before initiating treatment
May take >3 months for plasma succinylacetone to normalize
Glycerol content in oral suspension
- Oral doses of glycerol ≥10 g have been reported to cause headache, upset stomach and diarrhea
- The oral suspension contains 500 mg/mL of glycerol
- Patients who receive >20 mL of the oral suspension (ie, 10 g glycerol) as a single dose are at increased risk of these adverse reactions
- Consider switching patients who are unable to tolerate the oral suspension to the oral capsules (see Administration)
Pregnancy & Lactation
Pregnancy Category: C
Lactation: Not known if distributed into breast milk, use caution
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.
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
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)
Protein bound: >95%
Relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme
Half-life: 54 hr
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
May take without regard to meals
- 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
Oral capsules: Store refrigerated, 2-8°C (36-46°F)
- 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
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