A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Orfadin Warnings, Precautions, Pregnancy, Nursing, Abuse - Nitisinone
Orfadin Warnings, Precautions, Pregnancy, Nursing, Abuse - Nitisinone
WARNINGS
High Plasma Tyrosine Levels
Inadequate restriction of tyrosine and phenylalanine intake
can result in elevations in plasma tyrosine. Plasma tyrosine levels should be
kept below 500 µmol/L in order to avoid toxic effects to the eyes (corneal ulcers,
corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia), skin
(painful hyperkeratotic plaques on the soles and palms), and nervous system
(variable degrees of mental retardation and developmental delay). In most patients,
eye symptoms were transient, lasting less than one week. Six patients had prolonged
episodes lasting 16 to 672 days (see PRECAUTIONS
,
General).
Transient Thrombocytopenia and Leucopenia
Patients treated with Nitisinone and dietary restriction
in clinical trials were observed to develop transient thrombocytopenia (3%),
leucopenia (3%) or both (1.5%). One patient, who developed both leucopenia and
thrombocytopenia, improved after the dose of Nitisinone was decreased from 2
mg/kg to 1 mg/kg. Another patient, who developed thrombocytopenia, had Nitisinone
stopped for 2 weeks, but platelet values continued to be low for 3 months and
slowly returned to normal after 5 months. In all other patients, platelet values
and white blood cell counts normalized gradually without documented change in
Nitisinone dose. No patients developed infections or bleeding as a result of
the episodes of leucopenia and thrombocytopenia. Platelet and white blood
cell counts should be monitored regularly during Nitisinone therapy.
PRECAUTIONS
General
Ophthalmologic Care of Patients Treated with Nitisinone (see
WARNINGS
)
• Slit-lamp examination of the eyes should be performed before
initiation of Nitisinone treatment.
• Patients who develop photophobia, eye pain or signs of inflammation
such as redness, swelling, or burning of the eyes during treatment with Nitisinone
should undergo slit-lamp reexamination and immediate measurement of the plasma
tyrosine concentration.
• A more restricted diet should be implemented if the plasma
tyrosine level is above 500 µmol/L.
• Nitisinone dosage should not be adjusted in order to lower
the plasma tyrosine concentration, since the HT-1 metabolic defect may result
in deterioration of the patient’s clinical condition.
Risk of Porphyric Crises, Liver Failure, and Hepatic Neoplasms
Patients with hereditary tyrosinemia type 1 are at increased
risk of developing porphyric crises, liver failure, or hepatic neoplasms requiring
liver transplantation. These complications of HT-1 were observed in patients
treated with Nitisinone for a median of 22 months during the clinical trial
(liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%,
benign hepatic neoplasms 3%, porphyria 0.5%). Regular liver monitoring by
imaging (ultrasound, computerized tomography, magnetic resonance imaging) and
laboratory tests, including serum alpha-fetoprotein concentration is recommended.
An increase in serum alpha-fetoprotein concentration may be a sign of inadequate
treatment, but patients with increasing alpha-fetoprotein or signs of nodules
of the liver during treatment with Nitisinone should always be evaluated for
hepatic malignancy.
Information for Patients
Patients and their parents or caregivers should be advised
of the need to maintain dietary restriction of tyrosine and phenylalanine when
taking Nitisinone to treat hereditary tyrosinemia type 1.
Patients and their parents or caregivers should be advised
to report promptly unexplained eye symptoms, rash, jaundice, or excessive bleeding
(see WARNINGS
and ADVERSE
REACTIONS).
Laboratory Tests
• Plasma Nitisinone concentration, urine and plasma succinylacetone
levels, urine 5-ALA levels, and erythrocyte PBG-synthase activity were used
during clinical trials to guide drug dosage. The probability of recurrence of
abnormal values of urine succinylacetone was 1% at a Nitisinone concentration
of 37 µmol/L (95% confidence interval: 23-51 µmol/L). Assays for plasma Nitisinone
concentration, plasma succinyl acetone, urine 5-ALA, and erythrocyte PBG-synthase
activity are not routinely available in the U.S. However, urine succinylacetone
levels can be used to guide drug dose adjustment (see DOSAGE
and ADMINISTRATION).
• Serum alpha-fetoprotein concentrations are generally markedly
elevated at the time of diagnosis, and gradually decrease during the course
of Nitisinone treatment. Increases during therapy may be a sign of inadequate
treatment. An exponential increase in serum alpha-fetoprotein concentration
should be promptly evaluated for potential liver neoplasia. • Platelet and white
blood cell counts should be monitored regularly because of the risk of transient
thrombocytopenia and leukopenia (see WARNINGS
).
• Serum phosphate should be measured as a screening test for
patients with renal involvement at risk of secondary hypophosphatemia and rickets.
• Plasma tyrosine levels should be kept below 500 µmol/L in order to avoid toxic
effects (see WARNINGS
).
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