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The following serious adverse reactions are described below and elsewhere in the labeling:
- High Plasma Tyrosine Levels [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
ORFADIN was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 21.7 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of ORFADIN was 0.6 to 1 mg/kg/day, and the dose was increased in some patients to 2 mg/kg/day based on weight, biochemical, and enzyme markers. Median duration of treatment was 22.2 months (range 0.1 to 80 months).
The most serious adverse reactions reported during ORFADIN treatment were thrombocytopenia, leucopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see WARNINGS AND PRECAUTIONS]. Most patients with ocular/visual events had transient symptoms lasting less than one week, while 6 patients had symptoms lasting 16 to 672 days. Six patients had thrombocytopenia, with platelet counts 30,000/uL or lower in 3 patients. In 4 patients with thrombocytopenia, platelet counts returned to normal without change in ORFADIN dose. In 2 patients platelet count returned to normal 2 weeks to 5 months after ORFADIN treatment was discontinued. No patients developed infections or bleeding as a result of the episodes of leucopenia and thrombocytopenia.
Other serious adverse events reported during ORFADIN treatment were hepatic neoplasm, liver failure, and porphyric crises. Patients with hereditary tyrosinemia type 1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure 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 monitoring for these complications by hepatic imaging (ultrasound, computerized tomography, magnetic resonance imaging) and laboratory tests, including serum alpha-fetoprotein concentration is recommended. Patients with increasing alpha-fetoprotein levels or development of liver nodules during treatment with nitisinone should be evaluated for hepatic malignancy.
The most common adverse reactions reported in the clinical trial are summarized in Table 1.
TABLE 1 : Adverse Reactions Reported in 207 Patients
During an Open-Label, Uncontrolled Trial
|LIVER and BILIARY SYSTEM|
|HEMIC and LYMPHATIC SYSTEM|
|SKIN and APPENDAGES|
Adverse reactions reported in less than 1% of the patients, regardless of causality assessment, included death, seizure, brain tumor, encephalopathy, headache, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration, hepatic function disorder, elevated hepatic enzymes, liver enlargement, dehydration, hypoglycemia, thirst, infection, septicemia, otitis, infection (not otherwise specified), bronchitis, respiratory insufficiency, pathologic fracture, amenorrhea, nervousness, and somnolence.
Read the Orfadin (nitisinone) Side Effects Center for a complete guide to possible side effects
Use caution when administering ORFADIN with drugs that are metabolized by CYP2C9 because of a potential for increased systemic exposure of these drugs [see Pharmacokinetic].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/15/2014
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