Hereditary tyrosinemia type (HT-1)

Most frequent adverse reactions- 

Dermatologic-           alopecia, dry skin, exfoliative drmatitis, macropapular rash,  priritus 1%

Hematologic/lymphatic-  leukopenia,  thrombocytopenia, 3% 
                                             epistaxis,  prophyria  1%

Hepatic-                 hepatic neoplasm 8%    liver failure 7%

Special senses-    conjuntivitis, corneal opacity, keratitis, phtophobia 2%
                                blepharitis, cataracts, eye pain   1%

Adverse reactions occuring in less than 1% of patients-

Cardiovascular-     cyanosis

CNS-                      brain tumor, encephalopathy,  headache,  hyperkinesia, nervousness, seizures,
                               somnolence

GI-                          abdominal pain, diarrhea,  enanthema,  gastritis,   gasrtroenteritis,
                               GI haemorrhage,  melena,  tooth discolration

GU-                        amenorrhea

Hepatic-                 elevsted hepatic enzymes, hepatic function disorder,  liver ennlargement

Metabolic/nutrional -    dehydration,  hypoglycedmia,  thirst

Musculo-skeletal -   pathologic fracture

Respiratory  -           bronchitis, respiratory insufficiency

Miscellaneous -       death, infection, otitis, septicemia 
 

Special Precaution-
High plasma tyrosine levels-  inadequate restriction of tyrosine and phenylamine intake  can
result in elevation of plasma tyrosine.

Plasma tyrosine levels should be kept below 500mcmol/L in order to avoid toxic efects to the
eyes9 corneal ulcers,corneal opacities, keratitis, conjuntivitis, eye pain, photophobia)
skin ( painful hyperkeratotic plaques on the soles and palm andnervous system ( variable
degrees of mental retardation and development delay)

In most cases eye symptoms were transcient lasting less than 1 week.   

Transcient thrombocytoma and leukopenia- regularly monitor platelet and white blood cells
counts during nitisinone therapy

Risk of porphyric crises - an increase in serum alpha-fetoprotein concentration may be sign of
inadequate treatment but always evaluate patients with increasing alpha-fetoprotein or signs
of nodules of the liver during treatment with nitisinone malignancy

General ophthalmic care- peform slit lamp examination of the eyes before initiation of nitisinone
treatment.Patients who develop photophobia, eye pain, or signs of inflammation such as
redness, swelling, or burning of the eyes should undergo slit- lamp examination and immediate
 measurement of plasma  tyrosine concentration.

 Implement a more restricted diet if the plasma tyrosine level is above 500mcmol/L.
 Do not adjust nitisinone dosage  in order to lower the plasma tyrosine concentration because
the HT-1 metabolic defect may resut in deterioration of patients clinical condition.  

Pregnancy- give nitisonine to a pregnant woman only if clearly needed.

Lactation- excercise caution when nitisonine is administred to a breast feeding woman.

Children- nitisinone has been studied in patients ranging from  in age from birth to 21.7 years.

Elderly- in general dose selection for an elderly patient should be cautious , usually starting
at a low end of dosing range reflecting the greater frequency of decreased hepatic , renal
or cardiac function and concomittant disease or other drug therapy in this patient population

Indication-
Heriditary tyrosinemia type (HT-1) - adjunct to dietary  reduction of tyrosine and phenylamine in
the treatment of HT-1

Dosage-
Dose should be adjusted in each patient.
The recommended initial dosage is 1mg/kg/day divided for morning and evening administration.
ince the effect of food is unknown , nitisone should be taken at least 1 hour before a meal.

1. Advice patients and their caregivers of the need to maintain dietary resriction of tyrosine and
    phenylalanine when taking nitisinone to treat HT-1

2. Advice patients and their caregivers to promptly report unexplained eye symptoms , rash,
   jaundice, oe excessive bleeding

Pharmacolgy-
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase an enzyme upstream
of fumarylacetoacetase FAH in the tyrosine catabolic path way.

By inhibting the normal catabolism of tyrosine in patients with HT-1 these catabolic intermediates
are converted to toxic metabolites succinylacetone and succinylacetoacetate which are responsible
for the observed liver and kidney toxicity.

Succinyl acetone can also inhibit the porphyrin synthesis pathway leading to accumulation of
5-amnolevulinate , a neutoxin responsible for the porphyric crises charactetic of HT-1

Nitisone should be taken at least 1 hour before a meal.

Pregnancy-
Give nitisonine to a pregnant woman only if clearly needed.

Lactation-
Excercise caution when nitisonine is administred to a breast feeding woman.

Children-
Nitisinone has been studied in patients ranging from  in age from birth to 21.7 years.

Elderly-
In general dose selection for an elderly patient should be cautious , usually starting
at a low end of dosing range reflecting the greater frequency of decreased hepatic , renal
or cardiac function and concomittant disease or other drug therapy in this patient population