Nitisinone

Nitisinoneis a 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor belonging to Drug for Metabolic and Endocrine disorder.

Nitisinone is a hydroxy phenylpyruvate dioxygenase inhibitor used as an adjunct to dietary restrictions for the treatment of hereditary tyrosinemia type 1 (HT-1), which causes intolerance to tyrosine containing foods.

The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax). In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar concentration.The mean terminal plasma half-life of nitisinone in healthy male subjects is 54 hours. In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.

Nitisinone shows side effects like Black, tarry stools, bleeding gums, blindness, blood in the urine or stools, bloody nose, blurred vision, burning, dry, or itching eyes, change in colour vision, chest pain or discomfort, chills, cough, decreased vision, difficulty seeing at night, excessive eye tearing, eye redness, irritation, or pain, fever, increased sensitivity of the eyes to sunlight, painful or difficult urination, pinpoint red spots on the skin, redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid, sore throat, sores, ulcers, or white spots on the lips or in the mouth, swollen or painful glands, unusual bleeding or bruising, unusual tiredness or weakness.

Nitisinone is available in the form of Oral Tablet, oral suspension, and oral capsule.

Nitisinone is available in India, Canada, US, Australia, UK, China, Spain, and Japan.

Nitisinone is a 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor belonging to Drug for Metabolic and Endocrine disorder.

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolyase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.

The Data of Onset and duration of action of Nitisinoneis not clinically established.

Nitisinone is available in the form of Oral Tablet, oral suspension, and oral capsule.

Nitisinone tablet is taken orally, usually twice daily.

Nitisinone is a hydroxy phenylpyruvate dioxygenase inhibitor used as an adjunct to dietary restrictions for the treatment of hereditary tyrosinemia type 1 (HT-1), which causes intolerance to tyrosine containing foods.

Nitisinone is a 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor belonging to Drug for Metabolic and Endocrine disorder.

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumaryl acetoacetate hydrolyase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), Nitisinone prevents the accumulation of the catabolic intermediates maleylaceto acetate and fumarylacetoacetate.

Nitisinone is approved for use in the following clinical indications

• Hereditary tyrosinemia type 1 (HT-1)

Nitisinone is a hydroxy phenylpyruvate dioxygenase inhibitor used as an adjunct to dietary restrictions for the treatment of hereditary tyrosinemia type 1 (HT-1), which causes intolerance to tyrosine containing foods.

• Hereditary tyrosinemia type 1 (HT-1)

Oral: Initial: 0.5 mg/kg twice daily. Increase to 0.75 mg/kg twice daily if succinyl acetone is detectable 4 weeks after initiation. Further increase may be needed based on the evaluation of all biochemical parameters (maximum dose: 2 mg/kg/day); dose may be administered once daily (eg, 1 to 2 mg/kg once daily) if serum and urine succinyl acetone is undetectable after ≥4 weeks of therapy.

Nitisinone is available in various strengths as 2 mg; 5 mg; 10 mg; 20 mg; 4 mg/mL.

Nitisinone is available in the form of Oral Tablet, oral suspension, and oral capsule.

• Elevated Plasma Tyrosine Levels, Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway. Therefore, treatment with nitisinone may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on nitisinone treatment. Do not adjust nitisinone dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. Inadequate restriction of tyrosine and phenylalanine intake can lead to elevations in plasma tyrosine levels and levels greater than 500 micromol/L may lead to the following:

Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis, conjunctivitis, eye pain, and photophobia have been reported in patients treated with nitisinone. Therefore, ophthalmologic examination including slit-lamp examination should be performed prior to initiating 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.

Variable degrees of intellectual disability and developmental delay. In patients treated with nitisinone who exhibit an abrupt change in neurologic status, perform a clinical laboratory assessment including plasma tyrosine levels.

Painful hyperkeratotic plaques on the soles and palms. In patients with HT-1 treated with dietary restrictions and nitisinone who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.

• Leukopenia and Severe Thrombocytopenia

In clinical trials, patients treated with nitisinone and dietary restriction developed transient leukopenia (3%), thrombocytopenia (3%), or both (1.5%). One patient who developed both leukopenia and thrombocytopenia improved after the dose of nitisinone was decreased from 1 mg/kg to 0.5 mg/kg twice daily. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during nitisinone therapy.

• Risk of Adverse Reactions Due to Glycerol Content of nitisinone Oral Suspension

Oral doses of glycerol of 10 grams or more have been reported to cause headache, upset stomach and diarrhea. nitisinone oral suspension contains 500 mg/mL of glycerol. Patients receiving more than 20 mL of nitisinone oral suspension (10 grams 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 nitisinone capsules.

There are no data on the presence of nitisinone in human milk, the effects on the breastfed infant, or the effects on milk production. Data suggest that nitisinone is present in rat milk due to findings of ocular toxicity and lower body weight seen in drug naive nursing rat pups. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitisinone and any potential adverse effects on the breastfed infant from nitisinone or from the underlying maternal condition.

Pregnancy Category C

Limited data on nitisinone use in pregnant women are not sufficient to inform any drug associated risk. Animal reproduction studies have been conducted for nitisinone. In these studies, nitisinone was administered to mice and rabbits during organogenesis with oral doses of nitisinone up to 20 and 8 times respectively, the recommended human dose. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended human dose, and increased gestational length at doses 4 times the recommended human dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended human dose. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Common

• Increased plasma tyrosine, Alopecia, exfoliative dermatitis, maculopapular rash, pruritus, xeroderma, Porphyria, Leukopenia, thrombocytopenia, granulo cytopenia Hepatic failure, hepatic neoplasm, Conjunctivitis, corneal opacity, keratitis, photophobia, blepharitis, cataract, eye pain, Epistaxis.

Rare

• Abdominal pain, brain disease, brain neoplasm, bronchitis, corneal ulcer, cyanosis, diarrhea, Exanthema, gastric distress, gastrointestinal hemorrhage, headache, hepatomegaly, hyperkinesia, hypoglycemia, increased liver enzymes, melena, seizure, septicemia.
  

Interaction with CYP2C9 Substrates If nitisinone is 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.

The common side effectsof nitisinone include the following

Common side effects

• Black, tarry stools, bleeding gums, blindness, blood in the urine or stools, bloody nose, blurred vision, burning, dry, or itching eyes, change in colour vision, chest pain or discomfort, chills, cough, decreased vision, difficulty seeing at night, excessive eye tearing, eye redness, irritation, or pain, fever, increased sensitivity of the eyes to sunlight, painful or difficult urination, pinpoint red spots on the skin, redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid, sore throat, sores, ulcers, or white spots on the lips or in the mouth, swollen or painful glands, unusual bleeding or bruising, unusual tiredness or weakness.

Rare side effects

• Agitation, back pain, bluish colour of the fingernails, lips, skin, palms, or nail beds, confusion, cough with mucus, difficulty with breathing, dizziness, drowsiness, fast heartbeat, headache, irritability, seeing or hearing things that are not there, seizures, stiff neck, tightness in the chest, vomiting.

• Pregnancy

Pregnancy Category

Limited data on nitisinone use in pregnant women are not sufficient to inform any drug associated risk. Animal reproduction studies have been conducted for nitisinone. In these studies, nitisinone was administered to mice and rabbits during organogenesis with oral doses of nitisinone up to 20 and 8 times respectively, the recommended human dose. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended human dose, and increased gestational length at doses 4 times the recommended human dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended human dose. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

• Nursing Mothers

There are no data on the presence of nitisinone in human milk, the effects on the breastfed infant, or the effects on milk production. Data suggest that nitisinone is present in rat milk due to findings of ocular toxicity and lower body weight seen in drug naive nursing rat pups. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitisinone and any potential adverse effects on the breastfed infant from nitisinone or from the underlying maternal condition.

• Pediatric Use

Pediatric patients with HT-1, ages birth to 17 years, have been treated with nitisinone in one open-label, uncontrolled clinical study. Monitoring of plasma and urine succinylacetone levels are recommended in the pediatric patients to ensure adequate control. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine

• Geriatric Use

Clinical studies of nitisinone did not include any subjects aged 65 and over. No pharmacokinetic studies of nitisinone have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.

Pharmacodynamic

Hereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway. Nitisinone inhibits catabolism of tyrosine by preventing the catabolic intermediates. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

Pharmacokinetics

• Absorption

The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).

• Distribution

In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar concentration.

• Metabolism and Excretion

The mean terminal plasma half-life of nitisinone in healthy male subjects is 54 hours. In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021232s019lbl.pdf
• https://www.rxlist.com/orfadin-drug.htm#indications
• https://www.uptodate.com/contents/nitisinone-drug-information?search=nitisinone&source=panel_search_result&selectedTitle=1~4&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://go.drugbank.com/drugs/DB00348
• https://www.drugs.com/dosage/nitisinone.html