US Pharm. 2023;48(6):42-45.

ABSTRACT: In January 2023, the “first-generic” drug approval status was granted to Torrent Pharmaceuticals’ nitisinone 20-mg capsules. This approval helps increase access to this lifesaving medication indicated for hereditary tyrosinemia type 1 (HT-1), an inborn error of metabolism of the tyrosine pathway that results in early death from liver failure or hepatocellular carcinoma. Nitisinone blocks the metabolic pathway upstream, preventing the formation of toxic metabolites that lead to liver cancer, renal tubular dysfunction, and neurologic complications. Pharmacists should be familiar with this orphan drug, as it has revolutionized the treatment of HT-1 and has brought hope to patients afflicted with this once-fatal disease.

Torrent Pharmaceuticals’ 20-mg nitisinone recently received the designation of “first-generic” drug approval for the management of hereditary tyrosinemia type 1 (HT-1).1 This designation is a game changer for many patients who require this lifesaving drug for the management of HT-1, which is a rare, autosomal, recessively inherited inborn error of metabolism that, if left untreated, leads to hepatocellular carcinoma (HCC), renal failure, acute peripheral neuropathy, and death by age 10 years.2,3

A first-generic drug approval represents the first time that a manufacturer is permitted to market a generic drug product in the United States. First-generic submissions are given priority review status, as they are deemed to be important to public health.1 The FDA-proposed criteria for a first-generic Abbreviated New Drug Application (ANDA) for the purposes of review prioritization proposed under the Generic Drug User Fee Amendments include first-to-file ANDA eligibility for 180-day exclusivity or for which there are no blocking patents or exclusivities or no previously approved ANDA for the drug product.4

Nitisinone was first approved by the FDA for the management of HT-1 on January 18, 2002, under the brand-name Orfadin. It is manufactured by Swedish Orphan Biovitrum as 2-mg, 5-mg, and 10-mg capsules. On June 13, 2016, the 20-mg capsule formulation of Oradin was also approved for HT-1, allowing for ease of administration of higher doses.5 While generic versions of the 2-, 5-, and 10-mg strengths of nitisinone capsules first became available on August 25, 2019, when Novitium Pharma received an ANDA, it was not until January 9, 2023, that a 20-mg–strength capsule became available generically with the approval of Torrent Pharmaceuticals’ ANDA.5 This generic availability will allow for greater flexibility in dosing this orphan drug for patients with HT-1.

To understand the significance of this drug approval, it is important to be familiar with the pathophysiology of HT-1 and how nitisinone alters its disease course.

What Is HT-1?

HT-1 is a disorder of tyrosine metabolism. It is caused by a deficiency of fumarylacetoacetic acid hydroxylase (FAH), the last enzyme in tyrosine’s metabolic process. Tyrosine is a nonessential amino acid that is derived from phenylalanine, which is an essential amino acid. An essential amino acid cannot be made by the human body and must be derived from food sources, whereas the body produces nonessential amino acids.6

Once ingested, phenylalanine is converted to tyrosine by the enzyme phenylalanine hydroxylase. Tyrosine is then acted upon by the enzyme tyrosine aminotransferase to produce 4-hydroxyphenylpyruvic acid (4-HPPA). 4-HPPA is then converted to homogentisic acid via the enzyme 4-hydroxyphenylpyruvic acid dioxygenase. Homogentisic acid oxidase goes on to convert homogentisic acid to maleyfacetoacetic acid. Maleyfacetoacetic acid is acted up by maleylacetoacetate isomerase to become fumarylacetoacetic acid (FAA). The last enzyme in the tyrosine metabolic pathway is FAH, which converts FAA into fumaric acid and acetoacetic acid.6 (See FIGURE 1.)

As a result of FAH deficiency, the toxic tyrosine metabolites succinylacetoacetic acid and succinylacetone (SA) are formed instead of fumaric acid and acetoacetic acid. Left untreated, these toxic metabolites cause severe liver disease, HCC, neurologic crises, renal tubular dysfunction, and hypophosphatemic rickets.2

Nitisinone works by inhibiting the enzyme 4-HPPA, which prevents the upstream conversion to the toxic metabolites. However, it also leads to increased concentrations of serum tyrosine and should be utilized in conjunction with a phenylalanine- and tyrosine-restricted diet.7 

Complications of HT-1

Before the approval of nitisinone, almost all patients with HT-1 went on to develop liver failure or HCC, typically by age 4 to 5 years.8 Once this developed, the only management was liver transplantation with its inherent risks of surgery and lifelong immunosuppressive therapy. Complications of HT-1 develop over time. Therefore, it is essential to start nitisinone as early as possible to prevent potentially fatal hepatic changes. Nitisinone does not reverse established liver lesions. Formation of the toxic metabolites FAA and maleylacetoacetate cause mutagenic changes, resulting in chromosomal instability that leads to cell-cycle arrest and apoptosis.8

Renal tubular damage occurs as a result of the accumulation of FAA, which causes oxidative stress by reacting with glutathione and sulfhydryl groups of proteins in cells in the renal proximal tubule.8 Up to one-third of patients with HT-1 developed nephrocalcinosis or generalized calcium deposition in the kidney prior the availability of nitisinone. Chronic renal disease has also been reported. Tubular dysfunction can also lead to growth failure and rickets. Although liver transplantation typically reverses HT-1-associated renal tubular damage, injury has been found to persist in some patients.9 SA also inhibits the porphyrin synthesis pathway, leading to the accumulation of 5-aminolevulinate, a neurotoxin that cause porphyric crises in HT-1.7

Other complications of HT-1 include acute peripheral neuropathy caused by axonal degeneration and secondary demyelination, neuropsychological/neurobehavioral issues, ocular disease, hypertrophic cardiomyopathy, and pancreatic islet cell hyperplasia.3

How Is HT-1 Treated?

Nitisinone, 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC), a β-triketone reversible inhibitor of 4-HPPA, was initially under development as an herbicide.2,10

Nitisinone dosing is weight-based, with a recommended starting dosage of 0.5 mg/kg orally twice daily. The daily dosage is titrated based on biochemical and/or clinical response up to a maximum total daily dosage of 3 mg/kg orally.7 It is used in conjunction with a tyrosine- and phenylalanine-restricted diet. Foods that are high in tyrosine and/or phenylalanine include soy, tempeh, meat, chicken, turkey, fish, eggs, Quorn, peanuts, almonds, avocados, bananas, milk, cheese, yogurt, cottage cheese, gelatin, plant algae (spirulina), quinoa, wheat, oats, rye, barley, lentils, lima beans, pumpkin seeds, sesame seeds, and aspartame.11,12

The use of nitisinone along with dietary interventions has drastically reduced the incidence of HCC. In one report, no patient with HT-1 who was started on nitisinone prior to age 1 month developed HCC during a follow-up period of up to 20 years.13 Hepatic complications including HCC and death may still occur in patients in whom nitisinone therapy is started later.14,15 Monitoring for the development of HCC is lifelong despite treatment.16

The use of nitisinone has been found to improve biomarkers of renal impairment within a few weeks of therapy, as evidenced by the normalization of plasma phosphate levels and the tubular maximum reabsorption of phosphate corrected for glomerular filtration rate. Nitisinone use results in rapid improvement of kidney function.17 

In 2017, a U.S. and Canadian consensus group published recommendations on the diagnosis and treatment of HT-1. NTBC and dietary therapy should be started as soon as possible following the diagnosis of HT-1. NTBC should be initiated at a dosage of 1.0 mg/kg/day in two divided doses during the first year of life but later can be dosed once daily. The minimum dosage of NTBC should be used to achieve a blood concentration of 40–60 micromol/L and/or blood SA level within normal range. Routine immunizations and standard preventive care should be offered to patients. Strict adherence to dietary restrictions should be accomplished to maintain a plasma tyrosine concentration between 200 micromol/L and 600 micromol/L. Phenylalanine intake can be adjusted to maintain plasma phenylalanine concentrations within the normal range to prevent central nervous system (CNS) complications. Vitamin and mineral supplementation are encouraged to support growth and health maintenance.3  

Overall, nitisinone therapy for HT-1 has reduced liver failure by up to 90%, normalized renal dysfunction, nearly eliminated neurologic crises (which may still occur with abrupt discontinuation of therapy), and allowed afflicted children to survive into adulthood.15

Monitoring Patients With HT-1 on Nitisinone

The best way to ensure that HT-1 is diagnosed and treated early is through neonatal testing.2 The U.S./Canadian consensus group recommends that blood SA, not tyrosine, should be the primary marker to detect HT-1 in newborns as part of newborn screening (NBS). If NBS screening indicates the presence of HT-1, confirmatory testing should include diagnostic blood or urine SA and tests to assess liver function, coagulation status, alpha-fetoprotein, plasma amino acids, electrolytes, and glucose levels. Molecular testing to evaluate genetic alterations in the FAH gene should be performed. Siblings should be tested, and parents should be counseled about the risk for future pregnancies. Alpha-fetoprotein and liver imaging should be conducted periodically to detect HCC early. If present, patients should be referred to appropriate care. Patients having undergone a liver transplant should periodically be screened for renal disease.3 

Potential Nitisinone Adverse Drug Events

By blocking HPPA, nitisinone causes hypertyrosinemia. Nitisinone’s product labeling warns that plasma tyrosine levels >500 micromol/L can result in adverse intellectual and developmental outcomes, ocular effects, and dermatologic reactions. It advises adherence to dietary restrictions to help avoid these potential adverse events.7

The CNS effects seen with nitisinone are thought to be due not to the drug but rather to the high tyrosine levels induced by the medication. Both phenylalanine and tyrosine compete for transport into the brain. The presence of high tyrosine and low phenylalanine levels may result in insufficient phenylalanine transport into the brain. Phenylalanine is needed for protein and neurotransmitter synthesis.18,19 Behavioral and emotional problems as well as a lower quality of life have also been reported in NTBC-treated patients.20 It has also been suggested that there may be similar biological mechanisms between cognitive difficulties seen in attention-deficit/hyperactivity disorder and HT-1.21

Among the ocular adverse effects reported are conjunctivitis, corneal opacity, keratitis, photophobia, and eye pain secondary to corneal deposits of corneal crystals.22-25

Leukopenia and severe thrombocytopenia (platelet count <30,000/μL) have been reported. The product labeling carries a warning about these events, although increased risk of infection or bleeding has not been observed.7

Nitisinone is a weak inducer of CYP2E1, a weak inhibitor of OAT1 and OAT3, and a moderate inhibitor of CYP2C9. There is increased exposure of coadministered medications that are metabolized by CYP2C9 that warrant the reduction of dosage of the coadministered medication with a narrow therapeutic index, such as warfarin and phenytoin. For OAT1/OAT3 substrates such as adefovir, ganciclovir, and methotrexate, monitor for potential adverse reactions related to the coadministered medication.7,26

Nitisinone Counseling Points

Nitisinone is administered twice daily orally, although its half-life is 54 hours. The prescribing information indicates that for patients aged 5 years or older who have undetectable serum and urine SA concentrations for a minimum of 4 weeks on a stable dose of nitisinone, the total daily dose may be given once daily.7 However, a recent observational prospective study found that NTBC concentrations varied significantly during the day when administered once daily in the morning. Decreases in NTBC concentrations were associated with quantitatively detectable SA levels, prompting the investigators to conclude that once-daily dosing may be inadequate to totally suppress SA levels.27

Nitisinone should be administered 1 hour before or 2 hours after a meal. In children too young to swallow a capsule or in those with swallowing difficulties, the capsule may be opened and the contents suspended in a small amount of water, formula, or applesauce and   consumed immediately. It is imperative that the patient maintain a tyrosine- and phenylalanine-restricted diet unless instructed otherwise. Failure to adhere to dietary restrictions has been associated with increased tyrosine levels, resulting in ocular signs and symptoms, intellectual disability, developmental delays, and painful hyperkeratotic plaques on the soles and palms.7

The capsules should be refrigerated; however, patients may store the capsules at room temperature up to 77 degrees Fahrenheit for up to 45 days, after which time the unused supply should be safely discarded.7

Patients should be instructed to report any unexplained ocular, neurologic, or other symptoms to their prescriber promptly for evaluation.7

Patients should be counseled to not abruptly discontinue the use of nitisinone without consulting their provider. Abrupt discontinuation has been associated with an acute neurologic crisis, which is characterized by anorexia, vomiting, hyponatremia, paresthesia, paralysis of the extremities and diaphragm, and, in extreme cases, death.28

The prescribing information for nitisinone indicates that data are insufficient in pregnant women to determine a drug-associated risk of adverse developmental outcomes in the fetus. However, in several case reports of nitisinone use in pregnant women, there has been no evidence of teratogenic effects in the unborn child.29-31 Infants should receive follow-up to assess for unknown long-term adverse effects. Mothers taking NTBC should not breastfeed their infants.3  

Pharmacists can play a major role in encouraging adherence to the treatment regimen in HT-1. Research has shown that 32% to 41% of patients on NTBC are nonadherent, and this increases to 54% to 64% for nonadherence to dietary restrictions. Educational interventions have been shown to increase adherence to drug therapy but are not quite as successful in improving dietary adherence.32

Pharmacists should also assess the ability of patients to pay for nitisinone, as cost can be prohibitively expensive.33 As of May 1, 2023, GoodRx listed the average retail price of nitisinone at $16,469.24 for 60 capsules of the 10-mg strength; the price is not available for the 20-mg strength.34 The cost of the drug has resulted in some resource-poor countries advocating for continued use of liver transplantation as a safe, more cost-effective alternative to lifelong nitisinone therapy despite the surgical risks and the risks associated with lifelong immunosuppressive therapy.35

Pharmacists and other healthcare professionals caring for patients with HT-1 who are receiving nitisinone should remain vigilant for the occurrence of possible adverse events as the long-term data are limited on the safety and efficacy of the drug.33 However, a noninterventional, noncomparative multicenter study with a mean treatment duration of 11.2 years that was conducted in 77 sites across 17 European countries found that long-term nitisinone was well tolerated and did not demonstrate any new safety signals. These findings support the low incidence of hepatic, renal, ophthalmic, hematologic, and cognitive or developmental function adverse events seen in shorter studies.36


Nitisinone has significantly improved the prognosis for patients with HT-1. Patients who once would have died in childhood or would have required a liver transplant are now living into adulthood. The development of renal tubule dysfunction has also been drastically reduced. However, cost and nonadherence remain obstacles to effective treatment. The generic availability of nitisinone seeks to help overcome one of those barriers. Pharmacists can serve as patient advocates helping to ensure access to this lifesaving medication and educating patients on the importance of adherence to both pharmacologic and dietary interventions.


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