Nitisinone: The Drug That Changed Hereditary Tyrosinemia Type 1 and Alkaptonuria

Nitisinone is a prescription drug that blocks one step in the body's breakdown of the amino acid tyrosine. It is used for two rare inherited diseases in which a later step of that same breakdown is broken: hereditary tyrosinemia type 1, which without treatment destroys the liver in childhood, and alkaptonuria, which slowly darkens and stiffens cartilage, joints and heart valves through adult life. The chemical first came out of research on plant-killing compounds. Before it, only 29% of babies whose symptoms began before 2 months of age were alive two years later on diet alone. Since the first child was treated in 1991, patients with the disease have begun reaching adulthood. This page sets out where the drug came from, how it works, what the long-term patient studies and the alkaptonuria trials found, what the drug labels in the United States and the European Union say, the side effects that come from the high tyrosine levels it causes, the low-protein diet that goes with it, and what is still unknown.

Table of Contents

  1. What Nitisinone Is
  2. From Herbicide Research to a Medicine
  3. How Blocking One Enzyme Works
  4. Hereditary Tyrosinemia Type 1 Before 1992
  5. The 1992 Report and the First Patients
  6. Survival and Liver Transplants After Nitisinone
  7. The Liver Cancer Question
  8. Newborn Screening and the First Month of Life
  9. Alkaptonuria, the Black-Urine Disease
  10. The Alkaptonuria Trials
  11. Approvals in Europe and the United States
  12. Doses on the Labels and in the Trials
  13. Side Effects on the Labels
  14. The Low-Tyrosine Diet That Goes With It
  15. What Is Not Known
  16. Key Research Papers
  17. Connections
  18. Featured Videos

What Nitisinone Is

Nitisinone is a small synthetic molecule. Its chemical name, as the US label gives it, is 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione, and in the older research papers it is called NTBC after the initials of that name. It is taken by mouth as capsules, tablets or a liquid suspension.

The drug does one thing: it blocks an enzyme called 4-hydroxyphenylpyruvate dioxygenase (HPPD). That enzyme performs the second step in breaking down tyrosine, an amino acid that comes from protein in food and is also made in the body from another amino acid, phenylalanine. Blocking this early step stops the harmful substances that pile up further down the pathway in two inherited diseases.

The US labels describe nitisinone as a "hydroxyphenyl-pyruvate dioxygenase inhibitor." The first US approval was in 2002, according to the label. The European Union authorised it on 21 February 2005, according to the European Medicines Agency (EMA).

The price of blocking the pathway is that tyrosine itself builds up in the blood. Almost every safety warning on the labels, from eye inflammation to skin plaques, traces back to that high tyrosine, and it is the reason the drug is paired with a diet low in tyrosine and phenylalanine.

From Herbicide Research to a Medicine

Nitisinone belongs to a family of chemicals called triketones and was first made as a herbicide (weed killer). It kills plants by blocking the HPPD enzyme in them. Lock and colleagues described the history in 1998 (Lock 1998), and Lock again in 2022 (Lock 2022).

During routine safety testing of the compound, rats given it developed damage to the cornea, the clear front layer of the eye. Searching for the cause, the researchers found that the treated rats had developed very high blood tyrosine and were passing large amounts of two tyrosine breakdown products, 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, in their urine. The chemical was blocking the same enzyme in the rat liver that it blocked in weeds. The eye lesions looked like those seen in rats fed a diet with extra tyrosine, which led the team to conclude that the eye damage came from the sustained high tyrosine rather than from the chemical directly (Lock 1998).

Laboratory tests on rat liver enzyme showed how strong the effect was: at 100 nanomolar, about 90% of the enzyme's activity was lost, and the concentration that halved the activity was about 40 nanomolar. The binding was tight but reversible: the enzyme slowly recovered once the chemical let go (Ellis 1995, in rat liver enzyme).

A toxicology problem turned into a medical idea. Working with Professor Sven Lindstedt, the team showed that the compound was also a potent blocker of the purified human liver enzyme. That suggested it could stop the formation of toxic products in children with hereditary tyrosinemia type 1. With the approval of the Swedish medicines agency, a seriously ill child with the acute form of the disease was treated in February 1991 (Lock 1998).

How Blocking One Enzyme Works

The body breaks tyrosine down in a chain of steps, each run by its own enzyme. In simplified form the chain runs:

  1. Tyrosine becomes 4-hydroxyphenylpyruvate.
  2. 4-hydroxyphenylpyruvate dioxygenase turns that into homogentisic acid. This is the step nitisinone blocks.
  3. Homogentisate 1,2-dioxygenase turns homogentisic acid into maleylacetoacetate. This enzyme is missing in alkaptonuria.
  4. Maleylacetoacetate is rearranged into fumarylacetoacetate.
  5. Fumarylacetoacetate hydrolase splits fumarylacetoacetate into fumarate and acetoacetate, which the body uses as fuel. This enzyme is missing in hereditary tyrosinemia type 1.

In hereditary tyrosinemia type 1, the last step fails. Fumarylacetoacetate and maleylacetoacetate build up in liver and kidney cells and are turned into related compounds, succinylacetoacetate and succinylacetone. Succinylacetone is the marker doctors measure and the substance newborn screening looks for. Holme and Lindstedt described how these toxic products lead either to liver failure in infancy or early childhood, or to liver cancer later in childhood or adolescence (Holme 1998).

In alkaptonuria, the third step fails, so homogentisic acid builds up. It is passed in the urine in gram amounts, which is why the urine of people with the disease darkens on standing. Over decades it is deposited in cartilage and connective tissue as a blue-black pigment, a process called ochronosis (Introne 2011; Phornphutkul 2002).

Nitisinone works upstream of both broken steps. Because it blocks step two, little homogentisic acid is made, and almost nothing reaches the later steps where fumarylacetoacetate forms. One drug therefore treats two different diseases. The trade-off is that tyrosine and 4-hydroxyphenylpyruvate, which sit above the block, rise instead.

The same tyrosine pathway connects to phenylketonuria, where the enzyme that turns phenylalanine into tyrosine is missing. In both conditions, managing the diet means controlling phenylalanine, but for different reasons: in phenylketonuria phenylalanine itself is the problem, while on nitisinone phenylalanine matters because the body converts it into tyrosine.

Hereditary Tyrosinemia Type 1 Before 1992

Before nitisinone, the treatments were a diet low in tyrosine and phenylalanine and, for those who could get one, a liver transplant. The 1992 report in The Lancet opened with the plain statement that liver transplantation was then "the only effective treatment" (Lindstedt 1992).

The clearest picture of outcomes on diet alone comes from an international survey of 108 patients, published in 1994 by van Spronsen and colleagues. The earlier the symptoms began, the worse the outlook. For babies whose symptoms started before 2 months of age, the chance of surviving 1 and 2 years after symptoms began was 38% and 29%. For symptoms starting between 2 and 6 months it was 74% and 74%, and for symptoms after 6 months, 96% and 96%. The most common causes of death were liver failure and repeated bleeding (67%), liver cancer (hepatocellular carcinoma, 17%) and a porphyria-like nerve crisis with breathing failure (10%) (van Spronsen 1994).

The porphyria-like crises are tied to heme, the iron-carrying part of red blood cells. In the 1992 report, an enzyme of heme production in red cells (porphobilinogen synthase) was almost completely blocked before treatment, and the authors expected that restoring it would remove the risk of these crises (Lindstedt 1992). The drug label describes these crises as expected in 5 to 20% of cases per year in the untreated natural history of the disease.

The 1992 Report and the First Patients

In October 1992 Lindstedt and colleagues reported treating five children, one with the acute form of the disease and four with the subacute or chronic form, at daily doses of 0.1 to 0.6 mg per kilogram of body weight. The results were measured in the toxic products the disease makes (Lindstedt 1992):

The authors wrote that blocking the enzyme "may" prevent cirrhosis and lower the risk of liver cancer, and "may thus offer an alternative to liver transplantation". At that point these were hopes based on five children.

An international study run from Gothenburg followed. By 1998, more than 220 patients had been treated under its protocol. The report described the course of the acute form as changed dramatically: only 10% of patients had not responded clinically, half of those had a successful liver transplant, and death during infancy had fallen to 5% (Holme 1998).

Survival and Liver Transplants After Nitisinone

The US label reports the study used for approval: 207 patients aged 0 to 22 years, treated for a median of 22 months and compared with historical patients treated by diet alone. For patients whose disease appeared before 2 months of age, the 2- and 4-year survival on nitisinone plus diet was 88% and 88%, against 29% and 29% in the historical diet-only group. For disease appearing between 2 and 6 months, survival was 94% and 94%, against 74% and 60%. Porphyria-like crises occurred in 3 patients (0.3% of cases per year). The label adds that the drug's long-term effect on liver function was not assessed in that study.

The EMA's public summary describes a study of 257 patients: a baby under 2 months old with the disease had a 28% chance of surviving five years on diet alone, and 82% with nitisinone added.

The most detailed long-term comparison comes from Québec, Canada, where the disease is common and nitisinone has been offered since 1994. A study of 78 Québec patients born between 1984 and 2004 compared three groups: 28 never treated with nitisinone, 26 first treated after 1 month of age, and 24 treated before 1 month (Larochelle 2012):

A 15-year European study at 77 sites in 17 countries followed 315 patients, with 24 more added from post-marketing records for a total of 339. Median treatment was 11.2 years. None of the 70 patients who started treatment before 28 days of age had a liver transplant or died, against 35 of 268 (13%) who started at 28 days or later. Most patients were reported to be in good overall clinical condition: 176 of 203 (87%) throughout the study (Spiekerkoetter 2021). The authors wrote that patients with the disease are "now reaching adulthood for the first time in history." The study was funded by the company that markets the drug in Europe, and several authors are its employees.

A nationwide Finnish study of 22 children diagnosed from 1978 to 2019 found that kidney problems, high blood pressure and thin bones were more common in those who had a transplant than in those treated with nitisinone (Äärelä 2020).

The Liver Cancer Question

Liver cancer was the late killer of hereditary tyrosinemia type 1. The evidence on nitisinone and cancer points one way but carries a clear limit.

By 1998 the Gothenburg study had 101 patients aged 2 to 8 who had started treatment before 2 years of age, and no cancer had appeared after age 2 among them. The same report warned that "there is no safe age" for liver cancer: it had been found at diagnosis in a 1-year-old, and after a few months of treatment in an infant who started nitisinone at 5 months (Holme 1998).

The US label reports that in its 207-patient study, over a median 22 months of nitisinone, 13% of patients had a liver transplant, 7% liver failure, 5% malignant liver tumours and 3% benign liver tumours. These were described as complications of the disease seen during treatment.

In Finland, alpha-fetoprotein fell quickly on nitisinone in every patient but one, and that patient later developed liver cancer. The Finnish team also found that a low average nitisinone level in the blood was linked to a higher risk of severe complications, even when urine succinylacetone was undetectable (Äärelä 2020). The German-speaking consensus group lists liver cancer and problems with thinking and learning as the long-term complications of the disease, and states that early diagnosis and treatment are essential to lower that risk (Das 2025).

The blood marker and the cancer itself have their own pages: AFP test and hepatocellular carcinoma.

Newborn Screening and the First Month of Life

Every long-term study points to the same finding: the earlier nitisinone starts, the better the liver does. That has made newborn screening part of the treatment.

Screening looks for succinylacetone in the dried blood spot taken from a newborn's heel. Québec already screened newborns for the disease when the Larochelle study began (Larochelle 2012). In the 15-year European study, babies found by newborn screening started nitisinone at a median age of 0.8 months, against 8.5 months for those diagnosed after symptoms appeared. The authors concluded that "neonatal screening was the most effective way of ensuring early treatment" (Spiekerkoetter 2021).

In Finland, liver failure was found in 50% of the four children detected by screening and in 100% of the 18 diagnosed clinically; kidney tubule damage in 0% and 65%; and growth failure in 0% and 66% (Äärelä 2020).

A 2025 consensus group of specialists from Germany, Austria and Switzerland reported "strong consensus that newborn screening using succinylacetone (SA) and early treatment are essential for a good outcome" (Das 2025). A 2025 European survey of 32 centres in 16 countries found that, compared with 2014, more patients were being detected by newborn screening and doctors were using lower nitisinone doses (Kuypers 2025).

The story of the newborn heel-prick test is told on the Beadle, Tatum and Lederberg page, which also covers Archibald Garrod's early work on alkaptonuria.

Alkaptonuria, the Black-Urine Disease

Alkaptonuria is the disease Archibald Garrod studied in his early work on inherited errors of body chemistry. People with it lack the enzyme homogentisate 1,2-dioxygenase, so homogentisic acid builds up. The EMA describes it as affecting one in every 250,000 to 1 million people, and more common in certain areas of Slovakia.

Unlike hereditary tyrosinemia type 1, alkaptonuria is described in the research as a non-lethal condition (Khedr 2020). It does its damage slowly. A natural-history study of 58 patients aged 4 to 80 found that joint replacement was performed at a mean age of 55, kidney stones developed at 64, heart valve involvement at 54 and calcium in the heart arteries at 59. X-ray damage to the spine and joints began rising after age 30, faster in men than in women (Phornphutkul 2002). The first symptoms, in early adulthood, are a painful arthritis of the spine and large joints (Introne 2011).

The same paper gave short courses of nitisinone to two women. In a 51-year-old, urine homogentisic acid fell from 2.9 to 0.13 grams per day after 10 days. In a 59-year-old, it fell from 6.4 to 1.7 grams per day after 9 days. Their blood tyrosine rose from about 60 micromol per litre to about 700 and 1,300 micromol per litre, without symptoms. The authors wrote that the long-term safety and benefit "require further evaluation" (Phornphutkul 2002).

The Alkaptonuria Trials

The US three-year trial

A randomised trial in the United States, begun in 2005, followed 40 patients for 36 months. Nitisinone lowered homogentisic acid in urine and plasma by 95% throughout the 3 years. But the main clinical measure, the total range of movement of the hip, and the other measures of muscle and joint function did not show a benefit. Side effects were infrequent. The authors concluded that the drug needed to be studied in younger people, before crippling arthritis had set in (Introne 2011).

The US label for alkaptonuria rests on this trial, at 2 mg once daily. The label reports that urine homogentisic acid fell by an average of 88% from baseline after 1 year and 91% at year 3, while in untreated patients it rose by 107% and 108%.

SONIA 2

SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) was a 4-year randomised trial at three centres in the United Kingdom, France and Slovakia, funded by the European Commission's Seventh Framework Programme. It took 138 patients aged 25 or older, who already had signs of the disease, and gave half of them nitisinone 10 mg daily and the other half no treatment. Patients could not be blinded because the drug changes the colour of urine, but the assessors were blinded as far as possible (Ranganath 2020).

The authors concluded that nitisinone 10 mg daily "decreased ochronosis and improved clinical signs, indicating a slower disease progression" (Ranganath 2020). Eye problems were the main cost. Corneal keratopathy, an inflammation and clouding of the cornea, occurred in 10 of the 69 patients on nitisinone, 8 of them men (Ranganath 2022, keratopathy analysis).

A later comparison by the same group set SONIA 2 against patients treated with 2 mg daily at the UK National Alkaptonuria Centre, where patients also had dietary support. The 10 mg dose slowed disease progression more than the 2 mg dose, but keratopathy occurred in 14.5% of patients on 10 mg against 4.9% on 2 mg. These analyses were done after the fact (Ranganath 2022, dose comparison).

Approvals in Europe and the United States

Hereditary tyrosinemia type 1. The US labels give 2002 as the first US approval. Every US nitisinone label on DailyMed in November 2026, whether capsule, tablet or oral suspension, covers adult and pediatric patients with hereditary tyrosinemia type 1 "in combination with dietary restriction of tyrosine and phenylalanine." In the European Union the drug received its marketing authorisation on 21 February 2005, according to the EMA.

Alkaptonuria in Europe. On 18 September 2020 the EMA announced that its human medicines committee had recommended extending the European authorisation to adults with alkaptonuria. The EMA called it the first treatment for the disease and noted that there had been no approved medicines for it before. The recommendation was based on SONIA 2. The EMA listed the most common side effects in the alkaptonuria trials as high tyrosine, eye disorders such as eye pain and keratopathy, and airway infections. The European authorisation now lists the treatment of adults with alkaptonuria. The EMA's public summary notes that eye side effects occurred more often in patients with alkaptonuria than in those with tyrosinemia, and that new side effects such as infections were seen.

Alkaptonuria in the United States. As of November 2026, DailyMed lists one US nitisinone product with a different indication: a 2 mg tablet for "the reduction of urine homogentisic acid (HGA) in adult patients with alkaptonuria (AKU)." The wording matters. The US indication is a lowering of homogentisic acid in urine, a chemical measure, and the label's clinical studies section reports homogentisic acid results only. The label states that safety and effectiveness in children with alkaptonuria have not been established.

Doses on the Labels and in the Trials

The doses below are what the labels and trials give. They are listed for information, not as guidance.

The drug stays in the body a long time. The alkaptonuria label gives a mean terminal half-life of 59.3 hours in healthy adults. Nitisinone is a moderate inhibitor of the liver enzyme CYP2C9 and blocks the kidney transporters OAT1 and OAT3, so it can raise the levels of other drugs that depend on them. The labels state that the dose of a sensitive CYP2C9 drug is reduced by half when the two are combined.

Side Effects on the Labels

Most of nitisinone's side effects are the expected result of its action: tyrosine rises when its breakdown is blocked. The labels describe three groups.

High tyrosine and the eyes, skin and brain

Both US labels warn that tyrosine levels above 500 micromol per litre can lead to eye problems, including keratitis, corneal opacities, corneal ulcers, conjunctivitis, eye pain and sensitivity to light, and to painful thickened plaques on the soles and palms. The tyrosinemia label adds varying degrees of intellectual disability and developmental delay, and states that an abrupt change in neurological status calls for a tyrosine measurement. Both labels describe a slit-lamp eye examination before treatment and regularly afterwards, and an urgent re-examination and tyrosine measurement if eye pain, light sensitivity, redness, swelling or burning develops.

In the label's 207-patient tyrosinemia study, 14 patients had eye or vision events lasting from 5 days to 2 years, and elevated tyrosine was reported in more than 10% of patients. In the Québec study, one probable drug-related event occurred: transient crystals in the cornea with light sensitivity (Larochelle 2012).

In the alkaptonuria label's trial of 2 mg daily, elevated tyrosine was reported in 19 of 20 treated patients (95%), keratitis in 3 (15%) and low platelets in 2 (10%). Keratitis led one patient (5%) to stop treatment for good.

Low blood counts

The labels report that in tyrosinemia trials, patients on nitisinone and diet developed temporary low white cell counts (leukopenia, 3%), low platelets (thrombocytopenia, 3%) or both (1.5%). Six patients had low platelets, three of them at 30,000 per microlitre or lower; in four, the count returned to normal over up to 47 days without a dose change. No patient developed an infection or bleeding from these episodes. The labels describe monitoring platelet and white cell counts during treatment.

Other effects

Other side effects on the tyrosinemia label, each reported in 1% of patients, include blepharitis (eyelid inflammation), cataracts, nosebleeds, itching, peeling skin, dry skin, rash and hair loss. The oral suspension contains glycerol; the label states that single doses above 20 mL (10 grams of glycerol) can cause headache, stomach upset and diarrhoea.

Pregnancy and breastfeeding. The alkaptonuria label states that published case reports are too few to show whether the drug raises the risk of birth defects or miscarriage. In mice, nitisinone caused incomplete bone formation in the fetus and lower pup survival at 12 times the maximum human dose for alkaptonuria. There are no human data on nitisinone in breast milk; in rats, nursing pups not given the drug developed eye toxicity and lower body weight, which suggests it passes into rat milk.

The Low-Tyrosine Diet That Goes With It

For hereditary tyrosinemia type 1, nitisinone is approved only together with a diet restricted in tyrosine and phenylalanine. The label sets the target of keeping plasma tyrosine below 500 micromol per litre through diet. Because both amino acids come from protein, this in practice means a low-protein diet. The German-speaking consensus states that nitisinone "has to be combined with a low protein diet," in some patients a simplified diet in which protein is not counted (Das 2025).

Keeping to the diet gets harder with age. In the 15-year European study, 279 of 315 patients (89%) were judged to take the drug well, but both drug and diet compliance fell as patients grew older, and less-than-ideal phenylalanine and tyrosine levels were seen (Spiekerkoetter 2021).

For alkaptonuria the picture is different. The US alkaptonuria label states that there is "no routine dietary restriction requirement," but that a diet restricted in tyrosine and phenylalanine is used for patients who develop keratopathy, to keep tyrosine below 500 micromol per litre.

Research from the UK National Alkaptonuria Centre shows why diet comes up so often. In mice with alkaptonuria, nitisinone raised tyrosine in body tissues five- to nine-fold, and in people it significantly enlarged the body's total tyrosine pool. The authors called this "acquired tyrosinosis", meaning tyrosine is raised in the tissues and not only in the blood (Khedr 2020). In an observational study of 10 patients with tyrosine above 700 micromol per litre, restricting protein, alone or with a tyrosine- and phenylalanine-free amino-acid supplement, significantly lowered tyrosine; 4 of the 10 got below 700. In mice, removing phenylalanine alone from the diet did not lower tyrosine effectively, while removing both amino acids did (Hughes 2020).

Tyrosine in food and in the body is covered on the tyrosine and phenylalanine pages.

What Is Not Known

Decisions about this medicine and the diet that goes with it belong with the metabolic specialists who follow each patient.

Key Research Papers

  1. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet. 1992;340(8823):813-7. PubMed PMID: 1383656
  2. Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, et al. From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug. J Inherit Metab Dis. 1998;21(5):498-506. PubMed PMID: 9728330
  3. Lock EA. The Discovery of the Mode of Action of Nitisinone. Metabolites. 2022;12(10):902. PubMed PMID: 36295804
  4. Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, et al. Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol Appl Pharmacol. 1995;133(1):12-9. PubMed PMID: 7597701
  5. Holme E, Lindstedt S. Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione). J Inherit Metab Dis. 1998;21(5):507-17. PubMed PMID: 9728331
  6. van Spronsen FJ, Thomasse Y, Smit GP, Leonard JV, Clayton PT, Fidler V, et al. Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology. 1994;20(5):1187-91. PubMed PMID: 7927251
  7. Larochelle J, Alvarez F, Bussières JF, Chevalier I, Dallaire L, Dubois J, et al. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab. 2012;107(1-2):49-54. PubMed PMID: 22885033
  8. Spiekerkoetter U, Couce ML, Das AM, de Laet C, Dionisi-Vici C, Lund AM, et al. Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study. Lancet Diabetes Endocrinol. 2021;9(7):427-435. PubMed PMID: 34023005
  9. Äärelä L, Hiltunen P, Soini T, Vuorela N, Huhtala H, Nevalainen PI, et al. Type 1 tyrosinemia in Finland: a nationwide study. Orphanet J Rare Dis. 2020;15(1):281. PubMed PMID: 33046095
  10. Das AM, Ballhausen D, Haas D, Häberle J, Hagedorn T, Janson-Mutsaerts C, et al. Diagnosis, treatment, management and monitoring of patients with tyrosinaemia type 1: Consensus group recommendations from the German-speaking countries. J Inherit Metab Dis. 2025;48(1):e12824. PubMed PMID: 39676394
  11. Kuypers AM, Das AM, Maiorana A, Heiner-Fokkema MR, van Spronsen FJ. Overview of European Practices for Management of Tyrosinemia Type 1: Towards European Guidelines. J Inherit Metab Dis. 2025;48(5):e70089. PubMed PMID: 40965374
  12. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, et al. Natural history of alkaptonuria. N Engl J Med. 2002;347(26):2111-21. PubMed PMID: 12501223
  13. Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, et al. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011;103(4):307-14. PubMed PMID: 21620748
  14. Ranganath LR, Psarelli EE, Arnoux JB, Braconi D, Briggs M, Bröijersén A, et al. Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial. Lancet Diabetes Endocrinol. 2020;8(9):762-772. PubMed PMID: 32822600
  15. Ranganath LR, Milan AM, Hughes AT, Khedr M, Norman BP, Alsbou M, et al. Comparing nitisinone 2 mg and 10 mg in the treatment of alkaptonuria-An approach using statistical modelling. JIMD Rep. 2022;63(1):80-92. PubMed PMID: 35028273
  16. Ranganath LR, Milan AM, Hughes AT, Davison AS, Khedr M, Imrich R, et al. Comparing the Phenylalanine/Tyrosine Pathway and Related Factors between Keratopathy and No-Keratopathy Groups as Well as between Genders in Alkaptonuria during Nitisinone Treatment. Metabolites. 2022;12(8):772. PubMed PMID: 36005644
  17. Hughes JH, Wilson PJM, Sutherland H, Judd S, Hughes AT, Milan AM, et al. Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria. J Inherit Metab Dis. 2020;43(2):259-268. PubMed PMID: 31503358
  18. Khedr M, Cooper MS, Hughes AT, Milan AM, Davison AS, Norman BP, et al. Nitisinone causes acquired tyrosinosis in alkaptonuria. J Inherit Metab Dis. 2020;43(5):1014-1023. PubMed PMID: 32083330

Drug Labels and Regulatory Documents

  1. US National Library of Medicine, DailyMed. Nitisinone labels (hereditary tyrosinemia type 1 and alkaptonuria indications). DailyMed: nitisinone
  2. European Medicines Agency. First treatment for rare metabolic disorder alkaptonuria. News, 18 September 2020. EMA news, 18 September 2020

PubMed Topic Searches

  1. PubMed: nitisinone and tyrosinemia type 1
  2. PubMed: nitisinone and alkaptonuria
  3. PubMed: nitisinone and keratopathy
  4. PubMed: tyrosinemia newborn screening with succinylacetone
  5. PubMed: nitisinone and neurocognitive outcomes

Connections