Orfadin (Nitisinone)

What Is Orfadin and What Is It Used For?

Orfadin (nitisinone) is an orphan medicinal product approved by both the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) for the treatment of hereditary tyrosinemia type 1 (HT-1). It was first authorized in the EU in 2005 and subsequently gained approval for alkaptonuria (AKU) in adults. Nitisinone represents a groundbreaking advance in the management of these rare inborn errors of metabolism, transforming what were previously devastating conditions into manageable chronic diseases when used alongside appropriate dietary management.

Hereditary Tyrosinemia Type 1 (HT-1)

Hereditary tyrosinemia type 1 is a rare autosomal recessive disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), which catalyzes the final step in the tyrosine degradation pathway. Without adequate FAH activity, the amino acid tyrosine cannot be fully broken down, leading to the accumulation of highly toxic intermediary metabolites—fumarylacetoacetate and maleylacetoacetate—and their derivatives, succinylacetoacetate and succinylacetone. These toxins cause progressive damage to the liver, kidneys, and peripheral nerves.

Before the introduction of nitisinone therapy, HT-1 carried a poor prognosis. The acute form, presenting in infancy, often led to liver failure and death within the first year of life. Even the chronic form, which presented later in childhood, was associated with liver cirrhosis, hepatocellular carcinoma, renal tubular dysfunction (Fanconi syndrome), and recurrent neurological crises resembling acute porphyria. Dietary restriction of tyrosine and phenylalanine alone was insufficient to prevent disease progression, and liver transplantation was the only definitive treatment.

Nitisinone works by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), which acts at an earlier step in the tyrosine degradation pathway, upstream of the defective FAH enzyme. By blocking HPPD, nitisinone prevents the formation of the toxic metabolites that cause organ damage. Combined with dietary restriction of tyrosine and phenylalanine, nitisinone therapy has dramatically improved survival rates and quality of life for HT-1 patients. Studies from international registries show that over 90% of patients treated from early infancy survive to adulthood with preserved liver and kidney function.

Alkaptonuria (AKU)

Alkaptonuria is another rare autosomal recessive disorder, caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). This enzyme deficiency leads to accumulation of homogentisic acid (HGA) in the body. Over decades, HGA polymerizes to form a dark pigment (ochronotic pigment) that deposits in connective tissues throughout the body—a process known as ochronosis. This results in progressive darkening and deterioration of cartilage, tendons, heart valves, and other collagenous tissues, leading to early-onset severe osteoarthritis, aortic valve disease, and kidney stones.

Nitisinone reduces the production of HGA by approximately 95% by blocking its formation upstream in the tyrosine pathway. The SONIA 2 clinical trial, a landmark four-year randomized controlled trial involving 138 AKU patients across multiple European centers, demonstrated that nitisinone 10 mg daily significantly reduced the rate of ochronosis progression and clinical deterioration. Based on these results, Orfadin received EMA approval for AKU in adults in 2020.

What Should You Know Before Taking Orfadin?

Orfadin is a potent medication that requires careful medical supervision before, during, and after initiation of therapy. Because it modifies a fundamental metabolic pathway, comprehensive baseline assessments and ongoing monitoring are essential to ensure both safety and effectiveness. Treatment should only be started and managed by physicians with experience in treating hereditary tyrosinemia type 1 or alkaptonuria at specialized metabolic centers.

Contraindications

Orfadin must not be taken by individuals who have a known hypersensitivity (allergy) to nitisinone or to any of the excipients listed in the product. Additionally, breastfeeding is contraindicated during treatment with Orfadin. It is not known whether nitisinone passes into breast milk, and given the drug's mechanism of action, there is a theoretical risk to nursing infants.

Warnings and Precautions

Ophthalmological monitoring: One of the most important safety considerations with nitisinone therapy is the need for regular eye examinations. Because nitisinone raises blood tyrosine levels (by blocking its degradation), inadequate dietary control can lead to the formation of tyrosine crystals in the cornea, causing keratitis (corneal inflammation), conjunctivitis, photophobia (light sensitivity), and eye pain. Patients should undergo a comprehensive ophthalmological examination before starting treatment, and at regular intervals thereafter. Any signs of eye redness, irritation, or visual disturbance should prompt immediate medical evaluation, as these symptoms may indicate insufficient dietary tyrosine restriction.

Blood monitoring: Regular blood tests are essential during treatment. Nitisinone can affect blood cell counts, potentially causing thrombocytopenia (low platelets), leukocytopenia (low white blood cells), and granulocytopenia (low neutrophils). Complete blood counts should be monitored regularly, and any unexplained bruising, bleeding, or signs of infection should be reported promptly to the treating physician.

Liver monitoring (HT-1 patients): For patients with hereditary tyrosinemia type 1, regular liver function monitoring is critical. Despite nitisinone therapy, the underlying genetic defect in the liver remains, and there is a persistent (though significantly reduced) risk of hepatocellular carcinoma. Liver imaging studies (ultrasound and/or MRI) and alpha-fetoprotein (AFP) measurement should be performed at regular intervals as recommended by specialist guidelines. Follow-up visits should occur at least every six months, with shorter intervals if any adverse effects are detected.

Pregnancy and Breastfeeding

The safety of nitisinone during pregnancy has not been established in controlled clinical studies. Animal reproductive toxicity studies have shown adverse effects at high doses. Women of childbearing potential should be informed of the potential risks, and pregnancy should be discussed with their physician before starting or continuing treatment. If pregnancy occurs during treatment, the patient should contact their doctor immediately for careful evaluation of the benefits and risks of continuing therapy.

Breastfeeding is contraindicated during Orfadin treatment. It is not known whether nitisinone is excreted in human breast milk. Given the drug's pharmacological activity and the potential for serious adverse reactions in nursing infants, a decision should be made to either discontinue breastfeeding or discontinue Orfadin therapy, taking into account the importance of the drug to the mother.

Driving and Using Machines

Orfadin has a minor effect on the ability to drive and use machines. However, if you experience any visual disturbances or other side effects that could impair your ability to concentrate, you should not drive or operate machinery until your vision returns to normal. Visual side effects related to elevated tyrosine levels are among the most common adverse events and can affect driving safety.

How Does Orfadin Interact with Other Drugs?

Nitisinone has the potential to interact with other medications through its effects on drug-metabolizing enzymes. In vitro studies have demonstrated that nitisinone is an inhibitor of the cytochrome P450 enzyme CYP2C9, which is responsible for metabolizing a wide range of commonly prescribed drugs. This inhibition can lead to increased blood levels of co-administered medications that are substrates of CYP2C9, potentially increasing their effects and the risk of adverse reactions.

Patients should always inform their healthcare provider about all prescription medications, over-the-counter drugs, dietary supplements, and herbal products they are taking before starting Orfadin. Dose adjustments or more frequent monitoring may be required when Orfadin is used concomitantly with CYP2C9 substrates.

Food Interactions

If Orfadin treatment is started with food (i.e., taken together with a meal), it should continue to be taken with food throughout the treatment period to maintain consistent absorption. Conversely, if treatment is initiated on an empty stomach, patients should consistently take the medication without food. Switching between these two administration methods may alter drug absorption and affect treatment effectiveness.

For HT-1 patients, adherence to a strict low-tyrosine and low-phenylalanine diet is not merely a recommendation but a critical component of treatment. These amino acids are found in high concentrations in protein-rich foods such as meat, fish, eggs, dairy products, nuts, and legumes. Specialist dietitians experienced in metabolic disorders should be involved in planning and monitoring dietary management. For AKU patients, the treating physician may recommend dietary modifications, though the dietary requirements are generally less stringent than for HT-1.

What Is the Correct Dosage of Orfadin?

Orfadin dosing is determined by the specific condition being treated, the patient's body weight, and individual clinical response. Only physicians with experience in managing hereditary tyrosinemia type 1 or alkaptonuria should initiate and adjust treatment. The capsules are available in four strengths (2 mg, 5 mg, 10 mg, and 20 mg) to allow flexible dose adjustments.

Adults and Adolescents with HT-1

Children with HT-1

Adults with Alkaptonuria (AKU)

Difficulty Swallowing

For patients who have difficulty swallowing capsules, the capsules may be opened and the powder contents mixed into a small amount of water or a liquid dietary product immediately before administration. The mixture should be taken promptly and should not be stored for later use. This is particularly relevant for young children being treated for HT-1 who may not be able to swallow capsules whole.

Missed Dose

If a dose of Orfadin is missed, patients should not take a double dose to compensate. Instead, they should contact their doctor or pharmacist for specific guidance. For HT-1 patients, consistent dosing is important to maintain suppression of toxic metabolites, so any missed doses should be discussed with the treating team. It is important to take the medication at approximately the same time each day to maintain stable blood levels.

Overdose

If more Orfadin has been taken than prescribed, the patient should contact their doctor or pharmacist as soon as possible. There is limited clinical experience with nitisinone overdose. Given its mechanism of action, an overdose would be expected to lead to further elevation of blood tyrosine levels, potentially increasing the risk of tyrosine-related eye and skin symptoms. In the event of overdose, general supportive measures should be employed, tyrosine levels monitored closely, and dietary protein restriction may need to be intensified.

What Are the Side Effects of Orfadin?

Like all medicines, Orfadin can cause side effects, although not everyone experiences them. The most frequently reported side effects are linked to the drug's mechanism of action: by blocking tyrosine degradation at an early step, nitisinone inevitably raises blood tyrosine concentrations. If these levels are not adequately controlled through dietary restriction of tyrosine and phenylalanine, tyrosine-related adverse effects can occur, particularly affecting the eyes and skin.

It is critically important that patients report any eye symptoms immediately to their doctor for ophthalmological assessment. Most eye-related side effects are reversible with stricter dietary tyrosine control and do not require discontinuation of nitisinone therapy.

Side Effects in Hereditary Tyrosinemia Type 1 (HT-1)

Side Effects in Alkaptonuria (AKU)

The higher frequency of eye-related side effects in AKU patients compared to HT-1 patients likely reflects the fact that AKU patients are generally adults who may have less stringent dietary tyrosine restrictions. In clinical trials, most ocular events were mild to moderate and manageable with dietary advice.

Patients should be aware that routine blood monitoring is essential during Orfadin therapy. Blood count abnormalities, particularly decreased platelets, white blood cells, and neutrophils, require regular surveillance. If any unexplained bruising, unusual bleeding, or signs of infection (such as persistent fever or sore throat) occur, patients should seek medical attention promptly, as these may indicate blood count changes requiring clinical evaluation.

How Should You Store Orfadin?

Proper storage of Orfadin is essential to maintain the medication's effectiveness and safety. Because nitisinone is sensitive to temperature, specific storage conditions must be followed to ensure the capsules remain potent throughout their shelf life.

Primary storage: Orfadin should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). The capsules should be kept in their original container (plastic bottle with a tamper-evident closure) to protect them from moisture. Each bottle contains 60 capsules.

Room temperature storage: If needed, Orfadin may be stored at temperatures up to 25°C (77°F) for a single continuous period. The duration depends on the capsule strength:

• 2 mg capsules: Up to 2 months at room temperature
• 5 mg, 10 mg, and 20 mg capsules: Up to 3 months at room temperature

After the allowed room temperature storage period expires, any remaining capsules must be discarded and cannot be returned to the refrigerator. It is essential to write down the date on the bottle when it is first removed from the refrigerator so that the allowable storage period can be tracked accurately.

General precautions: Keep this medication out of the sight and reach of children. Do not use Orfadin after the expiry date printed on the container and carton (marked "EXP"). The expiry date refers to the last day of the stated month. Do not dispose of unused medicines via household waste or wastewater. Consult your pharmacist about proper disposal methods for medications you no longer need, as this helps protect the environment.

What Does Orfadin Contain?

Understanding what Orfadin capsules contain is important, particularly for patients with known allergies or sensitivities to specific excipients. The formulation is relatively simple, consisting of the active pharmaceutical ingredient and a limited number of inactive ingredients.

Active Ingredient

The active substance in Orfadin is nitisinone, also known by its chemical designation NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione). The capsules are available in four strengths:

• Orfadin 2 mg: Each capsule contains 2 mg nitisinone
• Orfadin 5 mg: Each capsule contains 5 mg nitisinone
• Orfadin 10 mg: Each capsule contains 10 mg nitisinone
• Orfadin 20 mg: Each capsule contains 20 mg nitisinone

Inactive Ingredients (Excipients)

The other ingredients in Orfadin are:

• Capsule contents: Pregelatinized starch (derived from corn/maize)
• Capsule shell: Gelatin, titanium dioxide (E 171)
• Printing ink: Iron oxide (E 172), shellac, propylene glycol, ammonium hydroxide

Appearance

Orfadin capsules are white, opaque, hard gelatin capsules. They are marked with "NTBC" and the strength ("2 mg", "5 mg", "10 mg", or "20 mg") printed in black ink. Inside, the capsules contain a white to off-white powder. The capsules are packaged in plastic bottles with a tamper-evident closure, with each bottle containing 60 capsules.

References

1. European Medicines Agency (EMA). Orfadin — Summary of Product Characteristics. Last updated 2024. Available at: EMA: Orfadin EPAR
2. Introne WJ, Perry MB, Chen MY, et al. “A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.” Molecular Genetics and Metabolism. 2011;103(4):307–314. doi:10.1016/j.ymgme.2011.04.016
3. Ranganath LR, Psarelli EE, Engam M, et al. “Efficacy and safety of once-daily nitisinone in patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.” The Lancet Diabetes & Endocrinology. 2020;8(9):762–772. doi:10.1016/S2213-8587(20)30228-X
4. Chinsky JM, Singh R, Ficicioglu C, et al. “Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.” Genetics in Medicine. 2017;19(12). doi:10.1038/gim.2017.101
5. van Spronsen FJ, van Rijn M, Meyer U, Das AM. “"; Dietary considerations in tyrosinemia type I.” Advances in Experimental Medicine and Biology. 2017;959:197–204.
6. World Health Organization (WHO). WHO Model List of Essential Medicines — 23rd List, 2023. Available at: WHO Essential Medicines List
7. De Laet C, Dionisi-Vici C, Leonard JV, et al. “Recommendations for the management of tyrosinaemia type 1.” Orphanet Journal of Rare Diseases. 2013;8:8. doi:10.1186/1750-1172-8-8
8. U.S. Food and Drug Administration (FDA). Orfadin Prescribing Information. Available at: FDA: Orfadin Label

Medical Editorial Team

This article has been written and reviewed by the iMedic Medical Editorial Team, consisting of licensed physicians specializing in clinical pharmacology and metabolic medicine. All medical information is based on current international guidelines from the EMA, FDA, and WHO, as well as peer-reviewed clinical research published in leading medical journals.