| Active Ingredient | NITISINONE |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ORFADIN | (NDA) 021232 | SWEDISH ORPHAN | CAPSULE;ORAL | 2MG , 5 MG, 10 MG | 10 MG | January 18, 2002 | _ | _ | 1 New molecular entity (NME) | P Priority review drug O Orphan drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione |
| CAS No | 104206-65-7 |
| Molecular Formula | C 14 H10 F3 NO5 |
| Molecular Weight | 329.23 |
| Appearance | White to yellowish-white, crystalline powder |
| Solubility | Soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.weak acid and it is highly soluble in the pH range 4.5-7.2 in phosphate buffer solutions. |
| Water Solubility | Practically insoluble in water |
| Polymorphism | It does not show polymorphism. |
| pKa (Strongest Acidic) | 2.71 (Predicted) |
| pKa (Strongest Basic) | -7.3 (Predicted) |
| Log P | 1.6 |
| Identification | IR, melting point DSC |
| Degradation | Stable |
| Hygroscopic | - |
| Photostability study | Not light-sensitive compound |
| Melting Point | - |
| BCS Class | - |
| Manufacture of API | Nitisinone is synthesized in two main steps followed by isolation and purification of the active substance. Adequate in-process controls are applied during the synthesis. |
| Parameters | Details |
|---|---|
| Indications and Usage | ORFADIN is a 4-hydroxyphenylpyruvate dioxygenase inhibitor indicated for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine. |
| Dosage and Administration |
Recommended Dosage : • The recommended initial dosage is 0.5 mg/kg orally twice daily. • Titrate the dose based on biochemical and/or clinical response, as described in the full prescribing information. • The maximum dosage is 1 mg/kg orally twice daily. Preparation and Administration Instructions: • For instructions on preparing, measuring and administering the oral suspension, see the full prescribing information. • Maintain dietary restriction of tyrosine and phenylalanine • Take ORFADIN capsules at least one hour before, or two hours after a meal • For patients who have difficulties swallowing capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use. • Take ORFADIN oral suspension without regard to meals. |
| Mechanism of action |
Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. 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 5aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1. Nitisinone inhibits catabolism of the amino acid tyrosine and can result in elevated plasma levels of tyrosine. Therefore, treatment with nitisinone requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine |
| Absorption | Following administration of ORFADIN 30 mg under fasting conditions, the peak serum nitisinone concentration (C max ) occurred at approximately 3.5 hours postdose for the capsules and 0.38 hours postdose for the oral suspension. |
| Food Effect | No food effect study was conducted with ORFADIN capsules. For ORFADIN oral suspension, a high calorie (800 to 1000 calories) and high fat meal (approximately 50% of total caloric content) did not affect nitisinone total exposure (AUC 72h ), but decreased the C max by approximately 20% |
| Distribution | In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar concentration. |
| Metabolism | In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme. |
| Elimination | The mean terminal plasma half-life of nitisinone in healthy male subjects is 54 hours.Excretion: Not known. |
| Peak plasma time (Tmax) | 3.50 hr [0.75 to 8.00] |
| Half life | 54 Hours |
| Bioavailability | - |
| Age, gender | - |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| - | - | - | - |
| Parameters | Details | |||
|---|---|---|---|---|
| Strength | 10 MG | 2 MG | 5 MG | |
| Excipients used | Pre-gelatinized starch | |||
| Composition of coating material | - | |||
| Composition of caspule shell | Gelatin and titanium dioxide and the imprint composition (black iron oxide (E 172) shellac, propylene glycol, ammonium hydroxide | |||
| Pharmaceutical Development |
The intrinsic physico-chemical properties of the active substance were taken into account for the development of an oral solid formulation. During the development of the product different excipients were used. A sufficiently stable preparation was obtained using pregelatinised starch as single excipient (diluent). Pregelatinised starch is the only excipient for the powder mixtures. Gelatin and titanium dioxide (E 171) are used for the capsules shell, and antifoam, iron oxide black (E 172), shellac, soya lecithin are used in the imprint. All the excipients comply with the Ph. Eur. The bovine gelatin used is in compliance with the European Commission Decision 2001/2/EC regulating the use of material presenting risks as regards transmissible spongiform encephalopathy. The components of the ink have been properly specified. The excipients have been chosen based on their function and on their compatibility with the active substance and with each other. |
|||
| Manufacture of the product | The manufacture comprises (1) grinding and sieving of active ingredient, (2) mixing of active ingredient with pregelatinised starch (3) capsule filling, (4) transfer of the capsule to a bulk container, and (5) filling/labelling of the container and packaging. | |||
| Tablet / Capsule Image |
|
|
|
|
| Appearance | 10 mg white capsules imprinted "NTBC 10 mg" in black ink | 2 mg white capsules imprinted "NTBC 2 mg" in black ink | 5 mg white capsules imprinted "NTBC 5 mg" in black ink | |
| Imprint code / Engraving / Debossment | Imprinted "NTBC 10 mg" in black ink | Imprinted "NTBC 2 mg" in black ink | Imprinted "NTBC 5 mg" in black ink | |
| Score | No score | No score | No score | |
| Color | White | White | White | |
| Shape | Capsule | Capsule | Capsule | |
| Dimension | 16mm | 16mm | 16mm | |
| Mfg by | Apotek Produktion & Laboratorier AB, Sweden (US, EU) | |||
| Mfg for | - | |||
| Marketed by | Sobi, Inc (US) | |||
| Distributed by | - | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| - | - | - | - | - | - | - |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| - | - | - | - | - |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | Orfadin | Download |
| UK | Orfadin | Download |
| US | Orfadin | Download |
| Date of first authorisation in EU: 21/02/2005 |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
