ORFADIN ® is indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

{ "type": "p", "children": [], "text": "ORFADIN\n \n \n ® is indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.\n\n \n\n " }

Starting Dosage

The recommended starting dosage of ORFADIN is 0.5 mg/kg administered orally twice daily.

Maintenance Regimen

In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose of ORFADIN may be given once daily (e.g., 1 to 2 mg/kg once daily) [see Clinical Pharmacology ( 12.2)] .

Dosage Titration

Titrate the dosage in each individual patient based on biochemical and/or clinical response.

Preparation of the Oral Suspension

The oral suspension will be dispensed with an oral syringe of appropriate size and a bottle adaptor provided by a pharmacist or other healthcare provider.

Preparing a Bottle Without the Adapter Already Inserted:

Preparing a Bottle With the Adapter Inserted:

Measuring and Administering the Dose

Once the bottle is prepared with the adapter:

Administration of ORFADIN Capsules and Oral Suspension

{ "type": "ul", "children": [ "Capsules: 2 mg, 5 mg, 10 mg and 20 mg white capsules imprinted with “NTBC” followed by “2 mg”, “5 mg”, “10 mg” or ”20 mg”, indicating the actual amount of nitisinone in each capsule.\n", "Oral suspension: 4 mg/mL, a white, slightly viscous opaque suspension.\n" ], "text": "" }

None.

{ "type": "p", "children": [], "text": "None.\n" }

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology ( 12.1)] . Therefore, treatment with ORFADIN may cause an increase in plasma tyrosine levels in patients with HT-1. Maintain concomitant reduction in dietary tyrosine and phenylalanine while on ORFADIN treatment. Do not adjust ORFADIN 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:

In patients with HT-1 treated with dietary restrictions and ORFADIN who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.

In clinical trials, patients treated with ORFADIN and dietary restriction developed transient leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions ( 6.1)] . No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during ORFADIN therapy.

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

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

ORFADIN was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of ORFADIN was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of ORFADIN is 0.5 mg/kg twice daily [see Dosage and Administration ( 2.1)] . Median duration of treatment was 22 months (range 0.1 to 80 months).

The most serious adverse reactions reported during ORFADIN treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions ( 5.1, 5.2)] . Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in ORFADIN dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia.

Patients with HT- 1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%).

The most common adverse reactions reported in the clinical trial are summarized in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 1 </span> </caption> <col align="left" width="66.850%"/> <col align="left" width="33.150%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"> <p class="First Footnote">*reported in at least 1% of patients </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone* </span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top"></td><td align="left" class="Rrule" valign="top"></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Elevated tyrosine levels <br/>Leukopenia <br/>Thrombocytopenia <br/>Conjunctivitis <br/>Corneal opacity <br/>Keratitis <br/>Photophobia <br/>Eye pain <br/>Blepharitis <br/>Cataracts <br/>Granulocytopenia <br/>Epistaxis <br/>Pruritus <br/>Exfoliative dermatitis <br/>Dry skin <br/>Maculopapular rash <br/>Alopecia <br/> </td><td align="center" class="Botrule Rrule" valign="top">&gt;10% <br/>3% <br/>3% <br/>2% <br/>2% <br/>2% <br/>2% <br/>1% <br/>1% <br/>1% <br/>1% <br/>1% <br/>1% <br/>1% <br/>1% <br/>1% <br/>1% <br/> </td> </tr> </tbody> </table></div>

Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. Table 2 includes drugs with clinically important drug interactions when administered concomitantly with ORFADIN and instructions for preventing or managing them.

{ "type": "p", "children": [], "text": "Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. \n \n \n Table 2 includes drugs with clinically important drug interactions when administered concomitantly with ORFADIN and instructions for preventing or managing them.\n\n \n\n " }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Clinically Relevant Interactions Affecting Co-Administered Drugs </span> </caption> <col align="left" width="16.650%"/> <col align="left" width="83.350%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with a Narrow Therapeutic Index (e.g., phenytoin, warfarin)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Clinical Impact </td><td align="left" class="Botrule Rrule" valign="top">Increased exposure of the co-administered drugs metabolized by CYP2C9. <span class="Italics">[see Clinical Pharmacology ( <a href="#s37">12.3</a>)] </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Intervention </td><td align="left" class="Botrule Rrule" valign="top">Reduce the dosage of the co-administered drugs metabolized by CYP2C9 drug by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. See prescribing information for those drugs. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">OAT1/OAT3 Substrates (e.g., adefovir, ganciclovir, methotrexate)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Clinical Impact </td><td align="left" class="Botrule Rrule" valign="top">Increased exposure of the interacting drug <span class="Italics">[see Clinical Pharmacology ( <a href="#s37">12.3</a>)] </span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Intervention </td><td align="left" class="Botrule Rrule" valign="top">Monitor for potential adverse reactions related to the co-administered drug. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 2: Clinically Relevant Interactions Affecting Co-Administered Drugs\n</span>\n</caption>\n<col align=\"left\" width=\"16.650%\"/>\n<col align=\"left\" width=\"83.350%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with a Narrow Therapeutic Index (e.g., phenytoin, warfarin)</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Clinical Impact\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Increased exposure of the co-administered drugs metabolized by CYP2C9. \n \n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n \n <a href=\"#s37\">12.3</a>)]\n \n \n </span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Intervention\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Reduce the dosage of the co-administered drugs metabolized by CYP2C9 drug by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. See prescribing information for those drugs.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">OAT1/OAT3 Substrates (e.g., adefovir, ganciclovir, methotrexate)</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Clinical Impact\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Increased exposure of the interacting drug \n \n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n \n <a href=\"#s37\">12.3</a>)]\n \n \n </span></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Intervention\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Monitor for potential adverse reactions related to the co-administered drug.\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. 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 initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose [see Data] .

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.

Data

Animal Data

Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended initial dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended initial dose, increased gestational length at 4 and 20 times the recommended initial dose, and decreased pup survival at 0.4 times the recommended initial dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended initial dose based on the body surface area.

Risk Summary

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 ORFADIN and any potential adverse effects on the breastfed infant from ORFADIN or from the underlying maternal condition.

The safety and effectiveness of ORFADIN have been established in pediatric patients for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Use of ORFADIN in pediatric patients is supported by evidence from one open-label, uncontrolled clinical study conducted in 207 patients with HT-1 ages 0 to 22 years (median age 9 months) [see Clinical Studies ( 14)] .

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.

Accidental ingestion of ORFADIN by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hyper-tyrosinemia has been reported with ORFADIN treatment [see Warnings and Precautions ( 5.1)] .

{ "type": "p", "children": [], "text": "Accidental ingestion of ORFADIN by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hyper-tyrosinemia has been reported with ORFADIN treatment \n \n \n [see Warnings and Precautions (\n \n \n 5.1)]\n \n \n .\n\n \n\n " }

ORFADIN contains nitisinone, which is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).

{ "type": "p", "children": [], "text": "ORFADIN contains nitisinone, which is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).\n" }

Nitisinone occurs as white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.

{ "type": "p", "children": [], "text": "Nitisinone occurs as white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.\n" }

Chemically, nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione, and the structural formula is:

{ "type": "p", "children": [], "text": "Chemically, nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione, and the structural formula is:\n" }

Capsules: Hard, white-opaque capsule, marked as 2 mg, 5 mg, 10 mg or 20 mg strengths of nitisinone, intended for oral administration. Each capsule contains 2 mg, 5 mg, 10 mg or 20 mg nitisinone, plus pre-gelatinized starch. The capsule shell is gelatin and titanium dioxide and the imprint is an iron oxide.

{ "type": "p", "children": [], "text": "Capsules: Hard, white-opaque capsule, marked as 2 mg, 5 mg, 10 mg or 20 mg strengths of nitisinone, intended for oral administration. Each capsule contains 2 mg, 5 mg, 10 mg or 20 mg nitisinone, plus pre-gelatinized starch. The capsule shell is gelatin and titanium dioxide and the imprint is an iron oxide.\n" }

Oral suspension: 4 mg/mL, a white, slightly viscous opaque suspension. The inactive ingredients are hydroxypropyl methylcellulose, glycerol, polysorbate 80, sodium benzoate, citric acid monohydrate, trisodium citrate dihydrate, strawberry aroma (artificial) and purified water.

{ "type": "p", "children": [], "text": "Oral suspension: 4 mg/mL, a white, slightly viscous opaque suspension. The inactive ingredients are hydroxypropyl methylcellulose, glycerol, polysorbate 80, sodium benzoate, citric acid monohydrate, trisodium citrate dihydrate, strawberry aroma (artificial) and purified water.\n" }

Glycerol: Each mL contains 500 mg.

{ "type": "p", "children": [], "text": "Glycerol: Each mL contains 500 mg.\n" }

Sodium: Each mL contains 0.7 mg (0.03 mEq).

{ "type": "p", "children": [], "text": "Sodium: Each mL contains 0.7 mg (0.03 mEq).\n" }

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 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with ORFADIN [see Clinical Studies ( 14)] . In all 186 patients whose urine succinylacetone was measured, the urinary succinylacetone concentration decreased to less than 1 mmol/mol creatinine, the lower limit of quantitation. The median time to normalization of urine succinylacetone was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 micromol/L (95% confidence interval: 23, 51 micromol/L). In 87% (150/172) of patients whose plasma succinylacetone was measured, the plasma succinylacetone concentration decreased to less than 0.1 micromol/L, the lower limit of quantitation. The median time to normalization of plasma succinylacetone was 3.9 months.

In another study, comparing two dosing regimens, succinylacetone was measured in urine and/or blood in 16 patients with HT-1 aged 5 years to 24 years. All study patients were on a stable ORFADIN daily dosage (0.4 mg/kg/day to 1 mg/kg/day) during both study dosing regimens. After at least 4 weeks of twice daily dosing with ORFADIN, both the urine and/or blood succinylacetone concentrations were below the limit of quantitation for the assay. Patients were then switched to once daily dosing with the same total daily dosage of ORFADIN and blood and/or urine succinylacetone concentrations remained undetectable when measured following at least 4 weeks of treatment with once daily dosing.

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 [see Warnings and Precautions ( 5.1)].

The single-dose pharmacokinetics of nitisinone have been studied for both ORFADIN capsules and ORFADIN oral suspension in healthy adult subjects and the multiple-dose pharmacokinetics have been studied for ORFADIN capsules in healthy subjects.

Absorption

The pharmacokinetic characteristics following single oral administration of ORFADIN 30 mg under fasting conditions are shown in Table 3. Compared to ORFADIN capsule, the median T max occurred about 3 hours earlier with ORFADIN oral suspension. The multiple-dose characteristics of ORFADIN 80 mg once daily are shown in Table 4. Steady-state (SS) was reached within 14 days dosing in all subjects.

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 3 Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following a Single Oral 30 mg Dose of ORFADIN Under Fasting Conditions </span> </caption> <col align="left" width="34.725%"/> <col align="left" width="24.700%"/> <col align="left" width="21.175%"/> <col align="left" width="19.400%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Treatment</span></th><th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">C</span><span class="Bold"><span class="Sub">max </span></span><span class="Bold"> <br/>(micromol/L) </span> <br/> <span class="Bold">[range]</span></th><th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">t</span><span class="Bold"><span class="Sub">max</span></span><span class="Bold">* <br/>(h) </span> <br/> <span class="Bold">[range]</span></th><th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">AUC</span><span class="Bold"><span class="Sub">0-72h </span></span><span class="Bold"> <br/>(micromol·h/L) </span> <br/> <span class="Bold">[range]</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top"> <p class="First Footnote">* presented as median [range] </p> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" valign="top">ORFADIN capsule (n=12) </td><td align="left" valign="top">10.5 (26) </td><td align="left" valign="top">3.5 </td><td align="left" valign="top">406 (13) </td> </tr> <tr> <td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top">[0.8 to 8.0] </td><td align="left" class="Botrule" valign="top"></td> </tr> <tr> <td align="left" valign="top">ORFADIN oral suspension (n=12) </td><td align="left" valign="top">10.1 (34) </td><td align="left" valign="top">0.4 </td><td align="left" valign="top">350 (17) </td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top">[0.2 to 4.0] </td><td align="left" class="Botrule" valign="top"></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="100%"> <caption> <span>TABLE 4 Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following Repeated Once Daily Administration of 80 mg ORFADIN Under Fasting Conditions. </span> </caption> <col align="left" width="28.367%"/> <col align="left" width="13.433%"/> <col align="left" width="11.317%"/> <col align="left" width="17.050%"/> <col align="left" width="14.917%"/> <col align="left" width="14.917%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">Treatment</span></th><th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">C</span><span class="Bold"><span class="Sub">max,ss </span></span><span class="Bold"> <br/>(micromol/L) </span> <br/> <span class="Bold">[CV%]</span></th><th align="left" class="Botrule Toprule" valign="top"><span class="Bold">C</span><span class="Bold"><span class="Sub">min,ss </span></span><span class="Bold"> <br/>(micromol/L) </span> <br/> <span class="Bold">[range]</span></th><th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">t</span><span class="Bold"><span class="Sub">max,ss</span></span><span class="Bold">* <br/>(h) </span> <br/> <span class="Bold">[range]</span></th><th align="left" class="Botrule Toprule" valign="bottom"><span class="Bold">AUC</span><span class="Bold"><span class="Sub">0-24h,ss </span></span><span class="Bold"> <br/>(micromol·h/L) </span> <br/> <span class="Bold">[range]</span></th><th align="left" class="Botrule Toprule" valign="top"></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="6" valign="top"> <p class="First Footnote">* presented as median [range] </p> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" valign="top">ORFADIN capsule (n=18) </td><td align="left" valign="top">120 (23) </td><td align="left" valign="top">73(24) </td><td align="left" valign="top">4.0 </td><td align="left" valign="top">2204(18) </td><td align="left" valign="top"></td> </tr> <tr class="Last"> <td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top">[0.0 to 16.0] </td><td align="left" class="Botrule" valign="top"></td><td align="left" class="Botrule" valign="top"></td> </tr> </tbody> </table></div>

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% [see Dosage and Administration ( 2.2)] .

Distribution

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

Elimination

The mean terminal plasma half-life of single dose nitisinone in healthy male subjects is 54 hours. The mean (CV%)apparent plasma clearance in 18 healthy adults following multiple once daily doses of ORFADIN 80 mg is  113 ( 16) mL/h.

Metabolism: In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.

Excretion: Renal elimination of nitisinone is of minor importance, since the mean of the fraction of dose excreted as unchanged nitisinone in the urine (fe(%)) was 3.0% (n=3) following multiple oral doses of 80 mg daily in healthy subjects. The estimated mean (CV%) renal clearance of nitisinone was 0.003 L/h (25%).

Drug Interaction Studies

Nitisinone does not inhibit CYP2D6. Nitisinone is a moderate inhibitor of CYP2C9, and a weak inducer of CYP2E1 ( Table 5). Nitisinone is an inhibitor of OAT1/3 ( Table 5).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5. Percent Change in AUC <span class="Sub">0-∞</span> and C <span class="Sub">max</span> for Co-administered Drugs in the Presence of ORFADIN in 18 Healthy Subjects </span> </caption> <col align="left" width="23.150%"/> <col align="left" width="27.475%"/> <col align="left" width="25.025%"/> <col align="left" width="24.350%"/> <tfoot> <tr class="First"> <td align="left" colspan="4" valign="top"> <p class="First Footnote">↑ = Increased; ↓ = Decreased </p> </td> </tr> <tr> <td align="left" colspan="4" valign="top"> <p class="First Footnote"> <span class="Bold"><span class="Sup">a</span></span> The interacting drug was administered alone on Day 1 and together with ORFADIN on Day 17. </p> </td> </tr> <tr> <td align="left" colspan="4" valign="top"> <p class="First Footnote"> <span class="Sup">b</span> Multiple doses of 80 mg ORFADIN were administered daily alone from Day 3 to Day 16. </p> </td> </tr> <tr class="Last"> <td align="left" colspan="4" valign="top"> <p class="First Footnote"> <span class="Sup">c</span> 16 subjects in Period 2 received ORFADIN and tolbutamide while 18 subjects in Period 1 received ORFADIN alone. </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">Co-administered Drug </span><span class="Bold"><span class="Sup">a</span></span></td><td align="center" class="Botrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">Dose of Co-administered Drug (Route of Administration)</span></td><td align="left" class="Botrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Effect of Nitisinone on the Pharmacokinetics of Co-administered Drug </span><span class="Bold"><span class="Sup">b</span></span></td> </tr> <tr> <td align="left" class="Botrule Rrule" valign="top"><span class="Bold">AUC</span><span class="Bold"><span class="Sub">0-∞</span></span></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">C</span><span class="Bold"><span class="Sub">max</span></span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CYP2C9 Substrate Tolbutamide <span class="Sup">c</span></td><td align="left" class="Botrule Rrule" valign="top">500 mg (oral) </td><td align="left" class="Botrule Rrule" valign="top">131% ↑ </td><td align="left" class="Botrule Rrule" valign="top">16% ↑ </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">CYP2E1 Substrate Chlorzoxazone </td><td align="left" class="Botrule Rrule" valign="top">250 mg (oral) </td><td align="left" class="Botrule Rrule" valign="top">27% ↓ </td><td align="left" class="Botrule Rrule" valign="top">18% ↓ </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">OAT1/3 Substrate Furosemide </td><td align="left" class="Botrule Rrule" valign="top">20 mg (intravenous) </td><td align="left" class="Botrule Rrule" valign="top">72% ↑ </td><td align="left" class="Botrule Rrule" valign="top">12% ↑ </td> </tr> </tbody> </table></div>

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

In vitro studies showed that nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinone does not induce CYP1A2, 2B6 or 3A4/5. Nitisinone does not inhibit P-gp, BCRP, OATP1B1, OATP1B3 and OCT2-mediated transports at therapeutically relevant concentrations.

The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/ day nitisinone (approximately 8.1 times the recommended initial dose of 1 mg/kg/day on a body surface area basis).

Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK +/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.

In a single dose-group study in rats given 100 mg/kg (16.2 times the recommended initial dose of 1 mg/kg/day on a body surface area basis), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.

The efficacy and safety of ORFADIN in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with ORFADIN at a starting dose of 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.

{ "type": "p", "children": [], "text": "The efficacy and safety of ORFADIN in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with ORFADIN at a starting dose of 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.\n" }

For patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients presenting with HT-1 at younger than 2 months of age and treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting with HT-1 between 2 months and 6 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients presenting with HT-1 between 2 months and 6 months of age treated with dietary restriction alone had 2- and 4-year survival probabilities of 74% and 60%, respectively.

{ "type": "p", "children": [], "text": "For patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients presenting with HT-1 at younger than 2 months of age and treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting with HT-1 between 2 months and 6 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients presenting with HT-1 between 2 months and 6 months of age treated with dietary restriction alone had 2- and 4-year survival probabilities of 74% and 60%, respectively.\n" }

The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.

{ "type": "p", "children": [], "text": "The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.\n" }

Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.

{ "type": "p", "children": [], "text": "Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.\n" }

Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 grams/mol creatinine (reference value for age less than or equal to 12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine).

{ "type": "p", "children": [], "text": "Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 grams/mol creatinine (reference value for age less than or equal to 12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine).\n" }

The long term effect of nitisinone on hepatic function was not assessed.

{ "type": "p", "children": [], "text": "The long term effect of nitisinone on hepatic function was not assessed.\n" }

Capsules: White capsules marked in black with "NTBC" and identified as 2 mg, 5 mg, 10 mg or 20 mg strengths of nitisinone. The capsules are packed in a high density (HD) polyethylene container with a tamper-resistant low density (LD) polyethylene snap-on cap. Each bottle contains 60 capsules.

{ "type": "p", "children": [], "text": "Capsules: White capsules marked in black with \"NTBC\" and identified as 2 mg, 5 mg, 10 mg or 20 mg strengths of nitisinone. The capsules are packed in a high density (HD) polyethylene container with a tamper-resistant low density (LD) polyethylene snap-on cap. Each bottle contains 60 capsules.\n" }

{ "type": "ul", "children": [ "2 mg white capsules imprinted \"NTBC 2 mg\" in black ink, NDC 66658-102-60\n\n ", "5 mg white capsules imprinted \"NTBC 5 mg\" in black ink, NDC 66658-105-60\n\n ", "10 mg white capsules imprinted \"NTBC 10 mg\" in black ink, NDC 66658-110-60\n\n ", "20 mg white capsules imprinted \"NTBC 20 mg\" in black ink, NDC 66658-120-60\n\n ", "Store refrigerated at 2° to 8°C (36° to 46°F). Alternatively, patients/caregivers may store ORFADIN capsules at room temperature up to 25°C (77°F) for up to 45 days. If not used within 45 days, discard ORFADIN capsules.\n\n " ], "text": "" }

Oral suspension: White, slightly viscous opaque suspension. 1 mL contains 4 mg of nitisinone. The suspension is provided in a 100 mL brown bottle (type III glass) with a white child resistant HDPE screw cap with sealing and tamper evidence. Each bottle contains 90 mL oral suspension.

{ "type": "p", "children": [], "text": "Oral suspension: White, slightly viscous opaque suspension. 1 mL contains 4 mg of nitisinone. The suspension is provided in a 100 mL brown bottle (type III glass) with a white child resistant HDPE screw cap with sealing and tamper evidence. Each bottle contains 90 mL oral suspension.\n" }

{ "type": "ul", "children": [ "Oral suspension 4 mg/mL, NDC 66658-204-90\n\n ", "Store refrigerated at 2°C to 8°C (36°F to 46°F) prior to first use. Do not freeze. Store upright.\n\n ", "After first opening, store the product at room temperature (up to 25°C (77°F)) for up to 60 days. If not used within 60 days, discard unused portion. The discard after date should be noted on the bottle\n\n " ], "text": "" }

Preparation and Administration Instructions [see Dosage and Administration ( 2.2)]

Preparation of the Oral Suspension

The oral suspension will be dispensed with an oral syringe of appropriate size and a bottle adaptor provided by a pharmacist or other healthcare provider.

Preparing a Bottle Without the Adapter Already Inserted:

Preparing a Bottle With the Adapter Inserted:

Measuring and Administering the Dose

Once the bottle is prepared with the adapter:

Administration of ORFADIN Capsules and Oral Suspension

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

Risk of Adverse Reactions Due to Glycerol Content of ORFADIN Oral Suspension

Advise patients receiving doses of greater than 20 mL of ORFADIN oral suspension that they may experience headache, upset stomach and diarrhea due to the glycerol component of the formulation and if they develop symptoms to report these to their healthcare provider [see Warnings and Precautions ( 5.3)].

Manufactured by: Apotek Produktion & Laboratorier AB, Sweden

Marketed by: Sobi, Inc 77  Fourth Avenue, 3 rd Floor, Waltham, MA 02451-7559

Instructions for Use

{ "type": "p", "children": [], "text": "\nInstructions for Use\n" }

ORFADIN (OR-fuh-din)

{ "type": "p", "children": [], "text": "\nORFADIN (OR-fuh-din)\n" }

(nitisinone)

{ "type": "p", "children": [], "text": "\n(nitisinone)\n" }

oral suspension

{ "type": "p", "children": [], "text": "\noral suspension\n" }

4 mg/mL

{ "type": "p", "children": [], "text": "\n4 mg/mL\n" }

Read this Instructions for Use before you start taking ORFADIN oral suspension and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start taking ORFADIN oral suspension and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.\n" }

Important information about measuring ORFADIN oral suspension:

{ "type": "p", "children": [], "text": "\nImportant information about measuring ORFADIN oral suspension:\n" }

{ "type": "ul", "children": [ "\nUse the oral syringe provided with your ORFADIN oral suspension to make sure you measure the right amount.\n", "You will be provided with:\n \n \n \n1 bottle of ORFADIN oral suspension\n\n1 oral syringe\n\n1 adapter (The adapter may or may not be inserted in your bottle of ORFADIN oral suspension when you receive it.)\n\n\n" ], "text": "" }

Figure A

{ "type": "p", "children": [], "text": "Figure A\n" }

If the adapter is not inserted in your bottle of ORFADIN oral suspension when you receive it, follow the instructions in “ How to prepare a bottle of ORFADIN oral suspension if the adapter is not inserted.”

{ "type": "p", "children": [], "text": "If the adapter \n \n \n is not inserted in your bottle of ORFADIN oral suspension when you receive it, follow the instructions in \n \n \n “\n \n \n How to prepare a bottle of ORFADIN oral suspension if the adapter is not inserted.”\n \n \n \n" }

If the adapter is inserted in your bottle of ORFADIN oral suspension when you receive it, follow the instructions in “ How to prepare a dose of ORFADIN oral suspension after the adapter is inserted.”

{ "type": "p", "children": [], "text": "If the adapter \n \n \n is inserted in your bottle of ORFADIN oral suspension when you receive it, follow the instructions in \n \n \n “\n \n \n How to prepare a dose of ORFADIN oral suspension after the adapter is inserted.”\n \n \n \n" }

How to prepare a bottle of ORFADIN oral suspension if the adapter is not inserted:

{ "type": "p", "children": [], "text": "\nHow to prepare a bottle of ORFADIN oral suspension if the adapter is not inserted:\n" }

See “ How should I store ORFADIN oral suspension?” for instructions on how to store ORFADIN oral suspension if the adapter is not inserted.

{ "type": "p", "children": [], "text": "See “\n \n \n How should I store ORFADIN oral suspension?” for instructions on how to store ORFADIN oral suspension if the adapter is not inserted.\n\n \n\n " }

{ "type": "", "children": [], "text": "" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="50.000%"/> <col align="left" width="50.000%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Shake the bottle well for <span class="Bold">at least 20 seconds</span> until the solid cake of particles at the bottom of the bottle is dissolved (See <a href="#f03">Figure B</a>). Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle. </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f03"></a><img alt="Figure B " src="/dailymed/image.cfm?name=orf02-0011-03.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p> <p>Figure B </p> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Remove the child resistant screw cap by pushing it down firmly and turning it counter-clockwise (See <a href="#f04">Figure C</a>). <br/> </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f04"></a><img alt="Figure C " src="/dailymed/image.cfm?name=orf02-0011-04.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure C <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Place the open bottle upright on a flat surface. Push the ribbed end of the adapter firmly into the neck of the bottle as far as it will go (See <a href="#f05">Figure D</a>). Replace the child resistant screw cap on the bottle. Do not remove the adapter from the bottle after it is inserted. <br/> </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f05"></a><img alt="Figure D " src="/dailymed/image.cfm?name=orf02-0011-05.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure D <br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"50.000%\"/>\n<col align=\"left\" width=\"50.000%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Shake the bottle well for \n \n \n <span class=\"Bold\">at least 20 seconds</span> until the solid cake of particles at the bottom of the bottle is dissolved (See \n \n \n <a href=\"#f03\">Figure B</a>). Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle.\n\n \n \n </li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f03\"></a><img alt=\"Figure B\n\" src=\"/dailymed/image.cfm?name=orf02-0011-03.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>\n<p>Figure B\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Remove the child resistant screw cap by pushing it down firmly and turning it counter-clockwise (See \n \n \n <a href=\"#f04\">Figure C</a>).\n \n \n <br/>\n</li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f04\"></a><img alt=\"Figure C\n\" src=\"/dailymed/image.cfm?name=orf02-0011-04.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure C\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Place the open bottle upright on a flat surface. Push the ribbed end of the adapter firmly into the neck of the bottle as far as it will go (See \n \n \n <a href=\"#f05\">Figure D</a>). Replace the child resistant screw cap on the bottle. Do not remove the adapter from the bottle after it is inserted.\n \n \n <br/>\n</li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f05\"></a><img alt=\"Figure D\n\" src=\"/dailymed/image.cfm?name=orf02-0011-05.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure D\n \n \n <br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "", "children": [], "text": "" }

How to prepare a dose of ORFADIN oral suspension after the adapter is inserted

{ "type": "p", "children": [], "text": "\nHow to prepare a dose of ORFADIN oral suspension after the adapter is inserted\n" }

See “ How should I store ORFADIN oral suspension?” for instructions on how to store ORFADIN oral suspension after the adapter is inserted.

{ "type": "p", "children": [], "text": "See “\n \n \n How should I store ORFADIN oral suspension?” for instructions on how to store ORFADIN oral suspension after the adapter is inserted.\n\n \n\n " }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="48.800%"/> <col align="left" width="51.200%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Shake the ORFADIN oral suspension bottle well for <span class="Bold">at least 5 seconds</span> (See <a href="#f06">Figure E</a>). Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle. <br/> </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f06"></a><img alt="Figure E " src="/dailymed/image.cfm?name=orf02-0011-06.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure E <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Remove the child resistant screw cap right away by pushing it down firmly and turning it counter-clockwise (See <a href="#f07">Figure F</a>). </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f07"></a><img alt="Figure F " src="/dailymed/image.cfm?name=orf02-0011-07.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure F <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Hold the oral syringe in one hand. With your other hand, fully push down (depress) the plunger (See <a href="#f08">Figure G</a>). <br/> </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f08"></a><img alt="Figure G " src="/dailymed/image.cfm?name=orf02-0011-08.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure G <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Keeping the bottle in an upright position, insert the oral syringe firmly into the adapter (See <a href="#f09">Figure H</a>). <br/> </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f09"></a><img alt="Figure H " src="/dailymed/image.cfm?name=orf02-0011-09.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure H <br/> <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Carefully turn the bottle upside down with the oral syringe in place (See <a href="#f10">Figure I</a>). Wait until you can see that the foam is at the top of the bottle to avoid withdrawing bubbles into the syringe. <br/> </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f10"></a><img alt="Figure I " src="/dailymed/image.cfm?name=orf02-0011-10.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure I <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Pull back slowly on the oral syringe plunger until the top edge of the black ring is at the line marking the dose prescribed by your healthcare provider (See <a href="#f11">Figure J</a>). Figure J shows a dose of 1 mL as an example. If you see air bubbles in the oral syringe, fully push in the plunger so that the oral suspension flows back into the bottle. Then, withdraw your prescribed dose of oral suspension. </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f11"></a><img alt="Figure J " src="/dailymed/image.cfm?name=orf02-0011-11.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure J <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Leave the oral syringe in the adapter and turn the bottle to an upright position. Place the bottle onto a flat surface. Remove the oral syringe by gently twisting it out of the bottle (See <a href="#f12">Figure K</a>). Do not pull straight up on the syringe to remove it from the bottle because this can cause the adapter to come out of the bottle. </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f12"></a><img alt="Figure K " src="/dailymed/image.cfm?name=orf02-0011-12.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure K <br/> </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Place the oral syringe in your mouth right away. Slowly push on the plunger until the oral syringe is empty. See <a href="#f13">Figure L</a>). </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f13"></a><img alt="Figure L " src="/dailymed/image.cfm?name=orf02-0011-13.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure L </td> </tr> <tr> <td align="left" valign="top"> <ol class="Arabic"> <li>Leave the adapter in the bottle. Put the child resistant screw cap back on the bottle (See <a href="#f14">Figure M</a>). </li> </ol> </td><td align="left" valign="top"> <br/> <p class="First"> <a name="f14"></a><img alt="Figure M " src="/dailymed/image.cfm?name=orf02-0011-14.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a"/></p>Figure M </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"48.800%\"/>\n<col align=\"left\" width=\"51.200%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Shake the ORFADIN oral suspension bottle well for \n \n \n <span class=\"Bold\">at least 5 seconds</span> (See \n \n \n <a href=\"#f06\">Figure E</a>). Check that there are no particles left at the bottom of the bottle. Foam will form in the bottle.\n \n \n <br/>\n</li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f06\"></a><img alt=\"Figure E\n\" src=\"/dailymed/image.cfm?name=orf02-0011-06.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure E\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Remove the child resistant screw cap right away by pushing it down firmly and turning it counter-clockwise (See \n \n \n <a href=\"#f07\">Figure F</a>).\n\n \n \n </li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f07\"></a><img alt=\"Figure F\n\" src=\"/dailymed/image.cfm?name=orf02-0011-07.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure F\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Hold the oral syringe in one hand. With your other hand, fully push down (depress) the plunger (See \n \n \n <a href=\"#f08\">Figure G</a>).\n \n \n <br/>\n</li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f08\"></a><img alt=\"Figure G\n\" src=\"/dailymed/image.cfm?name=orf02-0011-08.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure G\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Keeping the bottle in an upright position, insert the oral syringe firmly into the adapter (See \n \n \n <a href=\"#f09\">Figure H</a>).\n \n \n <br/>\n</li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f09\"></a><img alt=\"Figure H\n\" src=\"/dailymed/image.cfm?name=orf02-0011-09.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure H\n \n \n <br/>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Carefully turn the bottle upside down with the oral syringe in place (See \n \n \n <a href=\"#f10\">Figure I</a>). Wait until you can see that the foam is at the top of the bottle to avoid withdrawing bubbles into the syringe.\n \n \n <br/>\n</li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f10\"></a><img alt=\"Figure I\n\" src=\"/dailymed/image.cfm?name=orf02-0011-10.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure I\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Pull back slowly on the oral syringe plunger until the top edge of the black ring is at the line marking the dose prescribed by your healthcare provider (See \n \n \n <a href=\"#f11\">Figure J</a>). Figure J shows a dose of 1 mL as an example. If you see air bubbles in the oral syringe, fully push in the plunger so that the oral suspension flows back into the bottle. Then, withdraw your prescribed dose of oral suspension.\n\n \n \n </li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f11\"></a><img alt=\"Figure J\n\" src=\"/dailymed/image.cfm?name=orf02-0011-11.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure J\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Leave the oral syringe in the adapter and turn the bottle to an upright position. Place the bottle onto a flat surface. Remove the oral syringe by gently twisting it out of the bottle (See \n \n \n <a href=\"#f12\">Figure K</a>). Do not pull straight up on the syringe to remove it from the bottle because this can cause the adapter to come out of the bottle.\n\n \n \n </li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f12\"></a><img alt=\"Figure K\n\" src=\"/dailymed/image.cfm?name=orf02-0011-12.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure K\n \n \n <br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Place the oral syringe in your mouth right away. Slowly push on the plunger until the oral syringe is empty. See \n \n \n <a href=\"#f13\">Figure L</a>).\n\n \n \n </li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f13\"></a><img alt=\"Figure L\n\" src=\"/dailymed/image.cfm?name=orf02-0011-13.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure L\n\n \n \n </td>\n</tr>\n<tr>\n<td align=\"left\" valign=\"top\">\n<ol class=\"Arabic\">\n<li>Leave the adapter in the bottle. Put the child resistant screw cap back on the bottle (See \n \n \n <a href=\"#f14\">Figure M</a>).\n\n \n \n </li>\n</ol>\n</td><td align=\"left\" valign=\"top\">\n<br/>\n<p class=\"First\">\n<a name=\"f14\"></a><img alt=\"Figure M\n\" src=\"/dailymed/image.cfm?name=orf02-0011-14.jpg&amp;setid=00307f42-748d-4227-8c6f-ed5f0a89ae0a\"/></p>Figure M\n\n \n \n </td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "", "children": [], "text": "" }

{ "type": "ul", "children": [ "Talk to your healthcare provider or pharmacist if you have questions about how to use the oral syringe or if you lose the oral syringe.\n" ], "text": "" }

How should I store ORFADIN oral suspension?

{ "type": "p", "children": [], "text": "\nHow should I store ORFADIN oral suspension?\n" }

{ "type": "ul", "children": [ "Store the ORFADIN oral suspension bottle in an upright position. Keep the oral syringe with your medicine.\n" ], "text": "" }

Before the adapter is inserted into the bottle:

{ "type": "p", "children": [], "text": "\nBefore the adapter is inserted into the bottle:\n" }

{ "type": "ul", "children": [ "If the adapter has \n \n \n not been inserted into the bottle, store ORFADIN oral suspension in the refrigerator between 36°F to 46°F (2°C to 8°C).\n\n \n \n ", "Do not freeze ORFADIN oral suspension.\n" ], "text": "" }

After the adapter is inserted into the bottle:

{ "type": "p", "children": [], "text": "\nAfter the adapter is inserted into the bottle:\n" }

{ "type": "ul", "children": [ "After the adapter has been inserted into the bottle, store ORFADIN oral suspension at room temperature, 77°F (25°C) or below.\n", "Throw away (discard) ORFADIN oral suspension 60 days after the adapter is inserted in the bottle. You or your pharmacist should write the discard date on the bottle label.\n" ], "text": "" }

What are the ingredients in ORFADIN oral suspension?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in ORFADIN oral suspension?\n" }

Active ingredient: nitisinone

{ "type": "p", "children": [], "text": "\nActive ingredient: nitisinone\n\n \n\n " }

Inactive ingredients: hydroxypropyl methylcellulose, glycerol, polysorbate 80, sodium benzoate, citric acid monohydrate, trisodium citrate dihydrate, strawberry aroma (artificial) and purified water

{ "type": "p", "children": [], "text": "\nInactive ingredients: hydroxypropyl methylcellulose, glycerol, polysorbate 80, sodium benzoate, citric acid monohydrate, trisodium citrate dihydrate, strawberry aroma (artificial) and purified water\n\n \n\n " }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration.\n" }

Manufactured by: Apotek Produktion & Laboratorier AB, Sweden

{ "type": "p", "children": [], "text": "Manufactured by: \n \n \n Apotek Produktion & Laboratorier AB, Sweden\n\n \n\n " }

Marketed by: Sobi, Inc 77 Fourth Avenue, 3 rd Floor, Waltham, MA 02451-7559

{ "type": "p", "children": [], "text": "Marketed by:\n \n \n Sobi, Inc\n \n \n 77 Fourth Avenue, 3\n \n \n rd Floor, Waltham, MA 02451-7559\n\n \n\n " }

© Swedish Orphan Biovitrum AB (publ). All rights reserved.

{ "type": "p", "children": [], "text": "© Swedish Orphan Biovitrum AB (publ). All rights reserved.\n" }

Issued: 11/2021

{ "type": "p", "children": [], "text": "Issued: 11/2021\n" }

Principal Display Panel - 4mg/ml Carton Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - 4mg/ml Carton Label\n" }

Orfadin® (nitisinone)

{ "type": "p", "children": [], "text": "\nOrfadin®\n\n(nitisinone)\n\n \n\n " }

oral suspension 4 mg/ml

{ "type": "p", "children": [], "text": "oral suspension\n \n \n 4 mg/ml\n\n \n\n " }

For Oral Use.

{ "type": "p", "children": [], "text": "For Oral Use.\n" }

Rx only.

{ "type": "p", "children": [], "text": "Rx only.\n" }

Shake well for 20 seconds before first use. Shake well for 5 seconds before each use.

{ "type": "p", "children": [], "text": "\nShake well for 20 seconds before\n \n \n first use. Shake well for 5 seconds\n \n \n before each use.\n \n \n \n" }

90 ml

{ "type": "p", "children": [], "text": "90 ml\n" }

Principal Display Panel - 4mg/ml Vial Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - 4mg/ml Vial Label\n" }

Orfadin® (nitisinone)

{ "type": "p", "children": [], "text": "\nOrfadin®\n\n(nitisinone)\n\n \n\n " }

oral suspension 4 mg/ml

{ "type": "p", "children": [], "text": "oral suspension\n \n \n 4 mg/ml\n\n \n\n " }

Shake well before use.

{ "type": "p", "children": [], "text": "\nShake well before use.\n" }

Nitisinone capsules are indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

{ "type": "p", "children": [], "text": "Nitisinone capsules are indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine." }

Starting Dosage

The recommended starting dosage of nitisinone capsules is 0.5 mg/kg administered orally twice daily.

Maintenance Regimen

In patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, the total daily dose of nitisinone may be given once daily (e.g., 1 to 2 mg/kg once daily) [see Clinical Pharmacology (12.2)].

Dosage Titration

Titrate the dosage in each individual patient based on biochemical and/or clinical response.

Administration of nitisinone capsules:

Nitisinone Capsules are available as:

{ "type": "p", "children": [], "text": "Nitisinone Capsules are available as:" }

2 mg: White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as "008" on cap and "Novitium 2 mg" on body, filled with white to off white powder blend.

{ "type": "p", "children": [], "text": "2 mg: White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as \"008\" on cap and \"Novitium 2 mg\" on body, filled with white to off white powder blend." }

5 mg: White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as "009" on cap and "Novitium 5 mg" on body, filled with white to off white powder blend.

{ "type": "p", "children": [], "text": "5 mg: White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as \"009\" on cap and \"Novitium 5 mg\" on body, filled with white to off white powder blend." }

10 mg: White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as "010" on cap and "Novitium 10 mg" on body, filled with white to off white powder blend.

{ "type": "p", "children": [], "text": "10 mg: White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as \"010\" on cap and \"Novitium 10 mg\" on body, filled with white to off white powder blend." }

None.

{ "type": "p", "children": [], "text": "None." }

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme in the tyrosine metabolic pathway [see Clinical Pharmacology (12.1)]. 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:

In patients with HT-1 treated with dietary restrictions and nitisinone who develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake.

In clinical trials, patients treated with nitisinone and dietary restriction developed transient leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions (6.1)]. 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Nitisinone was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of nitisinone is 0.5 mg/kg twice daily [see Dosage and Administration (2.1)]. Median duration of treatment was 22 months (range 0.1 to 80 months).

The most serious adverse reactions reported during nitisinone treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)]. Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in nitisinone dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia.

Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%).

The most common adverse reactions reported in the clinical trial are summarized in Table 1.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="629.622"> <colgroup> <col width="49.4296577946768%"/> <col width="50.5703422053232%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">TABLE 1</span> <br/> <span class="Bold">Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone*</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Elevated tyrosine levels<br/>Leukopenia<br/>Thrombocytopenia<br/>Conjunctivitis<br/>Corneal opacity<br/>Keratitis<br/>Photophobia<br/>Eye pain<br/>Blepharitis<br/>Cataracts<br/>Granulocytopenia<br/>Epistaxis<br/>Pruritus<br/>Exfoliative dermatitis<br/>Dry skin<br/>Maculopapular rash<br/>Alopecia<br/> </td><td align="center" class="Rrule" valign="top">&gt;10%<br/>3%<br/>3%<br/>2%<br/>2%<br/>2%<br/>2%<br/>1%<br/>1%<br/>1%<br/>1%<br/>1%<br/>1%<br/>1%<br/>1%<br/>1%<br/>1%<br/> </td> </tr> </tbody> </table></div>

*reported in at least 1% of patients

Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. Table 2 includes drugs with clinically important drug interactions when administered concomitantly with nitisinone and instructions for preventing or managing them.

{ "type": "p", "children": [], "text": "Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. Table 2 includes drugs with clinically important drug interactions when administered concomitantly with nitisinone and instructions for preventing or managing them." }

Table 2: Clinically Relevant Interactions Affecting Co-Administered Drugs

{ "type": "p", "children": [], "text": "\nTable 2: Clinically Relevant Interactions Affecting Co-Administered Drugs\n" }

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="657"> <colgroup> <col width="16.6565164433618%"/> <col width="83.3434835566382%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First First"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with a Narrow Therapeutic Index (e.g., phenytoin, warfarin)</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Clinical Impact</td><td class="Rrule" valign="top">Increased exposure of the co-administered drugs metabolized by CYP2C9. <span class="Italics">[see Clinical Pharmacology (12.3)]</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Intervention</td><td class="Rrule" valign="top">Reduce the dosage of the co-administered drugs metabolized by CYP2C9 drug by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. See prescribing information for those drugs.</td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">OAT1/OAT3 Substrates (e.g., adefovir, ganciclovir, methotrexate)</span></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Clinical Impact</td><td class="Rrule" valign="top">Increased exposure of the interacting drug <span class="Italics">[see Clinical Pharmacology (12.3)]</span></td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Intervention</td><td class="Rrule" valign="top">Monitor for potential adverse reactions related to the co-administered drug.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0\" cellspacing=\"0\" width=\"657\">\n<colgroup>\n<col width=\"16.6565164433618%\"/>\n<col width=\"83.3434835566382%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First First\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with a Narrow Therapeutic Index (e.g., phenytoin, warfarin)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Clinical Impact</td><td class=\"Rrule\" valign=\"top\">Increased exposure of the co-administered drugs metabolized by CYP2C9. <span class=\"Italics\">[see Clinical Pharmacology (12.3)]</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Intervention</td><td class=\"Rrule\" valign=\"top\">Reduce the dosage of the co-administered drugs metabolized by CYP2C9 drug by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. See prescribing information for those drugs.</td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">OAT1/OAT3 Substrates (e.g., adefovir, ganciclovir, methotrexate)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td class=\"Lrule Rrule\" valign=\"top\">Clinical Impact</td><td class=\"Rrule\" valign=\"top\">Increased exposure of the interacting drug <span class=\"Italics\">[see Clinical Pharmacology (12.3)]</span></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule\" valign=\"top\">Intervention</td><td class=\"Rrule\" valign=\"top\">Monitor for potential adverse reactions related to the co-administered drug.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. 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 initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose [see Data].

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.

Data

Animal Data

Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended initial dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended initial dose, increased gestational length at 4 and 20 times the recommended initial dose, and decreased pup survival at 0.4 times the recommended initial dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended initial dose based on the body surface area.

Risk Summary

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.

The safety and effectiveness of nitisinone have been established in pediatric patients for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine. Use of nitisinone in pediatric patients is supported by evidence from one open-label, uncontrolled clinical study conducted in 207 patients with HT-1 ages 0 to 22 years (median age 9 months) [see Clinical Studies (14)].

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.

Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hyper-tyrosinemia has been reported with nitisinone treatment [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Accidental ingestion of nitisinone by individuals eating normal diets not restricted in tyrosine and phenylalanine will result in elevated tyrosine levels. In healthy subjects given a single 1 mg/kg dose of nitisinone, the plasma tyrosine level reached a maximum of 1200 micromol/L at 48 to 120 hours after dosing. After a washout period of 14 days, the mean value of plasma tyrosine was still 808 micromol/L. Fasted follow-up samples obtained from volunteers several weeks later showed tyrosine values back to normal. There were no reports of changes in vital signs or laboratory data of any clinical significance. One patient reported sensitivity to sunlight. Hyper-tyrosinemia has been reported with nitisinone treatment [see Warnings and Precautions (5.1)]." }

Nitisinone capsules contains nitisinone, which is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1).

{ "type": "p", "children": [], "text": "Nitisinone capsules contains nitisinone, which is a hydroxyphenyl-pyruvate dioxygenase inhibitor indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1)." }

Nitisinone occurs as white to yellow colored powder. It is practically insoluble in water and sparingly soluble in 2M Sodium Hydroxide, Ethanol and Methanol.

{ "type": "p", "children": [], "text": "Nitisinone occurs as white to yellow colored powder. It is practically insoluble in water and sparingly soluble in 2M Sodium Hydroxide, Ethanol and Methanol. " }

Chemically, nitisinone is 2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione, and the structural formula is:

{ "type": "p", "children": [], "text": "Chemically, nitisinone is 2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione, and the structural formula is:" }

Figure 1. The molecular formula is C14H10F3NO5 with a relative mass of 329.23

{ "type": "p", "children": [], "text": "\nFigure 1. The molecular formula is C14H10F3NO5 with a relative mass of 329.23\n" }

Inert ingredients in the formulation are: citric acid anhydrous, hypromellose, mannitol and stearic acid. The empty hard gelatin capsules contains gelatin, sodium lauryl sulfate and titanium dioxide.

{ "type": "p", "children": [], "text": "Inert ingredients in the formulation are: citric acid anhydrous, hypromellose, mannitol and stearic acid. The empty hard gelatin capsules contains gelatin, sodium lauryl sulfate and titanium dioxide." }

The capsules shells are imprinted in edible ink which contains black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

{ "type": "p", "children": [], "text": "The capsules shells are imprinted in edible ink which contains black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution." }

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 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with nitisinone [see Clinical Studies (14)]. In all 186 patients whose urine succinylacetone was measured, the urinary succinylacetone concentration decreased to less than 1 mmol/mol creatinine, the lower limit of quantitation. The median time to normalization of urine succinylacetone was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 micromol/L (95% confidence interval: 23, 51 micromol/L). In 87% (150/172) of patients whose plasma succinylacetone was measured, the plasma succinylacetone concentration decreased to less than 0.1 micromol/L, the lower limit of quantitation. The median time to normalization of plasma succinylacetone was 3.9 months.

In another study, comparing two dosing regimens, succinylacetone was measured in urine and/or blood in 16 patients with HT-1 aged 5 years to 24 years. All study patients were on a stable nitisinone daily dosage (0.4 mg/kg/day to 1 mg/kg/day) during both study dosing regimens. After at least 4 weeks of twice daily dosing with nitisinone, both the urine and/or blood succinylacetone concentrations were below the limit of quantitation for the assay. Patients were then switched to once daily dosing with the same total daily dosage of nitisinone and blood and/or urine succinylacetone concentrations remained undetectable when measured following at least 4 weeks of treatment with once daily dosing.

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 [see Warnings and Precautions (5.1)].

The single-dose pharmacokinetics of nitisinone have been studied for nitisinone capsules in healthy adult subjects and the multiple-dose pharmacokinetics have been studied for nitisinone capsules in healthy subjects.

Absorption

The pharmacokinetic characteristics following single oral administration of nitisinone 30 mg under fasting conditions are shown in Table 3. The multiple-dose characteristics of nitisinone 80 mg once daily are shown in Table 4. Steady-state (SS) was reached within 14 days dosing in all subjects.

TABLE 3

Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following a Single Oral 30 mg Dose of Nitisinone Under Fasting Conditions

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="635"> <colgroup> <col width="31.9899244332494%"/> <col width="21.5890008396306%"/> <col width="21.6204869857263%"/> <col width="24.8005877413938%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Treatment</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">max</span> (micromol/L)</span> <br/> <span class="Bold">[range]</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">t<span class="Sub">max</span>* (h)</span> <br/> <span class="Bold">[range]</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">AUC<span class="Sub">0-72h</span></span> <br/> <span class="Bold">(micromol·h/L)</span> <br/> <span class="Bold">[range]</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Nitisinone capsule (n=12)<br/> </td><td align="center" class="Rrule" valign="middle">10.5 (26)<br/> </td><td align="center" class="Rrule" valign="middle">3.5<br/>[0.8 to 8.0]<br/> </td><td align="center" class="Rrule" valign="middle">406 (13)<br/> </td> </tr> </tbody> </table></div>

* presented as median [range]

TABLE 4

Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following Repeated Once Daily Administration of 80 mg Nitisinone Under Fasting Conditions.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="637"> <colgroup> <col width="26.4998429483824%"/> <col width="16.637001361114%"/> <col width="15.2863574494817%"/> <col width="15.0769552926395%"/> <col width="26.4998429483824%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Treatment</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">max,ss</span> (micromol/L)</span> <br/> <span class="Bold">[CV%]</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">min,ss</span> (micromol/L)</span> <br/> <span class="Bold">[range]</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">t<span class="Sub">max,ss</span>* (h)</span> <br/> <span class="Bold">[range]</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">AUC0-24h,ss</span> <br/> <span class="Bold">(micromol·h/L)</span> <br/> <span class="Bold">[range]</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Nitisinone<span class="Bold"></span>capsule (n=18)<br/> </td><td align="center" class="Rrule" valign="middle">120 (23)<br/> </td><td align="center" class="Rrule" valign="middle">73 (24)<br/> </td><td align="center" class="Rrule" valign="middle">4.0<br/>[0.0 to 16.0]<br/> </td><td align="center" class="Rrule" valign="middle">2204 (18)<br/> </td> </tr> </tbody> </table></div>

* presented as median [range]

Food Effect: No food effect study was conducted with nitisinone capsules.

Distribution

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

Elimination

The mean terminal plasma half-life of single dose nitisinone in healthy male subjects is 54 hours. The mean (CV%) apparent plasma clearance in 18 healthy adults following multiple once daily doses of nitisinone 80 mg is 113 (16) mL/hr.

Metabolism: In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.

Excretion: Renal elimination of nitisinone is of minor importance, since the mean of the fraction of dose excreted as unchanged nitisinone in the urine (fe(%)) was 3.0% (n=3) following multiple oral doses of 80 mg daily in healthy subjects. The estimated mean (CV%) renal clearance of nitisinone was 0.003 L/h (25%).

Drug Interaction Studies

Nitisinone does not inhibit CYP2D6. Nitisinone is a moderate inhibitor of CYP2C9, and a weak

inducer of CYP2E1 (Table 5). Nitisinone is an inhibitor of OAT1/3 (Table 5).

Table 5. Percent Change in AUC0-∞ and Cmax for Co-administered Drugs in the Presence of Nitisinonein 18 Healthy Subjects

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="627"> <colgroup> <col width="23.1512962175946%"/> <col width="27.4755631109222%"/> <col width="25.0318742031449%"/> <col width="24.3412664683383%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="middle"><span class="Bold">Co-administered Drug <span class="Sup">a</span></span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"><span class="Bold">Dose of Co-administered Drug (Route of Administration)</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Effect of Nitisinone on the Pharmacokinetics of Co-administered Drug<span class="Sup"> b</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">AUC<span class="Sub">0-∞</span></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">C<span class="Sub">max</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">CYP2C9 Substrate Tolbutamide <span class="Sup">c</span> <br/> </td><td align="center" class="Rrule" valign="middle">500 mg (oral)<br/> </td><td align="center" class="Rrule" valign="middle">131% ↑<br/> </td><td align="center" class="Rrule" valign="middle">16% ↑<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">CYP2E1 Substrate Chlorzoxazone<br/> </td><td align="center" class="Rrule" valign="middle">250 mg (oral)<br/> </td><td align="center" class="Rrule" valign="middle">27% ↓<br/> </td><td align="center" class="Rrule" valign="middle">18% ↓<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">OAT1/3 Substrate Furosemide<br/> </td><td align="center" class="Rrule" valign="middle">20 mg (intravenous)<br/> </td><td align="center" class="Rrule" valign="middle">72% ↑<br/> </td><td align="center" class="Rrule" valign="middle">12% ↑<br/> </td> </tr> </tbody> </table></div>

↑ = Increased; ↓ = Decreased

a The interacting drug was administered alone on Day 1 and together with nitisinone on Day 17.

b Multiple doses of 80 mg nitisinone were administered daily alone from Day 3 to Day 16.

c 16 subjects in Period 2 received nitisinone and tolbutamide while 18 subjects in Period 1 received nitisinone alone.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

In vitro studies showed that nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinone does not induce CYP1A2, 2B6 or 3A4/5. Nitisinone does not inhibit P-gp, BCRP, OATP1B1, OATP1B3 and OCT2-mediated transports at therapeutically relevant concentrations.

The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/ day nitisinone (approximately 8.1 times the recommended initial dose of 1 mg/kg/day on a body surface area basis).

Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.

In a single dose-group study in rats given 100 mg/kg (16.2 times the recommended initial dose of 1 mg/kg/day on a body surface area basis), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.

The efficacy and safety of nitisinone in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with nitisinone at a starting dose of 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.

{ "type": "p", "children": [], "text": "The efficacy and safety of nitisinone in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with nitisinone at a starting dose of 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG-synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls. " }

For patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2-and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients presenting with HT-1 at younger than 2 months of age and treated with dietary restriction alone had 2-and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting with HT-1 between 2 months and 6 months of age who were treated with dietary restriction and nitisinone, 2-and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients presenting with HT-1 between 2 months and 6 months of age treated with dietary restriction alone had 2-and 4-year survival probabilities of 74% and 60%, respectively.

{ "type": "p", "children": [], "text": "For patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2-and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients presenting with HT-1 at younger than 2 months of age and treated with dietary restriction alone had 2-and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting with HT-1 between 2 months and 6 months of age who were treated with dietary restriction and nitisinone, 2-and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients presenting with HT-1 between 2 months and 6 months of age treated with dietary restriction alone had 2-and 4-year survival probabilities of 74% and 60%, respectively. " }

The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.

{ "type": "p", "children": [], "text": "The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study. " }

Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.

{ "type": "p", "children": [], "text": "Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone. " }

Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 grams/mol creatinine (reference value for age less than or equal to 12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine).

{ "type": "p", "children": [], "text": "Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5.0 to 3.0 grams/mol creatinine (reference value for age less than or equal to 12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2.0 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine)." }

The long term effect of nitisinone on hepatic function was not assessed.

{ "type": "p", "children": [], "text": "The long term effect of nitisinone on hepatic function was not assessed." }

Nitisinone Capsules 2 mg for oral administration containing 2 mg of nitisinone, are supplied as follows:

{ "type": "p", "children": [], "text": "\nNitisinone Capsules 2 mg for oral administration containing 2 mg of nitisinone, are supplied as follows:" }

White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as "008" on cap and "Novitium 2 mg" on body, filled with white to off white powder blend.

{ "type": "p", "children": [], "text": "White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as \"008\" on cap and \"Novitium 2 mg\" on body, filled with white to off white powder blend." }

NDC 0254-3020-02             Bottles of 60 capsules with child-resistant closure and tamper resistant induction sealing

{ "type": "p", "children": [], "text": "NDC 0254-3020-02             Bottles of 60 capsules with child-resistant closure and tamper resistant induction sealing" }

Nitisinone Capsules 5 mg for oral administration containing 5 mg of nitisinone, are supplied as follows:

{ "type": "p", "children": [], "text": "\nNitisinone Capsules 5 mg for oral administration containing 5 mg of nitisinone, are supplied as follows:" }

White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as "009" on cap and "Novitium 5 mg" on body, filled with white to off white powder blend.

{ "type": "p", "children": [], "text": "White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as \"009\" on cap and \"Novitium 5 mg\" on body, filled with white to off white powder blend." }

NDC 0254-3021-02             Bottles of 60 capsules with child-resistant closure and tamper resistant induction sealing

{ "type": "p", "children": [], "text": "NDC 0254-3021-02             Bottles of 60 capsules with child-resistant closure and tamper resistant induction sealing" }

Nitisinone Capsules 10 mg for oral administration containing 10 mg of nitisinone, are supplied as follows:

{ "type": "p", "children": [], "text": "\nNitisinone Capsules 10 mg for oral administration containing 10 mg of nitisinone, are supplied as follows:" }

White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as "010" on cap and "Novitium 10 mg" on body, filled with white to off white powder blend.

{ "type": "p", "children": [], "text": "White Opaque Hard gelatin capsule shell Size #3, imprinted with black ink as \"010\" on cap and \"Novitium 10 mg\" on body, filled with white to off white powder blend." }

NDC 0254-3022-02             Bottles of 60 capsules with child-resistant closure and tamper resistant induction sealing

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Store at room temperature between

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20°C to 25°C (68°F to 77°F), excursions permitted to 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

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Administration [see Dosage and Administration (2.2)]

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Administration of nitisinone capsules

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

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{ "type": "ul", "children": [ "Inform patients that inadequate restriction may be associated with ocular signs and symptoms, intellectual disability and developmental delay, and painful hyperkeratotic plaques on the soles and palms. Advise patients and caregivers of the need to maintain dietary restriction of tyrosine and phenylalanine and to report any unexplained ocular, neurologic, or other symptoms promptly to their healthcare provider [see Warnings and Precautions (5.1)].\n" ], "text": "" }

Manufactured by:

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Novitium Pharma LLC

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70 Lake Drive, East Windsor

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New Jersey 08520

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Manufactured for:

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Endo USA

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Malvern, PA 19355

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Revised: March, 2025

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OS3020-01-16-04

{ "type": "p", "children": [], "text": "OS3020-01-16-04" }

Nitisinone Capsules 2 mg

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NDC 0254-3020-02          Bottles of 60 capsules Container label

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Carton label

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Nitisinone Capsules 5 mg

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NDC 0254-3021-02          Bottles of 60 capsules Container label

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Carton label

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Nitisinone Capsules 10 mg

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NDC 0254-3022-02          Bottles of 60 capsules Container label

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Carton label    

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NITYR® is indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

{ "type": "p", "children": [], "text": "NITYR® is indicated for the treatment of adult and pediatric patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine." }

The recommended starting dosage of NITYR is 0.5 mg/kg (actual body weight) administered orally twice daily. Titrate the dose in each individual patient based on biochemical and/or clinical response.

Administer NITYR with or without food [see Clinical Pharmacology (12.3)].  

Maintain dietary restriction of tyrosine and phenylalanine when administering NITYR.

Maintenance Dosage

The recommended maintenance dosage of NITYR in patients 5 years of age and older who have undetectable serum and urine succinylacetone concentrations after a minimum of 4 weeks on a stable dosage of nitisinone, is 1 to 2 mg/kg once daily [see Clinical Pharmacology (12.2)].

A maximum total daily dosage of 2 mg/kg may be needed based on the evaluation of all biochemical parameters.

Missed Dose

If a dose of NITYR is missed, do not administer two doses at once to make up for a missed dose. Take the next dose at the scheduled time. 

Monitor plasma and/or urine succinylacetone concentrations, liver function parameters and alpha-fetoprotein levels.

Monitor all biochemical parameters more closely (i.e. plasma and/or urine succinylacetone, urine 5-aminolevulinate (ALA), and erythrocyte porphobilinogen (PBG)-synthase activity during initiation of therapy, when switching from twice daily to once daily dosing, or if there is a deterioration in the patient’s condition.

If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the NITYR dosage to 0.75 mg/kg twice daily. If the biochemical response is satisfactory (undetectable blood and/or urine succinylacetone), the dosage should be adjusted only according to body weight gain and not according to plasma tyrosine levels.

Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake [see Warnings and Precautions (5.1)]. In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosine and phenylalanine intake. Do not adjust the NITYR dosage in order to lower the plasma tyrosine concentration.

For patients who have difficulty swallowing intact tablets, disintegrate NITYR in water and administer using an oral syringe. For patients who can swallow semi-solid foods, NITYR tablets can be crushed and mixed with applesauce.

Administration of NITYR with other liquids or foods has not been studied and is not recommended.

Preparation and Administration of NITYR with Water in an Oral Syringe: Do not prepare more than two tablets at once within the same oral syringe.

If patient’s dosage requires more than two tablets, follow the steps below using multiple oral syringes and prescribed number of tablets to achieve the required dose.

One Tablet

1. Remove the plunger from the 5-mL oral syringe and insert a single, intact tablet.

2. Replace the plunger and draw up 2.6 mL of room temperature water.

3. Cap the oral syringe and leave the oral syringe for at least the length of time below:• 15 minutes for a 2 mg tablet • 60 minutes for a 5 mg or 10 mg tablet

4. Turn the oral syringe up and down for at least 30 seconds to suspend the material.

5. Inspect the syringe to ensure the tablet has fully disintegrated. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Do not administer unless the tablet has fully disintegrated. Before administration of the suspension, turn the oral syringe up and down for 30 seconds to ensure the particles are suspended.

6. Uncap the oral syringe and administer all the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.

7. Fill the oral syringe by drawing up 2 mL of water. Shake well and administer while this time fully depressing the plunger. If particles are still present in the syringe, repeat this step.

Two Tablets

1. Remove the plunger from the 5-mL oral syringe and insert two intact tablets.

2. Replace the plunger and draw up 5 mL of room temperature water.

3. Cap the oral syringe and leave it for at least the length of time below:• 15 minutes for 2 mg tablets • 60 minutes for 5 mg or 10 mg tablets

4. Turn the oral syringe up and down for at least 30 seconds to suspend the material.

5. Inspect the syringe to ensure the tablets have fully disintegrated. If the tablet is not fully disintegrated, leave the oral syringe for an additional 10 minutes. Do not administer unless the tablet has fully disintegrated. Before administration of the suspension, turn the oral syringe up and down for 30 seconds to ensure the particles are suspended.

6. Uncap the oral syringe and administer all the suspension into the patient's mouth. To facilitate full administration, avoid depressing the plunger to the end of the oral syringe and leave a gap between the plunger and the oral syringe.

7. Fill the oral syringe by drawing up 2 mL of water. Shake well and administer while this time fully depressing the plunger. If particles are still present in the syringe, repeat this step.

Storage Instructions for the NITYR with water in an Oral Syringe

The suspension can be stored at room temperature in the capped oral syringe, protected from direct sunlight for up to 24 hours after adding water to the tablets. Discard after 24 hours.

Preparation and Administration of NITYR Mixed in Applesauce For patients who can swallow semi-solid food, NITYR can be crushed and mixed with applesauce.

1. Measure approximately one teaspoon of applesauce and transfer it into a clean container (e.g., clean glass).

2. Crush only 1 tablet at a time between two teaspoons forming a fine powder. Repeat this step if more than 1 tablet is needed.

3. Transfer the powder to the applesauce container ensuring all the powder is transferred and no powder residue remains on the teaspoon.

4. Mix the powder into the applesauce until the powder is well dispersed.

5. Administer the entire NITYR-applesauce mixture to the patient immediately or within 2 hours of mixing.

6. To ensure that there is not any remaining NITYR-applesauce mixture, add approximately one teaspoon of applesauce to the same container and administer to the patient.

Storage Instructions for NITYR Mixed in Apple Sauce

The mixture can be stored at room temperature, out of direct sunlight, for up to 2 hours after adding the crushed tablets to the applesauce. Discard after 2 hours.

Tablets: 2 mg, 5 mg, and 10 mg white to beige, round, flat tablets, which may display light yellow to brown speckles, debossed with “L” on one side and the strength (“2” mg, “5” mg, or “10” mg), on the other side.

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None.

{ "type": "p", "children": [], "text": "None." }

Treatment with NITYR may cause elevated plasma tyrosine levels in patients with HT-1. 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:

Maintain concomitant reduction in dietary tyrosine and phenylalanine while on NITYR treatment. In patients with HT-1 who are treated with NITYR and dietary restriction and develop elevated plasma tyrosine levels, assess dietary tyrosine and phenylalanine intake. Do not adjust NITYR dosage in order to lower the plasma tyrosine concentration. Maintain plasma tyrosine levels below 500 micromol/L. 

In clinical trials, patients treated with another oral formulation of nitisinone and dietary restriction developed reversible leukopenia (3%), thrombocytopenia (3%), or both (1.5%) [see Adverse Reactions (6.1)]. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia. Monitor platelet and white blood cell counts during NITYR therapy.

Serious and or clinically significant adverse reactions described elsewhere in labeling include:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of NITYR has been established based on studies of another oral formulation of nitisinone in patients with HT-1 [see Clinical Studies (14)]. Below is a display of the adverse reactions of nitisinone in these studies.

Nitisinone was studied in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months), who were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. The starting dose of nitisinone was 0.3 to 0.5 mg/kg twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, biochemical, and enzyme markers. The recommended starting dosage of NITYR is 0.5 mg/kg twice daily [see Dosage and Administration (2.1)]. Median duration of treatment was 22 months (range 0.1 to 80 months).

The most serious adverse reactions reported during nitisinone treatment were thrombocytopenia, leukopenia, porphyria, and ocular/visual complaints associated with elevated tyrosine levels [see Warnings and Precautions (5.1, 5.2)]. Fourteen patients experienced ocular/visual events. The duration of the symptoms varied from 5 days to 2 years. Six patients had thrombocytopenia, three of which had platelet counts 30,000/microL or lower. In 4 patients with thrombocytopenia, platelet counts gradually returned to normal (duration up to 47 days) without change in the nitisinone dose. No patients developed infections or bleeding as a result of the episodes of leukopenia and thrombocytopenia.

Patients with HT-1 are at increased risk of developing porphyric crises, hepatic neoplasms, and liver failure requiring liver transplantation. These complications of HT-1 were observed in patients treated with nitisinone for a median of 22 months during the clinical trial (liver transplantation 13%, liver failure 7%, malignant hepatic neoplasms 5%, benign hepatic neoplasms 3%, porphyria 1%).

The most common adverse reactions reported in the clinical trial are summarized in TABLE 1.

<div class="scrollingtable"><table width="50%"> <colgroup> <col align="center" class="Lrule Rrule" width="50%"/> <col align="center" class="Lrule Rrule" width="50%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="center" colspan="2" valign="top">*reported in at least 1% of patients; ** another oral formulation of nitisinone</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Lrule Rrule Rrule" colspan="2" valign="top"><span class="Bold">TABLE 1<br/> Most Common Adverse Reactions<span class="Sup">*</span> in Patients with HT-1 Treated with Nitisinone<span class="Sup">**</span></span></td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Elevated tyrosine levels</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">&gt;10%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Leukopenia</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">3%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Thrombocytopenia</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">3%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Conjunctivitis</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">2%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Corneal Opacity</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">2%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Keratitis</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">2%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Photophobia</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">2%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Eye Pain</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Blepharitis</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Cataracts</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Granulocytopenia</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Epistaxis</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Pruritus</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Exfoliative Dermatitis</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Dry Skin</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Maculopapular Rash</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> <tr class="Last"> <td align="center" class="Lrule Lrule Rrule Rrule" valign="top">Alopecia</td><td align="center" class="Lrule Lrule Rrule Rrule" valign="top">1%</td> </tr> </tbody> </table></div>

Adverse reactions reported in less than 1% of the patients, included death, seizure, brain tumor, encephalopathy, hyperkinesia, cyanosis, abdominal pain, diarrhea, enanthema, gastrointestinal hemorrhage, melena, elevated hepatic enzymes, liver enlargement, hypoglycemia, septicemia, and bronchitis.

Nitisinone is a moderate CYP2C9 inhibitor, a weak CYP2E1 inducer and an inhibitor of OAT1/OAT3. TABLE 2 includes drugs with clinically significant drug interactions when administered concomitantly with NITYR and instructions for preventing or managing them.

                 TABLE 2. Clinically Significant Interactions Affecting Co-Administered Drugs

<div class="scrollingtable"><table border="4" width="80%"> <colgroup> <col align="left" width="20%"/> <col align="left" width="20%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" scope="col" valign="top"> <p class="First"> <span class="Bold">Sensitive CYP2C9 Substrates (e.g., celecoxib, tolbutamide) or CYP2C9 Substrates with a Narrow Therapeutic Index (e.g., phenytoin, warfarin)</span> </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Clinical Impact</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Increased exposure of the co-administered drugs metabolized by CYP2C9. <span class="Italics">[see Clinical Pharmacology (<a href="#s12_3">12.3</a>)]</span> </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="Default First First">Prevention or Management</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Reduce the dosage of the co-administered drugs metabolized by CYP2C9 drug by half. Additional dosage adjustments may be needed to maintain therapeutic drug concentrations for narrow therapeutic index drugs. See prescribing information for those drugs.</p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" scope="col" valign="top"> <p class="First"> <span class="Bold">OAT1/OAT3 Substrates (e.g., adefovir, ganciclovir, methotrexate)</span> </p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Clinical Impact</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Increased exposure of the interacting drug. <span class="Italics">[see Clinical Pharmacology (<a href="#s12_3">12.3</a>)]</span> </p> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Prevention or Management</p> </td><td align="left" class="Botrule Lrule Rrule Toprule" scope="col" valign="top"> <p class="First">Monitor for potential adverse reactions related to the co-administered drug.</p> </td> </tr> </tbody> </table></div>

Risk Summary Limited available data with nitisinone use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. 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 initial dose of 1 mg/kg/day. In mice, nitisinone caused incomplete skeletal ossification of fetal bones and decreased pup survival at doses 0.4 times the recommended initial dose, and increased gestational length at doses 4 times the recommended initial dose. In rabbits, nitisinone caused maternal toxicity and incomplete skeletal ossification of fetal bones at doses 1.6 times the recommended initial dose (see Data).

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.

Data Animal Data

Reproduction studies have been performed in mice at oral doses of about 0.4, 4 and 20 times the recommended initial dose (1 mg/kg/day) and in rabbits at oral doses of about 1.6, 4 and 8 times the recommended initial dose based on the body surface area. In mice, nitisinone has been shown to cause incomplete skeletal ossification of fetal bones at 0.4, 4 and 20 times the recommended initial dose, increased gestational length at 4 and 20 times the recommended initial dose, and decreased pup survival at 0.4 times the recommended initial dose based on the body surface area. In rabbits, nitisinone caused incomplete skeletal ossification of fetal bones at 1.6, 4 and 8 times the recommended initial dose based on the body surface area.

Risk Summary 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 NITYR and any potential adverse effects on the breastfed infant from NITYR or from the underlying maternal condition.

The safety and effectiveness of nitisinone have been established for the treatment of HT-1 in combination with dietary restriction of tyrosine and phenylalanine in pediatric patients. Use of NITYR for this indication is supported by evidence from one open-label, uncontrolled clinical study conducted with another oral formulation of nitisinone in 207 patients with HT-1 ages 0 to 22 years (median age 9 months) [see Clinical Studies (14)].

Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 of concomitant disease or other drug therapy in this patient population.

NITYR (nitisinone) is a hydroxyphenyl-pyruvate dioxygenase inhibitor.

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Nitisinone occurs as a white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol.

{ "type": "p", "children": [], "text": "Nitisinone occurs as a white to yellowish-white, crystalline powder. It is practically insoluble in water, soluble in 2M sodium hydroxide and in methanol, and sparingly soluble in alcohol." }

The chemical name of nitisinone is 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione. The empirical formula is C14H10F3NO5 and the molecular weight is 329.23. The structural formula is:

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Each NITYR (nitisinone) tablet contains 2, 5 or 10 mg of nitisinone. Inactive ingredients are: glyceryl dibehenate, and lactose monohydrate. NITYR tablets are intended for oral administration.

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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 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1.

In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with another oral formulation of nitisinone [see Clinical Studies (14)]. In all 186 patients whose urine succinylacetone was measured, the urinary succinylacetone concentration decreased to less than 1 mmol/mol creatinine, the lower limit of quantitation. The median time to normalization of urine succinylacetone was 0.3 months. The probability of recurrence of abnormal values of urine succinylacetone was 1% at a nitisinone concentration of 37 micromol/L (95% confidence interval: 23, 51 micromol/L). In 87% (150/172) of patients whose plasma succinylacetone was measured, the plasma succinylacetone concentration decreased to less than 0.1 micromol/L, the lower limit of quantitation. The median time to normalization of plasma succinylacetone was 3.9 months.

In another study, comparing two dosing regimens of another oral formulation of nitisinone, succinylacetone was measured in urine and/or blood in 16 patients with HT-1 aged 5 years to 24 years. All study patients were on a stable nitisinone daily dosage (0.4 mg/kg/day to 1 mg/kg/day) during both study dosing regimens. After at least 4 weeks of twice daily dosing with nitisinone, both the urine and/or blood succinylacetone concentrations were below the limit of quantitation for the assay. Patients were then switched to once daily dosing with the same total daily dosage of nitisinone and blood and/or urine succinylacetone concentrations remained undetectable when measured following at least 4 weeks of treatment with once daily dosing.

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 [see Warnings and Precautions (5.1)].

The single-dose pharmacokinetics of nitisinone have been studied for NITYR tablets in healthy adult subjects.

Absorption The pharmacokinetic characteristics following single oral administration of 10 mg NITYR under fasting conditions are shown in TABLE 3.

TABLE 3. Geometric Mean Pharmacokinetic Parameters in Healthy Subjects Following a Single Oral 10 mg Dose of NITYR Under Fasting Conditions

<div class="scrollingtable"><table border="4" width="80%"> <colgroup> <col align="left" width="20%"/> <col align="center" width="20%"/> <col align="center" width="20%"/> <col align="center" width="20%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">Treatment</span></th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">C<span class="Sub">max </span></span><span class="Bold">(ng/mL)</span> <br/>[range]</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">T</span><span class="Bold"><span class="Sub">max</span></span><span class="Bold">* (h)</span> <br/>[range]</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"><span class="Bold">AUC</span><span class="Bold"><span class="Sub">0-120h </span></span><span class="Bold">(ng•h/mL)</span> <br/>[range]</th> </tr> </thead> <tfoot> <tr class="First First Last Last"> <td align="left" colspan="4" valign="top"> <p class="First First Footnote">* presented as median [range]</p> </td> </tr> </tfoot> <tbody> <tr class="First Last"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Single 10 mg NITYR Tablet fasted (n=23)</td><td align="center" class="Botrule Lrule Toprule" valign="top">1278<br/>[780 to 1649]</td><td align="center" class="Botrule Lrule Toprule" valign="top"> <p class="First">3.5</p> <p>[1.0 to 4.0]</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">77874<br/>[42335 to 104211]</td> </tr> </tbody> </table></div>

Effect of Food: In a food effect study, a high-fat and high-calorie breakfast (973.6 cal distributed in carbohydrate 250.1 cal, proteins 157 cal, fat 566.5 cal) did not significantly affect the total exposure (AUC0-120h) and Cmax of nitisinone following single oral administration of 10 mg NITYR. The median Tmax was delayed to 6 hours under fed conditions [see Dosage and Administration (2.2)].

Distribution In vitro binding of nitisinone to human plasma proteins is greater than 95% at 50 micromolar concentration. For NITYR, the arithmetic mean (SD) apparent volume of distribution of nitisinone is 8.2 (1.6) L in healthy subjects (n=23).

Elimination For NITYR, the arithmetic mean (SD) terminal half-life of nitisinone is 59.3 (8.9) hours in healthy subjects (n=23).

Metabolism: In vitro studies have shown that nitisinone is relatively stable in human liver microsomes with minor metabolism possibly mediated by CYP3A4 enzyme.

Excretion: Renal elimination of nitisinone is of minor importance, since the mean of the fraction of dose excreted as unchanged nitisinone in the urine (fe(%)) was 3.0% (n=3) following multiple oral doses of 80 mg daily in healthy subjects. The estimated mean (CV%) renal clearance of nitisinone was 0.003 L/h (25%).

Drug Interaction Studies Nitisinone does not inhibit CYP2D6. Nitisinone is a moderate inhibitor of CYP2C9, and a weak inducer of CYP2E1 (TABLE 4). Nitisinone is an inhibitor of OAT1/3 (TABLE 4).

TABLE 4. Percent Change in AUC0-∞ and Cmax for Co-administered Drugs in the Presence of Nitisinone in 18 Healthy Subjects

<div class="scrollingtable"><table border="4" width="80%"> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="Default First First"> <span class="Bold">Co-administered Drug <span class="Sup">a</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="Default First First"> <span class="Bold">Dose of Co-administered Drug (Route of Administration)</span> </p> </td><td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="Default First First"> <span class="Bold">Effect of Nitisinone on the Pharmacokinetics of Co-administered Drug <span class="Sup">b</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-∞</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">C<span class="Sub">max</span></span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">CYP2C9 Substrate Tolbutamide <span class="Sup">c</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">500 mg (oral)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">131%↑</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">16%↑</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">CYP2E1 Substrate</p> <p class="Default">Chlorzoxazone</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">250 mg (oral)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">27%↓</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">18%↓</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">OAT1/3 Substrate Furosemide</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">20 mg (intravenous)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">72%↑</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="Default First First">12%↑</p> </td> </tr> </tbody> </table></div>

↑= Increased; ↓= Decreased

a The interacting drug was administered alone on Day 1 and together with nitisinone on Day 17. b Multiple doses of 80 mg nitisinone were administered daily alone from Day 3 to Day 16. c 16 subjects in Period 2 received nitisinone and tolbutamide while 18 subjects in Period 1 received nitisinone alone.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

In vitro studies showed that nitisinone does not inhibit CYP1A2, 2C19, or 3A4. Nitisinone does not induce CYP1A2, 2B6 or 3A4/5. Nitisinone does not inhibit P-gp, BCRP, OATP1B1, OATP1B3 and OCT2-mediated transports at therapeutically relevant concentrations.

The carcinogenic potential of nitisinone was assessed in a 26-week oral (gavage) carcinogenicity study in Tg.rasH2 mice. There were no drug-related neoplastic findings in male or female Tg.rasH2 mice at doses up to 100 mg/kg/ day nitisinone (approximately 8.1 times the recommended initial dose of 1 mg/kg/day on a body surface area basis).

Nitisinone was not genotoxic in the Ames test and the in vivo mouse liver unscheduled DNA synthesis (UDS) test. Nitisinone was mutagenic in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in an in vivo mouse bone marrow micronucleus test.

In a single dose-group study in rats given 100 mg/kg (16.2 times the recommended initial dose of 1 mg/kg/day on a body surface area basis), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.

The safety and efficacy of NITYR have been established based on studies of another oral formulation of nitisinone in patients with HT-1. Below is a display of the results of these studies.

{ "type": "p", "children": [], "text": "The safety and efficacy of NITYR have been established based on studies of another oral formulation of nitisinone in patients with HT-1. Below is a display of the results of these studies." }

The efficacy and safety of nitisinone in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with nitisinone at a starting dose of 0.3 to 0.5 mg/kg orally twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG- synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls.

{ "type": "p", "children": [], "text": "The efficacy and safety of nitisinone in patients with HT-1 was evaluated in one open-label, uncontrolled study of 207 patients with HT-1, ages 0 to 22 years at enrollment (median age 9 months). Patients were diagnosed with HT-1 by the presence of succinylacetone in the urine or plasma. All patients were treated with nitisinone at a starting dose of 0.3 to 0.5 mg/kg orally twice daily, and the dose was increased in some patients to 1 mg/kg twice daily based on weight, liver and kidney function tests, platelet count, serum amino acids, urinary phenolic acid, plasma and urine succinylacetone, erythrocyte PBG- synthase, and urine 5-ALA. The median duration of treatment was 22 months (range less than 1 month to 80 months). Efficacy was assessed by comparison of survival and incidence of liver transplant to historical controls." }

For patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients presenting with HT-1 younger than 2 months of age treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting between 2 months and 6 months of age who were treated with dietary restrictions and nitisinone, 2-and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients presenting with HT-1 between 2 months and 6 months of age treated with dietary restriction alone had 2-and 4-year survival probabilities of 74% and 60%, respectively.

{ "type": "p", "children": [], "text": "For patients presenting with HT-1 younger than 2 months of age who were treated with dietary restriction and nitisinone, 2- and 4-year survival probabilities were 88% and 88%, respectively. Data from historical controls showed that patients presenting with HT-1 younger than 2 months of age treated with dietary restriction alone had 2- and 4-year survival probabilities of 29% and 29%, respectively. For patients presenting between 2 months and 6 months of age who were treated with dietary restrictions and nitisinone, 2-and 4-year survival probabilities were 94% and 94%, respectively. Data for historical controls showed that patients presenting with HT-1 between 2 months and 6 months of age treated with dietary restriction alone had 2-and 4-year survival probabilities of 74% and 60%, respectively." }

The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study.

{ "type": "p", "children": [], "text": "The effects of nitisinone on urine and plasma succinylacetone, porphyrin metabolism, and urinary alpha-1-microglobulin were also assessed in this clinical study." }

Porphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.

{ "type": "p", "children": [], "text": "\nPorphyria-like crisis were reported in 3 patients (0.3% of cases per year) during the clinical study. This compares to an incidence of 5 to 20% of cases per year expected as part of the natural history of the disorder. An assessment of porphyria-like crises was performed because these events are commonly reported in patients with HT-1 who are not treated with nitisinone.\n" }

Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5 to 3 grams/mol creatinine (reference value for age less than or equal to 12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine).

{ "type": "p", "children": [], "text": "Urinary alpha-1-microglobulin, a proposed marker of proximal tubular dysfunction, was measured in 100 patients at baseline. The overall median pretreatment level was 4.3 grams/mol creatinine. After one year of treatment in a subgroup of patients (N=100), overall median alpha-1-microglobulin decreased by 1.5 grams/mol creatinine. In patients 24 months of age and younger in whom multiple values were available (N=65), median alpha-1-microglobulin levels decreased from 5 to 3 grams/mol creatinine (reference value for age less than or equal to 12 grams/mol creatinine). In patients older than 24 months in whom multiple values were available (N=35), median alpha-1-microglobulin levels decreased from 2.8 to 2 grams/mol creatinine (reference for age less than or equal to 6 grams/mol creatinine)." }

How Supplied

{ "type": "p", "children": [], "text": "\nHow Supplied\n" }

NITYR (nitisinone) tablet is white to beige, round, flat which may display light yellow to brown speckles, debossed with the “strength” in mg on one side and “L” on the other side. Each tablet contains 2, 5 or 10 mg nitisinone.

{ "type": "p", "children": [], "text": "NITYR (nitisinone) tablet is white to beige, round, flat which may display light yellow to brown speckles, debossed with the “strength” in mg on one side and “L” on the other side. Each tablet contains 2, 5 or 10 mg nitisinone." }

NITYR is supplied in a high-density polyethylene (HDPE) square bottle with a child-resistant tamper-evident polypropylene (PP) screw cap. Each bottle contains 60 tablets.

{ "type": "p", "children": [], "text": "NITYR is supplied in a high-density polyethylene (HDPE) square bottle with a child-resistant tamper-evident polypropylene (PP) screw cap. Each bottle contains 60 tablets." }

2 mg tablets: NDC 70709-002-60

{ "type": "p", "children": [], "text": "2 mg tablets: NDC 70709-002-60" }

5 mg tablets: NDC 70709-005-60

{ "type": "p", "children": [], "text": "5 mg tablets: NDC 70709-005-60" }

10 mg tablets: NDC 70709-000-60

{ "type": "p", "children": [], "text": "10 mg tablets: NDC 70709-000-60" }

Storage and Handling

{ "type": "p", "children": [], "text": "\nStorage and Handling\n" }

Store NITYR tablets at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store NITYR tablets at room temperature between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]." }

Pharmacist: Dispense in tight and light resistant container as defined in USP.                  Dispense 5-mL oral syringe with a cap to use for preparation.

{ "type": "p", "children": [], "text": "Pharmacist: Dispense in tight and light resistant container as defined in USP.                  Dispense 5-mL oral syringe with a cap to use for preparation." }

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Instructions for Use)." }

Dosage and Administration Instructions

{ "type": "p", "children": [], "text": "\nDosage and Administration Instructions\n" }

Advise the patient or caregiver to:

{ "type": "p", "children": [], "text": "Advise the patient or caregiver to:" }

{ "type": "ul", "children": [ "Combine NITYR with dietary restriction of tyrosine and phenylalanine.", "Take NITYR with or without food.", "Disintegrate the tablet(s) in water if patient has difficulty swallowing intact tablet(s), or if patient can swallow semi-solid foods, crush the tablet(s) and mix with applesauce." ], "text": "" }

[see Dosage and Administration (2)]

{ "type": "p", "children": [], "text": "\n[see Dosage and Administration (2)]\n" }

How Supplied/Storage and Handling

{ "type": "p", "children": [], "text": "\nHow Supplied/Storage and Handling\n" }

Advise the patient or caregiver to store NITYR in the container that it is dispensed in and keep the container tightly closed [see How Supplied/Storage and Handling (16)].

{ "type": "p", "children": [], "text": "Advise the patient or caregiver to store NITYR in the container that it is dispensed in and keep the container tightly closed [see How Supplied/Storage and Handling (16)].\n" }

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

{ "type": "p", "children": [], "text": "\nOcular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels\n" }

Advise the patient or caregiver that inadequate dietary restriction may be associated with ocular signs and symptoms, intellectual disability and developmental delay, and painful hyperkeratotic plaques on the soles and palms. Additionally, advise the patient or caregiver of the need to maintain dietary restriction of tyrosine and phenylalanine and to report any unexplained ocular, neurologic, or other symptoms promptly to their healthcare provider [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Advise the patient or caregiver that inadequate dietary restriction may be associated with ocular signs and symptoms, intellectual disability and developmental delay, and painful hyperkeratotic plaques on the soles and palms. Additionally, advise the patient or caregiver of the need to maintain dietary restriction of tyrosine and phenylalanine and to report any unexplained ocular, neurologic, or other symptoms promptly to their healthcare provider [see Warnings and Precautions (5.1)]." }

Manufactured by: PCI Pharma Services23-24 Tafarnaubach Industrial EstateTredegar, GwentNP22 3AA, United Kingdom

{ "type": "p", "children": [], "text": "\nManufactured by:\nPCI Pharma Services23-24 Tafarnaubach Industrial EstateTredegar, GwentNP22 3AA, United Kingdom" }

Rivopharm SACentro Insema6928 Manno, Switzerland

{ "type": "p", "children": [], "text": "Rivopharm SACentro Insema6928 Manno, Switzerland" }

Marketed by: Cycle Pharmaceuticals LtdThe Broers Building21 JJ Thomson AveCambridge, CB3 0FA, United Kingdom

{ "type": "p", "children": [], "text": "\nMarketed by:\nCycle Pharmaceuticals LtdThe Broers Building21 JJ Thomson AveCambridge, CB3 0FA, United Kingdom" }

Patented: see www.cyclepharma.com/product-patent-information

{ "type": "p", "children": [], "text": "Patented: see www.cyclepharma.com/product-patent-information" }

Important Information You Need to Know Before Taking NITYR Using an Oral Syringe

Before preparing NITYR using an oral syringe

Lay out the prescribed number of NITYR tablets and syringes for your dose. Place the tablet or tablets on a clean flat surface.

How to prepare and take 1 NITYR tablet using a 5 mL oral syringe:

<div class="scrollingtable"><table class="Noautorules" width="80%"> <colgroup> <col align="left" width="50.000%"/> <col align="left" width="30.000%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left" valign="middle"><span class="Bold">Step 1.</span> Remove the cap from the 5 mL oral syringe.<br/> <br/> <span class="Bold">Step 2.</span> Remove the plunger from the oral syringe and place 1 whole NITYR tablet inside the oral syringe (See Figure A).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 2" src="/dailymed/image.cfm?name=ifu-02.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 3.</span> Replace the plunger (See Figure B).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 3" src="/dailymed/image.cfm?name=ifu-03.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 4.</span> Draw up <span class="Bold">2.6 mL</span> of room temperature water into the oral syringe. Each line on the barrel of the syringe is 0.2 mL. There may be some air in the oral syringe. Leave the air in the oral syringe (See Figure C).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 4" src="/dailymed/image.cfm?name=ifu-04.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 5.</span> Replace the cap on the oral syringe and note the time. Let the oral syringe sit for at least the length of time below:<br/>• <span class="Bold">15 minutes</span> for a 2 mg tablet<br/>• <span class="Bold">60 minutes</span> for a 5 mg or 10 mg tablet<br/>(See Figure D)</td><td align="center" valign="top"><img alt="IFU 5" src="/dailymed/image.cfm?name=ifu-05.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 6.</span> Turn the oral syringe up and down for at least 30 seconds (See Figure E).</td><td align="center" valign="top"><img alt="IFU 6" src="/dailymed/image.cfm?name=ifu-06.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 7.</span> Check the oral syringe to see if the NITYR tablet has broken apart into very small pieces and the pieces are evenly spread through the water (suspension) (See Figure F). Do not take the suspension if there are any large pieces of the NITYR tablet in the suspension or if there are any pieces of the tablet that are not evenly spread through the water.<br/> <br/>If there are any pieces of the tablet that are not evenly spread through the water, let the oral syringe sit for 10 minutes.<br/> <br/>Before giving the suspension, turn the oral syringe up and down for 30 seconds to continue to spread the pieces of NITYR tablet in the suspension.</td><td align="center" valign="top"><img alt="IFU 7" src="/dailymed/image.cfm?name=ifu-07.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 8. </span>Remove the cap from the oral syringe (See Figure G).</td><td align="center" valign="top"><img alt="IFU 8" src="/dailymed/image.cfm?name=ifu-08.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 9.</span> Place the tip of the oral syringe in the mouth. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure H).</td><td align="center" valign="top"><img alt="IFU 9" src="/dailymed/image.cfm?name=ifu-09.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 10.</span> While keeping the oral syringe in the mouth, slowly push down on the plunger until a small amount of air is left in the oral syringe, between the plunger and the tip of the oral syringe (See Figure I). Do not press the plunger all the way down to the end of the syringe.</td><td align="center" valign="top"><img alt="IFU 10" src="/dailymed/image.cfm?name=ifu-10.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 11.</span> Draw up an additional <span class="Bold">2 mL</span> of water into the oral syringe (See Figure J).</td><td align="center" valign="top"><img alt="IFU 11" src="/dailymed/image.cfm?name=ifu-11.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 12.</span> Replace the cap on the oral syringe. Shake well to spread the remaining tablet pieces evenly through the water in the oral syringe (See Figure K).</td><td align="center" valign="top"><img alt="IFU 12" src="/dailymed/image.cfm?name=ifu-12.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 13. </span>Remove the cap from the oral syringe (See Figure L).</td><td align="center" valign="top"><img alt="IFU 13" src="/dailymed/image.cfm?name=ifu-13.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 14.</span> Place the tip of the oral syringe in the mouth. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure M).</td><td align="center" valign="top"><img alt="IFU 14" src="/dailymed/image.cfm?name=ifu-14.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 15.</span> While keeping the oral syringe in the mouth, slowly push down on the plunger until the oral syringe is empty (See Figure N). In case any pieces of the tablet are still present in the oral syringe, repeat steps 11 through 15.</td><td align="center" valign="top"><img alt="IFU 15" src="/dailymed/image.cfm?name=ifu-15.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> </tbody> </table></div>

Step 16. After use, remove the plunger from the syringe barrel. Rinse the syringe and the plunger with water after each use and let it dry. Do not replace the plunger into the barrel of the oral syringe until ready to use again to allow it to dry. Do not throw away the oral syringe or plunger.

If you are not taking the water and NITYR tablet suspension as soon as it is prepared, complete steps 1 through 5. When you are ready to take the suspension, complete steps 6 through 16.

How to prepare and take 2 NITYR tablets using a 5 mL oral syringe:

<div class="scrollingtable"><table border="0" class="Noautorules" width="80%"> <colgroup> <col align="left" width="50.000%"/> <col align="left" width="30.000%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left" valign="middle"><span class="Bold">Step 1.</span> Remove the cap from the 5 mL oral syringe.<br/> <br/> <span class="Bold">Step 2.</span> Remove the plunger from the oral syringe and place 2 whole NITYR tablets inside the oral syringe (See Figure A).</td><td align="center" valign="top"><img alt="IFU 16" src="/dailymed/image.cfm?name=ifu-16.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 3.</span> Replace the plunger (See Figure B).</td><td align="center" valign="top"><img alt="IFU 17" src="/dailymed/image.cfm?name=ifu-17.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 4.</span> Draw up <span class="Bold">5 mL</span> of room temperature water into the oral syringe. Each line on the barrel of the syringe is 0.2 mL. There may be some air in the oral syringe. Leave the air in the oral syringe (See Figure C).</td><td align="center" valign="top"><img alt="IFU 18" src="/dailymed/image.cfm?name=ifu-18.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 5.</span> Replace the cap on the oral syringe and note the time. Let the oral syringe sit for at least the length of time below:<br/>• <span class="Bold">15 minutes</span> for 2 mg tablets<br/>• <span class="Bold">60 minutes</span> for 5 mg or 10 mg tablets<br/>(See Figure D).</td><td align="center" valign="top"><img alt="IFU 19" src="/dailymed/image.cfm?name=ifu-19.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 6.</span> Turn the oral syringe up and down for at least 30 seconds (See Figure E).</td><td align="center" valign="top"><img alt="IFU 20" src="/dailymed/image.cfm?name=ifu-20.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 7.</span> Check the oral syringe to see if the NITYR tablets have broken apart into very small pieces and the pieces are evenly spread through the water (suspension) (See Figure F). Do not take the suspension if there are any large pieces of the NITYR tablets in the suspension or if there are any pieces of the tablets that are not evenly spread through the water.<br/> <br/>If there are any pieces of the tablets that are not evenly spread through the water, let the oral syringe sit for 10 minutes.<br/> <br/>Before giving the suspension, turn the oral syringe up and down for 30 seconds to continue to spread the pieces of NITYR tablets in the suspension.</td><td align="center" valign="top"><img alt="IFU 21" src="/dailymed/image.cfm?name=ifu-21.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 8. </span>Remove the cap from the oral syringe (See Figure G).</td><td align="center" valign="top"><img alt="IFU 22" src="/dailymed/image.cfm?name=ifu-22.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 9.</span> Place the tip of the oral syringe in the mouth. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure H).</td><td align="center" valign="top"><img alt="IFU 23" src="/dailymed/image.cfm?name=ifu-23.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 10.</span> While keeping the oral syringe in the mouth, slowly push down on the plunger until a small amount of air is left in the oral syringe, between the plunger and the tip of the oral syringe (See Figure I). Do not press all the way down on the plunger.</td><td align="center" valign="top"><img alt="IFU 24" src="/dailymed/image.cfm?name=ifu-24.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 11.</span> Draw up <span class="Bold">2 mL</span> of water into the oral syringe (See Figure J).</td><td align="center" valign="top"><img alt="IFU 25" src="/dailymed/image.cfm?name=ifu-25.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 12.</span> Replace the cap on the oral syringe. Shake well to spread the remaining tablet pieces evenly through the water in the oral syringe (See Figure K).</td><td align="center" valign="top"><img alt="IFU 26" src="/dailymed/image.cfm?name=ifu-26.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 13. </span>Remove the cap from the oral syringe (See Figure L).</td><td align="center" valign="top"><img alt="IFU 27" src="/dailymed/image.cfm?name=ifu-27.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 14.</span> Place the tip of the oral syringe in the mouth. If giving to a child, place the tip of the oral syringe along the inner cheek of the child’s mouth (See Figure M).</td><td align="center" valign="top"><img alt="IFU 28" src="/dailymed/image.cfm?name=ifu-28.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 15.</span> While keeping the oral syringe in the mouth, slowly push down on the plunger until the oral syringe is empty (See Figure N). In case any pieces of the tablets are still present in the oral syringe, repeat steps 11 through 15.</td><td align="center" valign="top"><img alt="IFU 29" src="/dailymed/image.cfm?name=ifu-29.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></td> </tr> </tbody> </table></div>

Step 16. After use, remove the plunger from the oral syringe barrel. Rinse the oral syringe with water after each use and let it dry. Do not replace the plunger into the barrel of the oral syringe until ready to use again to allow it to dry. Do not throw away the oral syringe.

If you are not taking the water and NITYR tablets suspension as soon as it is prepared, complete steps 1 through 5. When you are ready to take the suspension, complete steps 6 through 16.

How to prepare and take more than 2 NITYR tablets using an oral syringe:

If more than two NITYR tablets are needed for the prescribed dose follow the instructions for “How to prepare and take 1 NITYR tablet using an oral syringe” and “How to prepare and take 2 NITYR tablets using an oral syringe” until you get your prescribed dose. You should not add more than 2 tablets to one syringe at a time.  

How to prepare and take NITYR tablets in applesauce:

<div class="scrollingtable"><table class="Noautorules" width="80%"> <colgroup> <col align="left" width="50.000%"/> <col align="left" width="30.000%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left" valign="middle"><span class="Bold">Step 1.</span> Measure about 1 teaspoon of applesauce and put it into a clean container, such as a glass or bowl.<br/> <br/> <span class="Bold">Step 2.</span> Place 1 NITYR tablet onto a metal teaspoon (See Figure A).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 39" src="/dailymed/image.cfm?name=ifu-39.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 3.</span> Crush 1 tablet at a time between two spoons (See Figure B) until the tablet is crushed to a fine powder (See Figure C).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 40" src="/dailymed/image.cfm?name=ifu-40.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 4.</span> Carefully place all of the NITYR tablet powder from the teaspoon into the clean container of applesauce. Be sure that no tablet powder remains on the teaspoon (See Figure D).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 41" src="/dailymed/image.cfm?name=ifu-41.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 5.</span> If the prescribed dose is more than 1 tablet, repeat Steps 2 and 3, placing all of the NITYR tablet powder together in the container with the applesauce. You do not need to add more applesauce at this time if you take more than 1 tablet. <br/> <br/> <span class="Bold">Step 6.</span> Stir the NITYR tablet powder and the applesauce until all of the tablet powder is mixed well in the applesauce (See Figure E).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 42" src="/dailymed/image.cfm?name=ifu-42.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 7.</span> Remove the NITYR tablet powder and applesauce mixture from the container using a teaspoon and swallow the mixture right away or within 2 hours of mixing (See Figure F). Repeat this step until no mixture is left in the container.</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 43" src="/dailymed/image.cfm?name=ifu-43.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 8.</span> Measure another 1 teaspoon of applesauce and place it in the container used to mix the NITYR tablet powder and applesauce (See Figure G).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 44" src="/dailymed/image.cfm?name=ifu-44.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 9.</span> Stir the fresh applesauce with the remaining NITYR tablet powder and applesauce mixture until they are mixed well (See Figure H).</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 45" src="/dailymed/image.cfm?name=ifu-45.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Step 10.</span> Remove the NITYR tablet and applesauce mixture from the container using a teaspoon and swallow the mixture right away (See Figure I). Repeat this step until no mixture or powder is left in the container.</td><td align="center" valign="top"> <p class="First"> <img alt="IFU 46" src="/dailymed/image.cfm?name=ifu-46.jpg&amp;setid=00fd1905-27e4-420e-8dc5-a69e4ddc1526"/></p> </td> </tr> </tbody> </table></div>

Storing NITYR

After adding water to the tablet in the oral syringe you can keep NITYR tablet suspension at room temperature for 24 hours. Store the suspension in the oral syringe with the cap on and out of direct sunlight until use. The suspension does not need to be refrigerated. Throw away any suspension that is not used within 24 hours after adding water to the tablets in the oral syringe. Empty the syringe in the drain and throw away (dispose of) the syringe by placing it in a trash can.

Take the NITYR tablet and applesauce mixture within 2 hours after adding the NITYR tablet powder to the applesauce. Store the NITYR tablet and applesauce mixture at room temperature and out of direct sunlight until use. The mixture does not need to be refrigerated. Throw away any mixture that is not used within 2 hours after mixing in a trash can.

Keep NITYR and all medicines out of the reach of children. 

What are the ingredients in NITYR?

Active ingredient: nitisinone

Inactive ingredients: glyceryl dibehenate and lactose monohydrate

Talk to your healthcare provider or pharmacist if you have questions about NITYR tablets or how to use the oral syringe. You can also contact the CYCLE VITA on the U.S. toll free number 1-888-360-8482.For more information visit: www.nityr.us

Manufactured by:

PCI Pharma Services23-24 Tafarnaubach Industrial EstateTredegar, GwentNP22 3AA, United Kingdom

Rivopharm SACentro Insema6928 Manno, Switzerland

Marketed by:Cycle Pharmaceuticals LtdThe Broers Building21 JJ Thomson AveCambridge, CB3 0FA, United Kingdom

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: 1/2024

Principal Display Panel - 2 mg Carton Label

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Store at room temperature between 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C and 30°C (59° and 86°F). (See USP Controlled Room Temperature).

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Rx only 60 tablets

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Principal Display Panel – 2 mg Bottle Label

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NDC 70709-002-60

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Principal Display Panel - 5 mg Carton Label

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NDC 70709-005-60

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Rx only 60 tablets

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Principal Display Panel – 5 mg Bottle Label

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NDC 70709-005-60

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Rx only  60 tablets

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Principal Display Panel - 10 mg Carton Label

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NDC 70709-000-60

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Rx only 60 tablets

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Principal Display Panel – 10 mg Bottle Label

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NDC 70709-000-60

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NITYR® (nitisinone) tablets

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