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).

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.

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

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.

Each mL contains 500 mg. Sodium: Each mL contains 0.7 mg (0.03 mEq).

Figure 1.

Type 1 (HT-1) NITISINONE DIPHARMA is indicated for the treatment of adult and paediatric patients (regardless of age) with confirmed diagnosis of hereditary tyrosinaemia Type 1 (HT-1), in combination with a diet with low tyrosin and phenylalanine.

Alcaptonuria (AKU) NITISINONE DIPHARMA is indicated for the treatment of adult patients with alcaptonuria (AKU).

Monitoring visits should be conducted every 6 months; closer intervals are recommended for adverse reactions.

Monitoring plasma tyrosin levels

An eye examination with slit lamp is recommended before initiating treatment with nitisinone, and then regularly thereafter, at least once a year.

A patient with visual impairment during treatment with nitisinone should be promptly examined by an ophthalmologist.

HT-1: It is imperative to determine whether the patient adheres to his diet and to check plasma concentrations of tyrosin.

An even lower diet of tyrosin and phenylalanine should be initiated if plasma concentrations of tyrosin exceed 500 μmules/L. It is not advisable to lower the plasma concentrations of tyrosin and the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory for the laboratory.

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. 12.2 Pharmacodynamics In a clinical study, patients with HT-1 were diagnosed by the presence of succinylacetone in urine or plasma and treated with ORFADIN.

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. 12.3 Pharmacokinetics 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.

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.

TABLE 3 Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following a Single Oral 30 mg Dose of ORFADIN Under Fasting Conditions Treatment C max (micromol/L) [range] t max (h) [range] AUC 0-72h (micromol·h/L) [range] presented as median [range] ORFADIN capsule (n=12) 10.5 3.5 406 [0.8 to 8.0] ORFADIN oral suspension (n=12) 10.1 0.4 350 [0.2 to 4.0] TABLE 4 Nitisinone Arithmetic Mean (CV%) Pharmacokinetic Parameters in Healthy Subjects Following Repeated Once Daily Administration of 80 mg ORFADIN Under Fasting Conditions.

C max,ss (micromol/L) [CV%] C min,ss (micromol/L) [range] t max,ss (h) [range] AUC 0-24h,ss (micromol·h/L) [range] presented as median [range] ORFADIN capsule (n=18) 120 73 4.0 2204 [0.0 to 16.0] Food Effect: No food effect study was conducted with ORFADIN capsules.

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% .

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

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 mL/h.

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

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

AUC 0-∞ and C max for Co-administered Drugs in the Presence of ORFADIN in 18 Healthy Subjects ↑ = Increased; ↓ = Decreased a The interacting drug was administered alone on Day and together with ORFADIN on Day 17. b Multiple doses of 80 mg ORFADIN were administered daily alone from Day to Day 16. c 16 subjects in Period 2 received ORFADIN and tolbutamide while 18 subjects in Period 1 received ORFADIN alone.

Drug (Route of Administration) Effect of Nitisinone on the Pharmacokinetics of Co-administered Drug b AUC 0-∞ C max CYP2C9 Substrate Tolbutamide c 500 mg (oral) 131% ↑ 16% ↑ CYP2E1 Substrate Chlorzoxazone 250 mg (oral) 27% ↓ 18% ↓ OAT1/3 Substrate Furosemide 20 mg (intravenous) 72% ↑ 12% ↑ 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 enzyme is a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a drug-like disorder, a.

The following are common in patients with d-HT-1 as well as those with d-AK.

Among patients with d-AK.

Among patients with d-HT-1, other common adverse reactions include thrombocytopenia, leukopenia and granulocytopenia.

Uncommon, exfoliative dermatitis may occur.

List of adverse reactions listed below by classes of systems of organs of MedDRA and in absolute frequency.

Among patients with d-HT-1, the other common adverse reactions include thrombocytopenia, leukopenia and granulocytopenia.

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 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.

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

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 may be given once daily.

Titrate the dosage based on biochemical and/or clinical response, as described in the full prescribing information.

The maximum total daily dosage is 2 mg/kg orally.

For instructions on preparing, measuring and administering the oral suspension, see the full prescribing information.

Maintain dietary restriction of tyrosine and phenylalanine Take ORFADIN capsules at least one hour before, or two hours after a meal For patients who have difficulties swallowing capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use.

ORFADIN oral suspension without regard to meals. 2.1 Dosage Starting Dosage The recommended starting dosage of ORFADIN is 0.5 mg/kg administered orally twice daily.

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) .

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

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

If succinylacetone is still detectable in blood or urine 4 weeks after the start of nitisinone treatment, increase the nitisinone dosage to 0.75 mg/kg twice daily.

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

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.

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

Maintain plasma tyrosine levels below 500 micromol/L by dietary restriction of tyrosine and phenylalanine intake.

In patients who develop plasma tyrosine levels above 500 micromol/L, assess dietary tyrosine and phenylalanine intake.

Do not adjust the

ORFADIN dosage in order to lower the plasma tyrosine concentration. 2.2 Preparation and Administration Instructions 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: Store the bottle in the refrigerator prior to first use.

Remove the bottle from the refrigerator.

Calculate 60 days from when the bottle is removed from the refrigerator.

Write this date as the “Discard after” date on the bottle label.

Allow the bottle to warm to room temperature (30 to 60 minutes).

Shake the bottle vigorously for at least 20 seconds until the solid cake at the bottom of the bottle is completely dispersed.

Check that there are no particles left at the bottom of the bottle.

Foam will form in the bottle.

Insert the bottle adapter.

Preparing a Bottle With the Adapter Inserted: Shake the bottle vigorously for at least 5 seconds.

Once the bottle is prepared with the adapter: Use the oral syringe to measure the dose.

Keep the bottle upright and insert the oral syringe into the adapter.

Carefully turn the bottle upside down with the oral syringe in place.

Wait for the foam to rise to the top of the bottle.

Pull back on the syringe plunger to withdraw the dose.

Leave the syringe in the adapter and turn the bottle upright.

Remove the syringe from the adapter by gently twisting it out of the bottle.

Dispense the dose into the patient's mouth.

Do not remove the bottle adapter.

Store the bottle at room temperature (not above 25°C).

Administration of ORFADIN Capsules and Oral Suspension Maintain dietary restriction of tyrosine and phenylalanine when taking ORFADIN.

Take at least one hour before, or two hours after a meal.

For patients who have difficulty swallowing the capsules and who are intolerant to the oral suspension, the capsules may be opened and the contents suspended in a small amount of water, formula or apple sauce immediately before use.

Oral suspension

Take without regard to meals.

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. 2 mg white capsules imprinted "NTBC 2 mg" in black ink, NDC 66658-102-60 5 mg white capsules imprinted "NTBC 5 mg" in black ink, NDC 66658-105-60 10 mg white capsules imprinted "NTBC 10 mg" in black ink, NDC 66658-110-60 20 mg white capsules imprinted "NTBC 20 mg" in black ink, NDC 66658-120-60 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.

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.

Oral suspension 4 mg/mL, NDC 66658-204-90 Store refrigerated at 2°C to 8°C (36°F to 46°F) prior to first use.

Do not freeze.

Store upright.

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.

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 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.

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 to 4% and to 20%, respectively.

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 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.

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 to 22 years (median age 9 months) .

Clinical studies of nitisinone did not include any subjects aged 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.