Get your patient on Nitisinone - Nitisinone capsule (Nitisinone)

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 Capsules 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.

• 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 [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 Nitisinone Capsules dosage in order to

lower the plasma tyrosine concentration.

Administration of Nitisinone Capsules

• Maintain dietary restriction of tyrosine and phenylalanine when taking Nitisinone

Capsules.

• Capsules : Take at least one hour before, or two hours after a meal [see Clinical

Pharmacology (12.3)] . For patients who have difficulty swallowing the capsules, the

capsules may be opened and the contents suspended in a small amount of water,

formula or apple sauce immediately before use.

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.

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:

• Ocular signs and symptoms including corneal ulcers, corneal opacities, keratitis,

conjunctivitis, eye pain, and photophobia have been reported in patients treated with

nitisinone [see Adverse Reactions (6.1)] . In a clinical study in a non HT-1 population

without dietary restriction and reported tyrosine levels >500 micromol/l both

symptomatic and asymptomatic keratopathies have been observed. Therefore, perform

a baseline ophthalmologic examination including slit-lamp examination prior to

initiating nitisinone treatment and regularly thereafter. Patients who develop

photophobia, eye pain, or signs of inflammation such as redness, swelling, or burning

of the eyes or tyrosine levels are > 500 micromol/L during treatment with Nitisinone

Capsules should undergo slit- lamp reexamination and immediate measurement of the

plasma tyrosine concentration.

• Variable degrees of intellectual disability and developmental delay. In patients treated

with nitisinone who exhibit an abrupt change in neurologic status, perform a clinical

laboratory assessment including plasma tyrosine levels.

• Painful hyperkeratotic plaques on the soles and palms

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 daysto 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.

Table 1: Most Common Adverse Reactions in Patients with HT-1 Treated with Nitisinone•

•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 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

•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.

•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 AUC 0-∞ and Cmax for Co-administered Drugs in the

Presence of Nitisinone in 18 Healthy Subjects

↑ = 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 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.