NULIBRY 9.5 mg powder for solution for injection – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

NULIBRY 9.5 mg powder for solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 12.5 mg fosdenopterin hydrobromide dihydrate equivalent to 9.5 mg fosdenopterin.

After reconstitution with 5 mL of sterile water for injections, each mL of solution contains 1.9 mg of fosdenopterin (1.9 mg/mL).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection (powder for injection).

White to pale yellow powder.

The reconstituted solution has a pH in the range of 5-7, a viscosity of 1.0 cSt, and an osmolarity within the range of 260-320 mOsmol/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

NULIBRY is indicated for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.

4.2 Posology and method of administration

NULIBRY is to be administered only if the patient has a confirmed genetic diagnosis or presumptive diagnosis of MoCD Type A.

Patients with a presumptive diagnosis of MoCD Type A need to have a genetic test to confirm the diagnosis of MoCD Type A. NULIBRY must be discontinued if the MoCD Type A diagnosis is not confirmed by genetic testing.

Treatment with NULIBRY is to be initiated and supervised in hospital by a healthcare professional experienced in the management of inborn errors of metabolism. NULIBRY is a chronic substrate replacement therapy intended for long-term use.

Posology

Paediatric population less than 1 year of age (by gestational age)

In patients less than one year of age, the recommended dose of NULIBRY is titrated based on gestational age.

For patients less than 1 year of age who are preterm neonates (gestational age < 37 weeks), the recommended starting dose of NULIBRY is 0.40 mg/kg/day administered intravenously once daily. The dose is to be titrated to the target dose of 0.90 mg/kg/day over a period of 3 months as shown in Table 1.

For patients less than 1 year of age who are term neonates (gestational age ≥ 37 weeks), the recommended starting dose of NULIBRY is 0.55 mg/kg/day administered intravenously once daily. The dose is to be titrated to the target dose of 0.90 mg/kg/day over a period of 3 months as shown in Table 1.

Table 1 Starting dose and titration schedule of NULIBRY for patients less than one year of age by gestational age

Paediatric population from 1 year to less than 18 years of age and adults

The recommended dose of NULIBRY is 0.90 mg/kg (based on actual body weight) administered intravenously once daily.

Missed dose

If a dose is missed, the missed dose is to be administered as soon as possible. The next scheduled dose must be given at least 6 hours after the administration of the missed dose.

Method of administration

NULIBRY is for intravenous use only.

NULIBRY is intended for administration at an infusion rate of 1.5 mL/min after reconstitution with 5 mL of sterile water for injection. Dose volumes below 2 mL may require syringe administration by slow intravenous push.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

NULIBRY may be administered at home by the patient/patient’s caregiver if:

• MoCD Type A symptoms have been stabilized upon treatment with

  NULIBRY,

• the attending physician is confident it is safe to use the medication at home, and

• the patient/patient’s caregiver has been trained and well prepared to follow the administration requirements properly; including how to conduct syringe administration by slow intravenous push (dose injection volume below 2 mL

  • see section 6.6), and use the syringe pump (dose injection volume higher than 2 mL – section 6.6) if needed,

• the patient/patient’s caregiver has received the Infusion Diary, the Home

  Infusion Guide and the age and weight-based specific posology required to prepare and administer NULIBRY.

The healthcare professional will provide training to the patient/patient’s caregiver on how to prepare and administer NULIBRY at home once the patient is deemed eligible for home infusions. The healthcare professional should utilise the Home Infusion Guide when conducting this training. The healthcare provider should evaluate at each visit if the patient/patient’s caregiver is preparing and administering the medication correctly.

The healthcare professional should refer to the Healthcare Professional Home Infusion Checklist when considering patients for home infusion.

If NULIBRY is administered by a patient/patient’s caregiver, the patient/patient’s caregiver must read and follow carefully the detailed “Home Infusion Guide”, provided on the preparation, administration, storage, and disposal of NULIBRY.

The healthcare professional should calculate and provide the volume of NULIBRY in millilitres (mL) and the number of vials needed for each dose to the caregiver/patient, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Potential for photosensitivity

Photosensitivity is a potential risk based on in vitro and in vivo animal studies, see section 5.3.

Fosdenopterin-treated patients or their caregivers must be advised that patients avoid or minimise exposure to direct sunlight and artificial UV light exposure (i.e., UVA or UVB phototherapy) and adopt precautionary measures (e.g., use broad spectrum sunscreen with high sun protection factor, and wear clothing, a hat, and sunglasses that protects against sun exposure). Caregivers/patients must be advised to seek medical attention immediately if the patient develops a rash or if they notice symptoms of photosensitivity reactions (redness, burning sensation of the skin, blisters). Physicians should consider Vitamin D supplementation due to the use of sunscreens and sun protective clothing and advise the caregiver/patients accordingly.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

No clinical drug-drug interaction studies have been performed with fosdenopterin.

The likelihood of metabolism-based and transporter-based drug-drug interactions with fosdenopterin are minimal, and co-administration of other medicinal products is not likely to affect the pharmacokinetics of fosdenopterin (see section 5.2).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of fosdenopterin in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).

NULIBRY is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding

It is unknown whether fosdenopterin/metabolites are excreted in human milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from NULIBRY therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Fertility studies have not been conducted with fosdenopterin.

4.7 Effects on ability to drive and use machines

NULIBRY has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The adverse drug reactions described in this section were evaluated in 11 patients with MoCD Type A. The most frequent (> 20%) adverse reaction observed during clinical trials were complications associated with device, which have been attributed to the catheter and not to fosdenopterin. No patients had to have their treatment discontinued due to adverse events.

Tabulated list of adverse reactions

Adverse drug reactions (ADRs) observed are listed below by MedDRA system organ class and by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated from available data).

Table 2 presents the most common ADRs that occurred in patients treated with NULIBRY.

Table 2 Adverse reactions reported by SOC/PT and frequency

Description of selected adverse reactions

Catheter-related complications

Eight of ten patients treated with NULIBRY experienced at least one device-related adverse event. The events reported in more than one patient included complications associated with device (7 patients), device dislocation and catheter site infection (3 patients each), and catheter site extravasation, catheter site pain, central venous catheterization, catheter site discharge, device leakage, device occlusion, bacteraemia, sepsis, and vascular device infection (2 patients each).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The maximum tolerated dose of NULIBRY has not been established, and there is no known antidote for fosdenopterin. In the event a patient receives a dose of NULIBRY greater than the intended dose, frequent monitoring of vital signs and clinical status is recommended for a minimum of 8 hours after dosing.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products; ATC code: A16AX19

Mechanism of action

Patients with MoCD Type A have mutations in the Molybdenum Cofactor Synthesis 1 (MOCS1) gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with NULIBRY provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulphite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulphites.

Clinical efficacy and safety

The efficacy of NULIBRY and rcPMP was assessed in a combined analysis of the 15 patients with genetically confirmed MoCD Type A who received substrate replacement therapy with NULIBRY and/or rcPMP, which has the same active moiety as fosdenopterin and is considered therapeutically equivalent to NULIBRY.

Of the 15 treated patients included in the combined analysis, 47% were male, 73% were white and 27% were Asian; the median gestational age was 39 weeks (range 35 to 41 weeks). Median age at genetic diagnosis was 4 days across the 15 patients and included 6 patients with a prenatal diagnosis.

Overall survival is presented in Table 3.

Table 3 Overall survival in patients with MoCD type A treated with NULIBRY or rcPMP

Abbreviations: CI=confidence interval; rcPMP=recombinant Escherichia coli derived cPMP.

Findings from the overall survival analysis were compared with an untreated natural history control group. Overall survival was significantly prolonged in patients who received NULIBRY compared to the untreated natural history control group.

Compared to the untreated natural history group, patients who received NULIBRY were more likely to be ambulatory, feed orally, gain weight, progress developmentally, and attain a head circumference closer to their age matched peers. Neurological damage that occurred prior to therapy, including in utero, is not reversible.

MoCD urinary biomarkers

Treatment with NULIBRY resulted in a reduction in urine concentrations of S-sulfocysteine (SSC) in patients with MoCD Type A and the reduction was sustained with long-term treatment over 48 months. The baseline level of urinary SSC normalised to creatinine was characterised in two patients with a mean value of 92.0 µmol/mmol. Following treatment with NULIBRY (n=15), the mean ± SD levels of urinary SSC normalised to creatinine ranged from 12.9 (±7.3) to 8.6 (±5.8) µmol/mmol from Month 3 to the last visit.

Adolescent and adult population

There are limited data in adolescents ages 12 to less than 18 years of age and adults.

Exceptional circumstances

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The MHRA will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

The pharmacokinetics of fosdenopterin in healthy adult subjects following a single intravenous administration of fosdenopterin are summarised in Table 4. The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C_max) of fosdenopterin increased in an approximately proportional manner with increasing doses.

Table 4 Mean (SD) pharmacokinetic parameters following a single intravenous dose of fosdenopterin in healthy subjects

¹ 0.075 mg/kg, 0.24 mg/kg, and 0.68 mg/kg doses are 0.08, 0.27, and 0.76 times the recommended maximum dose, respectively.

Distribution

The volume of distribution (Vd) of fosdenopterin was approximately 300 mL/kg. The plasma protein binding of fosdenopterin ranged from 6 to 12%.

Biotransformation

Fosdenopterin is predominantly metabolised through nonenzymatic degradation processes to an inactive oxidation product of endogenous cPMP.

Investigation of potential for drug interaction

The potential for drug-drug interactions based on cytochrome P450 (CYP) and/or transporter interactions was studied in a number of in vitro studies.

Fosdenopterin does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 isozymes when tested in vitro in human liver microsomes. There was little or no direct time-dependent or metabolism-dependent inhibition of these isozymes, and the half maximal inhibitory concentration (IC₅₀) values were reported as > 500 µM. Fosdenopterin did not demonstrate induction of CYP1A2, CYP2B6, or CYP3A4. Treatment of cultured human hepatocytes with up to 100 µM fosdenopterin produced little or no increase in CYP1A2, CYP2B6, or CYP3A4 mRNA and enzyme activity levels.

Fosdenopterin does not inhibit efflux or uptake transporters. Inhibition of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 (20 μM), OAT3, MATE1, and MATE2-K (20 μM) was reported as < 10% at 200 μM, while cPMP demonstrated slight inhibition of MATE2-K (25%) and OAT1 (33%) at 200 μM. Fosdenopterin is not a substrate of P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or MATE2-K, and is possibly a weak substrate for MATE1.

Elimination

The mean total body clearance (CL) of fosdenopterin ranged from 167 to 195 mL/h/kg. The mean half-life of fosdenopterin ranged from 1.2 to 1.7 hours.

Renal clearance of fosdenopterin accounts for approximately 40% of total body clearance.

Specific populations

Studies have not been conducted to evaluate the pharmacokinetics of fosdenopterin in specific patient populations, identified by race, age, or the presence of renal or hepatic impairment. The effect of renal and hepatic impairment on the pharmacokinetics of fosdenopterin is unknown.

Paediatric population

Pharmacokinetic properties of fosdenopterin in paediatric MoCD Type A patients are similar to healthy adult subjects.

5.3 Preclinical safety data

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity in juvenile animals, and genotoxicity.

Carcinogenicity

Carcinogenicity studies have not been conducted with fosdenopterin.

Reproductive and developmental toxicity

Reproductive and developmental toxicity studies have not been conducted with fosdenopterin.

Phototoxicity

Fosdenopterin was phototoxic in vitro and in vivo. In rats, cutaneous skin reactions (erythema, oedema, flaking, and eschar) and ophthalmic and histopathologic changes were observed after UV radiation.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ascorbic acid (E300)

Mannitol (E421)

Sucrose

Hydrochloric acid (E507) (for pH adjustment)

Sodium hydroxide (E524) (for pH adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

2 years

After reconstitution

Reconstituted NULIBRY may be stored at room temperature (15 °C to 25 °C) or refrigerated (2 °C to 8 °C) for up to 4 hours including infusion time. Do not freeze NULIBRY after reconstitution. Do not shake.

Chemical and physical in-use stability has been demonstrated for 4 hours at 2 °C to 8 °C or 15 °C to 25 °C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than the above mentioned conditions when reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Unopened vial

Store in a freezer at -25 °C to -10 °C.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution and first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

10 mL type I clear glass vial with an aluminium seal and butyl rubber stopper.

Pack size of 1 vial.

6.6 Special precautions for disposal

Each vial is intended for single use only and the excess of unused product must be properly disposed. Sterile water for injection, syringes, needle tips, and alcohol wipes are to be provided to the patient.

Reconstitution

NULIBRY must be reconstituted with 5 mL of sterile water for injections prior to use. Reconstituted NULIBRY must not be shaken nor heated. Aseptic technique is to be used during preparation and these instructions are to be followed:

1. 1. The total dose, number of vials needed, and total reconstituted dose volume based on the patient's weight and prescribed dose must be determined. Dose volumes can range from 0.4 mL for a 2 kg preterm neonate (0.40 mg/kg/day) to 23.7 mL for a 50 kg adult (0.90 mg/kg/day). See section 4.2. Number of vials to be reconstituted is determined by patient’s dose divided by 9.5 mg/vial (content of one vial). If the number of calculated vials includes a fraction, it should be rounded up to the next whole number.
2. 2. The required number of vials is to be removed from the freezer to allow them to reach room temperature (by rolling each vial gently between your hands for 3 to 5 minutes (do not shake) or by leaving it at room temperature for approximately 30 minutes).
3. 3. Each required NULIBRY vial must be reconstituted with 5 mL of sterile water for injections. Each vial is reconstituted by slowly injecting 5 mL of water for injections to the inside of the wall of each vial. The vial must be gently and continuously swirled until the powder is completely dissolved. The vial must not be shaken. After reconstitution, the final concentration of NULIBRY reconstituted solution is 9.5 mg/5 mL (1.9 mg/mL). Only the volume corresponding to the recommended dose should be administered.
4. 4.

   Reconstituted NULIBRY is a clear and colourless to pale yellow solution.

   NULIBRY is to be visually inspected for particulate matter and discoloration prior to administration. NULIBRY must not be used if there are particles present or if the solution is discoloured.

5. 5. The total volume of the daily dose (which may be the content of more than one vial) should be in a single syringe in accordance with the Healthcare Professional, Instructions for Use appended to the Patient Information Leaflet.

If reconstituted NULIBRY is refrigerated, allow it to come to room temperature before administration by rolling each vial gently between your hands 3 to 5 minutes (do not shake) or by leaving it at room temperature for approximately 30 minutes.

Administration

NULIBRY is intended for administration by a healthcare professional. If deemed appropriate by a healthcare professional, NULIBRY may be administered at home by the patient’s caregiver (see section 4.2). If NULIBRY can be administered by a caregiver/patient, caregiver/patient must read the detailed instructions on the preparation, administration, storage, and disposal of NULIBRY.

NULIBRY is for intravenous use only. NULIBRY must be administered with di(2-ethylhexyl)phthalate (DEHP)-free tubing with a 0.2 micron filter. NULIBRY must not be mixed with other medicinal products (note NULIBRY is reconstituted with sterile water for injections). NULIBRY must not be administered as an infusion with other medicinal products.

NULIBRY is given through a syringe pump at a rate of 1.5 mL per minute.

Dose volumes below 2 mL may require syringe administration through slow intravenous push.

Administration of NULIBRY must be completed within 4 hours of reconstitution.

Disposal of medicinal product and auxiliary components

Any unused medicinal product or waste material including materials used for reconstitution and administration should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Integral Pharma Solutions EU Limited

1 Windmill Lane

Dublin 2

D02 F206

Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 62447/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

09/04/2024

10 DATE OF REVISION OF THE TEXT

02/09/2026