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Burosumab-twza Injection

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Burosumab-twza is a human immunoglobulin G subclass 1 (IgG1), anti-human fibroblast growth factor 23 (FGF23) antibody produced by recombinant DNA technology using Chinese hamster ovary cells. Burosumab-twza is composed of two heavy chain (γ1-chain) molecules and two light chain (κ-chain) molecules. Each heavy chain has an N-linked carbohydrate moiety at asparagine 297 (Asn297). The molecular weight of burosumab-twza determined by mass spectrometry is approximately 147,000.

Burosumab-twza injection for subcutaneous administration is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution in a single-dose vial.

Each 1 mL of solution contains 10 mg, 20 mg or 30 mg of burosumab-twza, L-histidine (1.55 mg), L-methionine (1.49 mg), polysorbate 80 (0.5 mg), D-sorbitol (45.91 mg) in Water for Injection, USP. Hydrochloric acid may be used to adjust to a pH of 6.25.

2. INDICATIONS AND USAGE

Burosumab-twza is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older.

3. DOSAGE AND ADMINISTRATION

Burosumab-twza is administered by subcutaneous injection and should be administered by a healthcare provider.

Discontinue oral phosphate and active vitamin D analogs 1 week prior to initiation of treatment. Fasting serum phosphorus concentration should be below the reference range for age prior to initiation of treatment.

3.1 Pediatric Patients with X-linked Hypophosphatemia (1 to less than 18 years of age)

The recommended starting dose regimen is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg.

After initiation of treatment with burosumab-twza, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule below to maintain serum phosphorus within the reference range for age.

Dose Adjustment

Reassess fasting serum phosphorus level 4 weeks after dose adjustment.

Do not adjust burosumab-twza more frequently than every 4 weeks.

Dose Increase: If serum phosphorus is below the reference range for age, the dose may be increased stepwise up to approximately 2 mg/kg, administered every two weeks (maximum dose of 90 mg) according to the dosing schedule shown in Table 1.

Table 1: Pediatric Dose Schedule for Stepwise Dose Increase

Dose Decrease: If serum phosphorus is above 5 mg/dL, withhold the next dose and reassess the serum phosphorus level in 4 weeks. The patient must have serum phosphorus below the reference range for age to reinitiate burosumab-twza. Once serum phosphorus is below the reference range for age, treatment may be restarted according to the dose schedule shown in Table 2. Reassess serum phosphorus level 4 weeks after dose adjustment. If the level remains below the reference range for age after the re-initiation dose, the dose can be adjusted according to Table 1.

Table 2: Pediatric Dose Schedule for Re-Initiation of Therapy

3.2 Adult Patients with X-linked Hypophosphatemia (18 years of age and older)

The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.

After initiation of treatment with burosumab-twza, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose.

Dose Decrease

Reassess fasting serum phosphorus level 2 weeks after dose adjustment.

Do not adjust burosumab-twza more frequently than every 4 weeks.

If serum phosphorus is above the normal range, withhold the next dose and reassess the serum phosphorus level after 4 weeks. The patient must have serum phosphorus below the normal range to be able to reinitiate burosumab-twza. Once serum phosphorus is below the normal range, treatment may be restarted at approximately half the initial starting dose up to a maximum dose of 40 mg every 4 weeks according to the dose schedule shown in Table 3. Reassess serum phosphorus 2 weeks after any change in dose.

Table 3: Adult Dose Schedule for Re-Initiation of Therapy

3.3 Missed Dose

If a patient misses a dose, resume burosumab-twza as soon as possible at the prescribed dose.

3.4 General Considerations for Subcutaneous Administration

Injection sites should be rotated with each injection administered at a different anatomic location (upper arms, upper thighs, buttocks, or any quadrant of abdomen) than the previous injection. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. The maximum volume of burosumab-twza per injection site is 1.5 mL. If more than 1.5 mL is required on a given dosing day, the total volume of burosumab-twza should be split and administered at two different injection sites. Monitor for signs of reactions.

Visually inspect burosumab-twza for particulate matter and discoloration prior to administration. Burosumab-twza is a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution for subcutaneous injection. Do not use if the solution is discolored or cloudy or if the solution contains any particles or foreign particulate matter.

4. CONTRAINDICATIONS

Do not use burosumab-twza with oral phosphate and active vitamin D analogs.

Do not initiate burosumab-twza treatment if serum phosphorus is within or above the normal range for age.

Burosumab-twza is contraindicated in patients with severe renal impairment or end stage renal disease because these conditions are associated with abnormal mineral metabolism.

5. WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients with burosumab-twza. Discontinue burosumab-twza if serious hypersensitivity reactions occur and initiate appropriate medical treatment [see Adverse Reactions (6.1)].

5.2 Hyperphosphatemia and Risk of Nephrocalcinosis

Increases in serum phosphorus to above the upper limit of normal may be associated with an increased risk of nephrocalcinosis. For patients already taking burosumab-twza, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels [see Dosage and Administration (3)].

5.3 Injection Site Reactions

Administration of burosumab-twza may result in local injection site reactions. Discontinue burosumab-twza if severe injection site reactions occur and administer appropriate medical treatment [see Adverse Reactions (6.1)].

6. ADVERSE REACTIONS

The following adverse reactions are described below and elsewhere in the labeling:

• Hypersensitivity [see Warnings and Precautions (5.1)]

• Hyperphosphatemia and Risk of Nephrocalcinosis [see Warnings and Precautions (5.2)]

• Injection Site Reactions [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

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.

Adverse Reactions in Pediatric Patients with XLH

The safety data described below reflect exposure to burosumab-twza in 65 pediatric XLH patients that included 52 exposed for at least 64 weeks (Study 1) and 13 exposed for at least 40 weeks (Study 2). Overall, pediatric XLH patients have been exposed to burosumab-twza for a mean duration of 108 weeks (min 40.9, max 150.0). Burosumab-twza was studied in two pediatric open-label phase 2 studies (Study 1, ages 5 to 12 years, n = 52; Study 2, ages ≥ 1 to < 5 years, n = 13). Overall, the patient population was 1-12 years (mean age 7.4 years), 51% male, and 89% white/Caucasian and diagnosed with XLH. In Study 1, 26 of the patients received burosumab-twza at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 mg/kg) every 2 weeks at Week 64; the other 26 patients received burosumab-twza every 4 weeks. In Study 2, patients received burosumab-twza at a mean dose of 0.89 mg/kg (range 0.8 – 1.2 mg/kg) every 2 weeks at Week 40. Adverse reactions reported in more than 10% of burosumab-twza-treated patients from Studies 1 and 2 are shown in Table 4.

Table 4: Adverse Reactions Reported in More Than 10% of Pediatric Patients Receiving Burosumab-twza in Studies 1 and 2

n = number of patients with an event; N = total number of patients who received at least one dose of burosumab-twza

1 Injection site reaction includes: injection site reaction, injection site erythema, injection site pruritus, injection site swelling, injection site pain, injection site rash, injection site bruising, injection site discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria

2 Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased

3 Rash includes: rash, rash pruritic, rash maculopapular, and rash pustular

4 Dizziness includes: dizziness, and dizziness exertional

Hypersensitivity Reactions

In pediatric patients, the most frequent potential hypersensitivity events were rash (22%), injection site rash (6%), and urticaria (5%).

Hyperphosphatemia

In pediatric studies, there were no events of hyperphosphatemia reported.

Injection Site Reactions (ISR)

In pediatric studies, approximately 58% of the patients had a local reaction (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) at the site of burosumab-twza injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.

Adverse Reactions in Adult Patients with XLH

The safety data described below reflect exposure to burosumab-twza in 68 adult XLH patients, age 20-63 years (mean age 41 years), of whom most were white/Caucasian (81%) and female (65%). These patients were enrolled in a randomized, double-blind, placebo-controlled Phase 3 study in adults with XLH (Study 3: burosumab-twza = 68, Placebo = 66), in which patients received burosumab-twza at a mean dose of 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks at Week 24. Adverse reactions reported in more than 5% of burosumab-twza-treated patients and 2 patients or more than with placebo from the 24-week placebo-controlled portion of Study 3 are shown in Table 5.

Table 5: Adverse Reactions Occurring in More Than 5% of Burosumab-twza-Treated Adult Patients and in at Least 2 Patients More Than with Placebo in Study 3

n = number of patients with an event; N = total number of patients who received at least one dose of burosumab-twza or placebo

1 Headache includes: headache, and head discomfort

2 Tooth infection includes: tooth abscess, and tooth infection

3 Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased

4 Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphatemia

Hypersensitivity Reactions

In the double-blind period of Study 3, approximately 6% of patients in both the burosumab-twza and placebo treatment groups experienced a hypersensitivity event. The events were mild or moderate and did not require discontinuation.

Hyperphosphatemia

In the double-blind period of Study 3, 7% of patients in the burosumab-twza treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single serum phosphorus greater than 5.0 mg/dL or serum phosphorus greater than 4.5 mg/dL [the upper limit of normal] on two occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced 50 percent. A single patient required a second dose reduction for continued hyperphosphatemia.

Injection Site Reactions (ISR)

In the double-blind period of Study 3, approximately 12% of patients in both the burosumab-twza and placebo treatment groups had a local reaction (e.g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.

Restless Leg Syndrome (RLS)

In the double-blind period of Study 3, approximately 12% of the burosumab-twza treatment group had worsening of baseline restless leg syndrome (RLS) or new onset RLS of mild to moderate severity; these events did not lead to dose discontinuation. Nonserious RLS has also been reported in other repeat dose adult XLH studies; in one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event.

Spinal Stenosis

Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. In the burosumab-twza phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 6 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if burosumab-twza therapy exacerbates spinal stenosis or spinal cord compression.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to burosumab-twza in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Pre-existing anti-drug antibodies (ADA) have been detected in up to 10% of patients in clinical studies. ADA was not detected in patients who were antibody negative at the start of treatment. However, the assay used to measure ADA is subject to interference by serum burosumab-twza, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to burosumab-twza is not known.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on burosumab-twza use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In utero, burosumab-twza exposure in cynomolgus monkeys did not result in teratogenic effects. Adverse effects such as late fetal loss and preterm birth were observed in pregnant cynomolgus monkeys, however, these effects are unlikely to indicate clinical risk because they occurred at a drug exposure that was 64-fold higher, by AUC, than the human exposure at 1 mg/kg every 4 weeks and were accompanied in the non-XLH monkeys by maternal hyperphosphatemia and placental mineralization (see Data). Serum phosphorus levels should be monitored throughout pregnancy [see Dosage and Administration (2.2)]. Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In a reproductive toxicity study in pregnant cynomolgus monkeys without XLH, burosumab-twza was administered intravenously once every two weeks from Day 20 of pregnancy to parturition or cesarean section on Day 133, which includes the period of organogenesis, at doses of 1-, 7- and 64-fold human exposure at the adult human dose of 1 mg/kg every 4 weeks. The treatment did not result in teratogenic effects in fetuses or offspring. An increase in late fetal loss, a shortened gestation period, and an increased incidence of preterm births were observed at 64-fold the human exposure at the adult human dose of 1 mg/kg every 4 weeks, concomitant with maternal hyperphosphatemia and placental mineralization. Burosumab-twza was detected in serum from fetuses indicating transport across the placenta. Hyperphosphatemia but no ectopic mineralization was present in fetuses and offspring of dams exposed to 64-fold human exposure at the 1 mg/kg dose every 4 weeks. Burosumab-twza did not affect pre- and postnatal growth including survivability of the offspring.

8.2 Lactation

Risk Summary

There is no information regarding the presence of burosumab-twza in human milk, or the effects of burosumab-twza on milk production or the breastfed infant. Maternal IgG is present in breast milk. However, the effects of local gastrointestinal exposure and limited systemic exposure to burosumab-twza in the breastfed infant are unknown. The lack of clinical data during lactation precludes a clear determination of the risk of burosumab-twza to an infant during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for burosumab-twza and any potential adverse effects on the breastfed infant from burosumab-twza or from the underlying maternal condition.

8.4 Pediatric Use

Safety and efficacy of burosumab-twza have been established in pediatric patients 1 year and older. Efficacy in pediatric patients 1 year and older with XLH is based on open label studies of 52 pediatric patients 5 to 12 years of age with XLH (Study 1), and in 13 pediatric patients 1 to 4 years of age with XLH (Study 2) evaluating serum phosphorus and radiographic findings. Efficacy in adolescents is supported by studies in pediatric patients less than 13 years of age. Dosing in this age group was derived using modeling and simulation of adult and pediatric PK and PD data.

Safety and efficacy for burosumab-twza in pediatric patients with XLH below the age of 1 have not been established [see Adverse Reactions (6.1) and Clinical Studies].

8.5 Geriatric Use

Clinical studies of burosumab-twza did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

9. OVERDOSAGE

There have been no reports of overdose with burosumab-twza. Burosumab-twza has been administered in pediatric clinical trials without dose limiting toxicity using doses up to 2 mg/kg body weight with a maximal dose of 90 mg, administered every two weeks. In adult clinical trials, no dose limiting toxicity has been observed using doses up to 1 mg/kg or a maximal total dose of 128 mg every 4 weeks. In non-XLH rabbits and cynomolgus monkeys, ectopic mineralization in multiple tissues and organs was observed at doses of burosumab-twza that resulted in supra-physiologic serum phosphate levels. Adverse effects on bone including reductions in bone mineral density, bone mineralization and bone strength were also observed at exposure greater than human exposure [see Nonclinical Toxicology].

In case of overdose, it is recommended that serum phosphorus levels, serum calcium levels and renal function be measured immediately and monitored periodically until resolution to normal/baseline levels. In case of hyperphosphatemia, withhold burosumab-twza and initiate appropriate medical treatment.

10. MECHANISM OF ACTION

X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.

11. PHARMACODYNAMICS

Following SC administration in XLH patients, higher burosumab-twza concentrations were associated with greater increase of serum phosphorus levels. The increase in serum phosphorus was reversible and returned to baseline with elimination of systemic burosumab-twza.

Ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) showed dose-dependent increases from baseline [see Clinical Studies].

Elevation in serum total FGF23 was observed after initiation of burosumab-twza treatment, however, the clinical implication is unknown.

12. PHARMACOKINETICS

The following pharmacokinetic parameters were observed in patients with XLH administered the approved recommended starting dosage based on a 70 kg patient, unless otherwise specified.

Burosumab-twza exhibited linear pharmacokinetics following SC injections within the dose range of 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient).

The steady-state trough mean (± SD) concentration of burosumab-twza was 5.8 (± 3.4) mcg/mL in adult patients.

Absorption

The burosumab-twza mean Tmax values ranged from 8 to 11 days.

Distribution

The apparent volume of distribution of burosumab-twza is 8 L.

Elimination

The apparent clearance is 0.290 L/day. The half-life of burosumab-twza is approximately 19 days.

Metabolism

The exact pathway for burosumab-twza metabolism has not been characterized. Burosumab-twza is expected to be degraded into small peptides and amino acids via catabolic pathways.

Specific Populations

No clinical significant difference in burosumab-twza pharmacokinetics was observed based on age.

The effect of renal or hepatic impairment on the pharmacokinetics of burosumab-twza is unknown.

Pediatric Patients

The steady-state trough concentration was 15.8 (± 9.4) mcg/mL in patients aged 5-12 years, and 11.2 (± 4.6) mcg/mL in patients aged 1-4 years.

Body Weight

Clearance and volume of distribution of burosumab-twza increases with body weight.

Drug Interaction Studies

No drug interaction studies have been conducted with burosumab-twza.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

CRYSVITA (burosumab-twza) injection for subcutaneous administration is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to pale brown-yellow solution. The product is available as one single-dose vial per carton in the following strengths:

10 mg/mL (NDC# 69794-102-01)

20 mg/mL (NDC# 69794-203-01)

30 mg/mL (NDC# 69794-304-01)

Storage and Handling:

CRYSVITA vials must be stored in the original carton until the time of use under refrigerated conditions at 36°F to 46°F (2°C to 8°C). Keep CRYSVITA vial in the original carton to protect from light until time of use.

Do not freeze or shake CRYSVITA.

Do not use CRYSVITA beyond the expiration date stamped on the carton.

CRYSVITA vials are single-dose only. Discard any unused product.

Rx only

Rev 04/18