Drug Interaction Studies-                                                                                                   No drug interaction studies have been conducted with CRYSVITA.

BRIEF SUMMARY

BUROSUMABTWZA- (April 2018)

Indn-   To treat adults and children ages 1 year and older with x-linked                         hypophosphatemia (XLH) a rare, inherited form of rickets 

Comp-   Injection: 10 mg/mL, 20 mg/mL, or 30 mg/mL in a single-dose vial                      • Pediatric XLH: 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. 

ADR- Most common adverse reactions (=25%) in pediatric XLH patients are: headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased.

 Most common adverse reactions (=5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless leg syndrome, vitamin D decreased, dizziness, constipation, blood phosphorus increased.

CI-   • Do not use  with oral phosphate and active vitamin D analogs.

WARNINGS -

 • Hypersensitivity:                                                                                              Discontinue if serious hypersensitivity reactions occur and initiate appropriate medical treatment.

Pat Inform- 

 Hypersensitivity Reactions-                                                                                     Advise patients that may cause hypersensitivity events such as rash, injection site rash and urticaria.Instruct the patients to contact their physician if such reactions occur .

Inform patients that injection site reactions (e.g. erythema, rash, swelling, bruising, pain, pruritus, urticaria, and hematoma) have occurred at the site of  injection. Instruct the patients to contact their physician if such reactions occur

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  8

ADVERSE REACTIONS-

Most common adverse reactions (=25%) in pediatric XLH patients are: headache, injection site reaction, vomiting, pyrexia, pain in extremity, vitamin D decreased.

 Most common adverse reactions (=5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless leg syndrome, vitamin D decreased, dizziness, constipation, blood phosphorus increased.

WARNINGS AND PRECAUTIONS-

 • Hypersensitivity:                                                                                              Discontinue CRYSVITA if serious hypersensitivity reactions occur and initiate appropriate medical treatment.

• Hyperphosphatemia and Risk of Nephrocalcinosis:                                                For patients already taking CRYSVITA, dose interruption and/or dose reduction may be required based on a patient’s serum phosphorus levels.

• Injection Site Reactions:                                                                            Administration of CRYSVITA may result in local injection site reactions. Discontinue CRYSVITA if severe injection site reactions occur and administer appropriate medical treatment.

 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions-                                                                                     Advise patients that CRYSVITA may cause hypersensitivity events such as rash, injection site rash and urticaria.Instruct the patients to contact their physician if such reactions occur .

Inform patients that injection site reactions (e.g. erythema, rash, swelling, bruising, pain, pruritus, urticaria, and hematoma) have occurred at the site of CRYSVITA injection. Instruct the patients to contact their physician if such reactions occur

Restless Leg Syndrome-                                                                                          Advise patients that CRYSVITA can induce RLS or worsen the symptoms of existing RLS. Instruct the patients to contact their physician if such a reaction occurs

 Pregnancy                                                                                                                Report pregnancies to the Ultragenyx Adverse Event reporting line at 1-888-756-8657 

Manufactured by:                                                                                                    Ultragenyx Pharmaceutical Inc. Novato, CA 94949 U.S. License No. 2040 Distributed by: Ultragenyx Pharmaceutical Inc. Novato, CA 94949 USA

 CLINICAL PHARMACOLOGY

1. 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

2. 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 .

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

3.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 CRYSVITA.

USE IN SPECIFIC POPULATION-

1.Pregnancy Risk Summary-

 There are no available data on CRYSVITA 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  

Serum phosphorus levels should be monitored throughout pregnancy..

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.  

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 CRYSVITA to an infant during lactation.

Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRYSVITA and any potential adverse effects on the breastfed infant from CRYSVITA or from the underlying maternal condition.

3. Pediatric Use-                                                                                                        Safety and efficacy of CRYSVITA 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. 

9 patients 5 to 12 years of age with XLH), 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 CRYSVITA in pediatric patients with XLH below the age of 1 have not been established.

4.Geriatric Use-                                                                                                         Clinical studies of CRYSVITA 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.

 OVERDOSAGE-

There have been no reports of overdose with CRYSVITA. CRYSVITA 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 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 CRYSVITA and initiate appropriate medical treatment.