U.S. FDA APPROVED  DRUGS DURING 2021

Sr.No-  45

ADVERSE REACTIONS-

­ Most common adverse reactions (>10%) are injection site erythema, injection site swelling, vomiting, injection site urticaria, arthralgia, decreased blood pressure, and gastroenteritis.

CONTRAINDICATIONS-

­ None.

WARNINGS AND PRECAUTIONS-

­ Risk of Low Blood Pressure: Transient decreases in blood pressure have been reported.

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PATIENT COUNSELING INFORMATION-

Advise the patient and caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Preparation and Administration-

Instruct caregivers on proper preparation and administration of VOXZOGO.

Ensure caregivers have demonstrated the ability to perform a subcutaneous injection 

Instruct caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items.

Instruct caregivers to dispose needles and syringes in a puncture-resistant container.

Risk of Low Blood Pressure-                                                                                          Inform caregivers and patients that VOXZOGO may lower blood pressure after administration.

Instruct caregivers and patients that prior to VOXZOGO administration, the patient should have adequate food intake and within the hour prior to administration, the patient should drink approximately 8-10 ounces (240-300 mL) of fluid.

Manufactured for: BioMarin Pharmaceutical Inc. 105 Digital Drive, Novato, CA 94949

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                                  In patients with achondroplasia, endochondral bone growth is negatively regulated due to a gain of function mutation in fibroblast growth factor receptor 3 (FGFR3).

2. Pharmacodynamics-                                                                                                    NPR-B Binding Activity Biomarker and Bone Metabolism Biomarker An increase in urinary cyclic guanosine monophosphate (cGMP) concentrations from pre-dose baseline were observed within the first four hours post-dose, with a maximum level at 2 hours post-dose, after VOXZOGO administration to pediatric patients with achondroplasia.

Cardiac Electrophysiology-                                                                                                At the maximum approved recommended dose, Voxzogo does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                     The area under the concentration-time curve (AUC) and peak concentration (Cmax) of vosoritide increased greater than proportionally following subcutaneous administration to pediatric subjects with achondroplasia in the dose range of 7.5 to 30.0 mcg/kg.

Absorption-                                                                                                               Reference ID: 4905458 Absolute bioavailability for vosoritide following subcutaneous injection was not determined. Vosoritide was absorbed with a median Tmax of 15 minutes after dosing.

Distribution-                                                                                                                   The mean (± SD) apparent volume of distribution of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 2880 (± 2450) to 3020 (± 1980) mL/kg.

Elimination-                                                                                                                    The mean (± SD) apparent clearance of vosoritide across 52 weeks of subcutaneous administration of VOXZOGO 15 mcg/kg once daily ranged from 79.4 (± 53.0) to 104 (± 98.8) mL/min/kg. The mean (± SD) half-life ranged from 21.0 (± 4.7) to 27.9 (± 9.9) minutes.

Metabolism-                                                                                                                   The metabolism of vosoritide is expected to occur via catabolic pathways with degradation into small peptide fragments and amino acids.

Special Populations-                                                                                                      No clinically significant differences in the vosoritide pharmacokinetics were observed based on age (0.9 to 16 years), sex or race.

The effect of hepatic or renal impairment on the pharmacokinetics of vosoritide is unknown

Body weight-                                                                                                                 Population pharmacokinetic analyses indicated that body weight is a significant covariate for vosoritide clearance and volume of distribution.

The apparent clearance and volume of distribution of vosoritide increased with increasing body weight in patients with achondroplasia (9 to 74.5 kg).

Drug Interaction Studies-                                                                                                In vitro assessment of drug-drug interactions In vitro studies showed that vosoritide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. In vivo assessment of drug-drug interactions

No clinical studies evaluating the drug-drug interaction potential of vosoritide have been conducted.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

There are no available data on vosoritide use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The estimated background risk of major birth defects for the indicated population is higher than the general population. The estimated background risk of miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

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.

2. Lactation Risk Summary-

There is no information regarding the presence of vosoritide in human milk, the effects on the breastfed infant, or the effects on milk production. Vosoritide is present in rat milk.

When a drug is present in animal milk, it is likely that the drug will be present in human milk.

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

3.Pediatric Use-                                                                                                             The safety and effectiveness of VOXZOGO have been established in pediatric patients aged 5 years and older for the improvement in linear growth in patients with achondroplasia.

Use of VOXZOGO for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients aged 5 years and older .

Safety and effectiveness of VOXZOGO in pediatric patients with achondroplasia below the age of 5 years have not been established.

4. Renal Impairment-                                                                                                      The influence of renal impairment on the pharmacokinetics of VOXZOGO has not been evaluated. No dosage adjustment is needed for patients with eGFR = 60 mL/min/1.73 m2 . VOXZOGO is not recommended for patients with eGFR < 60 mL/min/1.73 m2 .