U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  44

 ADVERSE REACTIONS-

­ The most common adverse reaction (reported in =20% of patients) is injection site reactions. 

CONTRAINDICATIONS-                                                                                                             • None. 

 DOSAGE FORMS AND STRENGTHS-

• Injection: 94.5 mg/0.5 mL in a single-dose vial. 

STORAGE AND HANDLING

 OXLUMO is a clear, colorless-to-yellow solution available in single-dose vials of 94.5 mg/0.5 mL in cartons containing one vial (NDC 71336-1002-1).

 Storage and Handling-                                                                                                             Store at 2°C to 25°C [36°F to 77°F]. Store OXLUMO in its original container until ready for use.

Manufactured for:                                                                                                                       Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142 Manufactured by: Vetter Pharma-Fertigung GmbH & Co. KG, Eisenbahnstrasse 2-4, 88085 Langenargen, Germany

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                                     Lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference.

2. Pharmacodynamics-                                                                                                         The pharmacodynamic effects of OXLUMO have been evaluated in adult and pediatric patients with PH1 across a range of doses and dosing frequency.

Cardiac Electrophysiology-                                                                                                       At the recommended dose, OXLUMO does not lead to clinically relevant QT interval prolongation.

3. Pharmacokinetics-                                                                                                                    The pharmacokinetic (PK) properties of OXLUMO were evaluated following administration of single and multiple dosages in patients with PH1

 Pharmacokinetic Parameters of Lumasiran-                                                                   Lumasiran- General Information Steady-State Exposure Cmax [Median (Range)] 462 (38.5 to 1500) ng/mL AUC0-last [Median (Range)] 6810 (2890 to 10700) ng?h/mL

Dose Proportionality

• Lumasiran exhibited an approximately dose proportional increase in plasma exposure following single subcutaneous doses ranging from 0.3 to 6 mg/kg.

• Lumasiran exhibited time-independent pharmacokinetics with multiple doses of 1 and 3 mg/kg once monthly or 3 mg/kg quarterly.

Accumulation •                                                                                                                        No accumulation of lumasiran was observed in plasma after repeated monthly or quarterly dosing.

Absorption-                                                                                                                          Tmax [Median (Range)] 4 (0.5 to 12) hours

Distribution-                                                                                                                               a Estimated Vd/F 4.9 L Protein Binding 85%

Elimination-                                                                                                                                   Half-Life (Mean (%CV)]) 5.2 (47%) hours Estimated CL/F 26.5 L/hour Metabolism

Primary Pathway Lumasiran is metabolized by endo­ and exonucleases to oligonucleotides of shorter lengths.

Excretion-                                                                                                                                   Primary Pathway Less than 26% of the administered dose of lumasiran is excreted unchanged into the urine within 24 hours with the rest excreted as inactive metabolite. a

Specific Populations-                                                                                                             No clinically significant differences in the pharmacokinetics or pharmacodynamics of lumasiran were observed based on age (4 months to < 65 years old), sex, race/ethnicity, eGFR 30 to < 90 mL/min/1.73 m2, or mild to moderate hepatic impairment (total bilirubin = ULN and AST > ULN; or total bilirubin = 3× ULN).

Body Weight In children <20 kg, lumasiran Cmax was twice as high due to the higher 6 mg/kg dose and faster absorption rate. At the approved recommended dosage, lumasiran AUC was similar across the 6.2 kg to 110 kg body weight range.

Drug Interaction Studies-                                                                                                       Clinical Studies-                                                                                                                     No clinical studies evaluating the drug interaction potential of lumasiran have been conducted. Concomitant use of pyridoxine (vitamin B6) did not influence the pharmacodynamics or pharmacokinetics of lumasiran.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                              There are no available data with the use of OXLUMO in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The estimated background risk of major birth defects and miscarriage in 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 are no data on the presence of OXLUMO in human milk, the effects on the breastfed child, or the effects of the drug on milk production.

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

3.Pediatric Use-                                                                                                                        The safety and effectiveness of OXLUMO have been established in pediatric patients aged birth and older.

4.Geriatric Use-                                                                                                                   Clinical studies of OXLUMO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

5.Hepatic Impairment-                                                                                                            No dose adjustment is recommended for patients with mild (total bilirubin > upper limit of normal (ULN) to 1.5 × ULN or AST > ULN) or moderate hepatic impairment (total bilirubin >1.5–3 × ULN with any AST).

6.Renal Impairment- No dose adjustment is necessary in patients with an estimated glomerular filtration rate (eGFR) of =30 mL/min/1.73 m2