Drug Interaction Studies-                                                                                                      No formal clinical drug interaction studies have been performed. The components of ONPATTRO are not inhibitors or inducers of cytochrome P450 enzymes or transporters.

Patisiran is not a substrate of cytochrome P450 enzymes. In a population pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not impact the pharmacokinetic parameters of patisiran.

ONPATTRO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes.

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  28

ADVERSE REACTIONS-

The most frequently reported adverse reactions (that occurred in at least 10% of ONPATTRO-treated patients and at least 3% more frequently than on placebo) were upper respiratory tract infections and infusion-related reactions

CONTRAINDICATIONS-                                                                                                       None

WARNINGS AND PRECAUTIONS-

• Infusion-related reactions:                                                                                               Monitor for signs and symptoms during infusion. Slow or interrupt the infusion if clinically indicated. Discontinue the infusion if a serious or life-threatening infusion-related reaction occurs

 • Reduced serum vitamin A levels and recommended supplementation:                    Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur.

HOW SUPPLIED/STORAGE AND HANDLING-

1 How Supplied-                                                                                                                 ONPATTRO is a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for intravenous infusion supplied as a 10 mg/5 mL (2 mg/mL) solution in a single-dose glass vial.

The vial stopper is not made with natural rubber latex.

ONPATTRO is available in cartons containing one single-dose vial each.

2 Storage and Handling-                                                                                                      Store at 2°C to 8°C (36°F to 46°F).                                                                                      Do not freeze.                                                                                                                      Discard vial if it has been frozen.

 If refrigeration is not available, ONPATTRO can be stored at room temperature up to 25°C (up to 77°F) for up to 14 days.

 For storage conditions of ONPATTRO after dilution in the infusion bag.

 PATIENT COUNSELING INFORMATION-

Infusion-Related Reactions-                                                                                              Inform patients about the signs and symptoms of infusion-related reactions (e.g., flushing, dyspnea, chest pain, rash, increased heart rate, facial edema).       

 Advise patients to contact their healthcare provider immediately if they experience signs and symptoms of infusion-related reactions.

Recommended Vitamin A Supplementation-                                                                   Inform patients that ONPATTRO treatment leads to a decrease in vitamin A levels measured in the serum.

Instruct patients to take the recommended daily allowance of vitamin A.

 Advise patients to contact their healthcare provider if they experience ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness) and refer them to an ophthalmologist if they develop these symptoms.

Pregnancy-                                                                                                                           Instruct patients that if they are pregnant or plan to become pregnant while taking ONPATTRO they should inform their healthcare provider. Advise female patients of childbearing potential of the potential risk to the fetus .

Manufactured for:  Alnylam Pharmaceuticals, Inc. 300 Third Street, Cambridge, MA 02142                                                                                                                               By: Ajinomoto Althea, Inc. 11040 Roselle Street, San Diego, CA 92121

CLINICAL PHARMACOLOGY-

1. Mechanism of Action-                                                                                                     Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

2. Pharmacodynamics-                                                                                                      The pharmacodynamic effects of ONPATTRO were evaluated in hATTR amyloidosis patients treated with 0.3 mg/kg ONPATTRO via intravenous infusion once every 3 weeks.

 Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose. With repeat dosing every 3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively.

3. Pharmacokinetics-                                                                                                        Following a single intravenous administration, systemic exposure to patisiran increases in a linear and dose-proportional manner over the range of 0.01 to 0.5 mg/kg. Greater than 95% of patisiran in the circulation is associated with the lipid complex.

At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks of treatment. The estimated mean ± SD steady state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCt) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg·h/mL, respectively.

Distribution-                                                                                                                     Plasma protein binding of ONPATTRO is low, with =2.1% binding observed in vitro with human serum albumin and human a1-acid glycoprotein.

 ONPATTRO distributes primarily to the liver. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, the mean ± SD steady state volume of distribution of patisiran (Vss) was 0.26 ± 0.20 L/kg.

Elimination-                                                                                                                   The terminal elimination half-life (mean ± SD) of patisiran is 3.2 ± 1.8 days. Patisiran is mainly cleared through metabolism, and the total body clearance (mean ± SD) at steady state (CLss) is 3.0 ± 2.5 mL/h/kg.

 Metabolism-                                                                                                                       Patisiran is metabolized by nucleases to nucleotides of various lengths.

Excretion-                                                                                                                             Less than 1% of the administered dose of patisiran is excreted unchanged into urine.

Specific Populations-                                                                                                        Age, race (non-Caucasian vs. Caucasian), and sex had no impact on the steady state pharmacokinetics of patisiran or TTR reduction.

 Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment (eGFR =30 to <90 mL/min/1.73m2) or mild hepatic impairment (bilirubin =1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN) on patisiran exposure or TTR reduction.

ONPATTRO has not been studied in patients with severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver transplant.

Drug Interaction Studies-                                                                                               No formal clinical drug interaction studies have been performed. The components of ONPATTRO are not inhibitors or inducers of cytochrome P450 enzymes or transporters.

Patisiran is not a substrate of cytochrome P450 enzymes. In a population pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not impact the pharmacokinetic parameters of patisiran. ONPATTRO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes.

USE IN SPECIFIC POPULATIONS-

Pregnancy-                                                                                                                           Risk Summary There are no available data on ONPATTRO use in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

 ONPATTRO treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking ONPATTRO. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects.

The effects on the fetus of a reduction in maternal serum TTR caused by ONPATTRO and of vitamin A supplementation are unknown.           

 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. The background risk of major birth defects and miscarriage for the indicated population is unknown.

2. Lactation-                                                                                                                        Risk Summary -There is no information regarding the presence of ONPATTRO in human milk, the effects on the breastfed infant, or the effects on milk production.

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

4. Pediatric Use-                                                                                                                 Safety and effectiveness in pediatric patients have not been established.

5. Geriatric Use-                                                                                                                    No dose adjustment is required in patients =65 years old                                                   A total of 62 patients =65 years of age, including 9 patients =75 years of age, received ONPATTRO in the placebo-controlled study. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

6. Hepatic Impairment-                                                                                                       No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin =1 x ULN and AST >1 x ULN, or bilirubin >1.0 to 1.5 x ULN)

 ONPATTRO has not been studied in patients with moderate or severe hepatic impairment.        

7. Renal Impairment-                                                                                                          No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] =30 to <90 mL/min/1.73m2).

ONPATTRO has not been studied in patients with severe renal impairment or end-stage renal disease.