BRIEF DETAILS

PATISIRAN -(Aug 2018)

Indn-      To treat the polyneuropathy of heridirary transthreetin-mediated                                            amyloididsis in adult patients                                                                                                                                               

Comp-   Lipid Complex Injection: 10 mg/5 mL (2 mg/mL) in a single-dose vial                   • For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg

ADR-

CI-  None

WARNINGS -

­ • 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

Pat Inform

-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 .

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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

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

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.

enous 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.

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.

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.

 USE IN SPECIFIC POPULATIONS

1. 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.

In the US rural ral 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-  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

In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG2000-CDMG) were present in milk.

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

4.Geriatric use-                                                                                                  Pharmacology (12.3)]. 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.

5.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. 

6. 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