DRUG INTERACTIONS-                                                                                                                                                                                                                                      1.Antiplatelet Drugs or Anticoagulant Medications-                                                        Because of the risk of thrombocytopenia, caution should be used when using antiplatelet drugs (e.g., adenosine, clopidogrel, prasugrel, ticagrelor, or ticlopidine), including non-prescription products that affect platelets (e.g., aspirin, nonsteroidal anti-inflammatory drugs), or anticoagulants (e.g., heparin, warfarin), concomitantly with TEGSEDI      

 2.Nephrotoxic Drugs -                                                                                                       Because of the risk of glomerulonephritis and renal toxicity, caution should be used when using nephrotoxic drugs and other drugs that may impair renal function concomitantly with TEGSEDI          

BRIEF SUMMARY

IONTERSEN- (Oct 2018)

Indn-          to treat polyneuropathy of heriditary  transthyretin- mediated amyloidosis in adults

Comp-       Injection: 284 mg/ 1.5 mL in a single-dose prefilled syringe                       * The recommended dosage is 284 mg administered by subcutaneous injection once weekly.                                                                                                                                 * Laboratory tests must be measured prior to treatment, continue to be monitored after treatment initiation, and for 8 weeks following discontinuation of treatment, as directed

Pat Infrm-

Thrombocytopenia-                                                                                                             Inform patients that can cause reductions in platelet count that may result in thrombocytopenia. Instruct patients to notify a healthcare provider immediately if they show symptoms of thrombocytopenia (e.g., unusual or prolonged bleeding, neck stiffness, or atypical severe headache). Advise patients of the importance of monitoring during treatment 

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  45

  ADVERS E REACTIONS-

The most common adverse reactions (those that occurred in at least 20% of TEGSEDI-treated patients and more frequently than on placebo) were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever

 CONTRAINDICATIONS-

* Platelet count less than 100 x 109 /L                                                                                  * History of acute glomerulonephritis caused by TEGSEDI *                                              * Patients with a history of a hypersensitivity reaction to TEGSEDI

 WARNINGS AND PRECAUTIONS-

* Stroke and Cervicocephalic Arterial Dissection: These adverse events occurred within 2 days of first dose and with symptoms of cytokine release. Educate patients on  symptoms of stroke and central nervous system arterial dissection.                                                                                                                                                          * Inflammatory and Immune Effects: Serious neurologic adverse reactions consistent with inflammatory and immune effects occurred.                                                                                                                                                                                                            * Liver Effects: Monitor alanine amino transferase, aspartate aminotransferase, and total bilirubin every 4 months during treatment and in case of symptoms of hepatic dysfunction.                                                                                                                                                                                                                                              *Hypersensitivity Reactions:If these occur, discontinue and initiate appropriate therapy.                                                                                                                                                                                                                                                 * Uninterpretable Platelet Counts: Reaction between Antiplatelet Antibodies and ethylenediaminetetra-acetic acid: Platelet clumping can cause uninterpretable platelet measurement; repeat test if this is suspected.                                                                                                                                                                                                     * 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-

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

Thrombocytopenia-                                                                                                             Inform patients that TEGSEDI can cause reductions in platelet count that may result in thrombocytopenia. Instruct patients to notify a healthcare provider immediately if they show symptoms of thrombocytopenia (e.g., unusual or prolonged bleeding, neck stiffness, or atypical severe headache). Advise patients of the importance of monitoring during treatment with TEGSEDI

 Also instruct patients to notify their healthcare provider of all medications, including over-the-counter, that they are taking.

Glomerulonephritis and Renal Toxicity-                                                                            Inform patients that glomerulonephritis has occurred in patients treated with TEGSEDI.                                                                                                                                     Advise patients of the importance of monitoring of urine protein to creatinine ratio (UPCR during treatment with TEGSEDI.                                                                                                                                                                                                              TEGSEDI REMS Program TEGSEDI is available only through a restricted program called the TEGSEDI REMS Program.

 Inform the patient of the following notable requirements:                                                    i. Patients must enroll in the program and comply with ongoing monitoring requirements  ii TEGSEDI is available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.                                                                                                   

 Stroke and Cervicocephalic Arterial Dissection -                                                           Educate patient on symptoms of stroke and central nervous system arterial dissection and instruct them to seek help as soon as possible if symptoms of these or other serious neurologic adverse reactions occur.                                                                                                                                                                                                                                   Liver Effects-                                                                                                                 Instruct patients to inform a healthcare professional of symptoms suggestive of hepatic dysfunction that occur after administration of TEGSEDI.                                                                                                                                                                         Hypersensitivity-                                                                                                                 Instruct patients to inform a healthcare professional of symptoms suggestive of hypersensitivity that occur after administration of TEGSEDI.                                                                                                                 

Recommended Vitamin A Supplementation-                                                                Inform patients that TEGSEDI 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.                                                                                                                            

 Administration Instructions-                                                                                              Train patients and caregivers on proper subcutaneous administration technique and how to use the single-dose prefilled syringe. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use TEGSEDI.

Pregnancy -                                                                                                                        Instruct patients that if they are pregnant or plan to become pregnant while taking TEGSEDI they should inform their healthcare provider. Advise female patients of childbearing potential of the potential risk to the fetus.                                                                                                                                                                                                 For more information about TEGSEDI, go to www.TEGSEDIREMS.com or call 1-844-483- 4736.

Distributed by: Ionis Pharmaceuticals, Inc. Carlsbad, CA 92010 TEGSEDI is a trademark of Ionis Pharmaceuticals, Inc.

CLINICAL PHARMACOLOGY-

1.Mechanism of Action-                                                                                                    Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

2. Pharmacodynamics-                                                                                                       The pharmacodynamic effects of TEGSEDI were evaluated in hATTR amyloidosis patients treated with 284 mg TEGSEDI via subcutaneous injection once weekly. With repeat dosing, the mean percent decreases from baseline in serum TTR from Week 13 to Week 65 of treatment ranged from 68% to 74% (median range: 75% to 79%).

Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race. Reference ID: 4330796 18 Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood.

3. Pharmacokinetics-                                                                                                           Following subcutaneous administration, systemic exposure to inotersen increase in a doseproportional manner over the range of 150-400 mg of inotersen sodium salt. At the recommended TEGSEDI dosing regimen of 284 mg every week, steady state is reached after approximately 3 months.

The estimated geometric mean (90% confidence interval) steady state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCt) were 6.39 (5.65, 7.20) µg/mL, 0.034 (0.031, 0.038) µg/mL, and 90 (82.4, 97.4) µg·h/mL, respectively. Plasma Cmax and AUC do not exhibit accumulation at steady state.

Absorption-                                                                                                                       Following subcutaneous administration, TEGSEDI is absorbed rapidly into systemic circulation in a dose-dependent fashion, with the median time to maximum plasma concentrations (Cmax) of 2 to 4 hours.

Distribution-                                                                                                                        TEGSEDI is highly bound to human plasma proteins (>94%) and the fraction bound is independent of drug concentration.

  Elimination-                                                                                                                       The terminal elimination half-life (mean and 90% confidence interval) for TEGSEDI is 32.3 (29.4, 35.5) days. Inotersen is mainly cleared through metabolism, and the total body clearance (mean and 90% confidence interval) is 3.18 (3.08, 3.29) L/h.

 Metabolism-                                                                                                                         Inotersen is metabolized by nucleases to nucleotides of various lengths. Excretion Less than 1% of the administered dose of inotersen is excreted unchanged into urine within 24 hours.

 Specific Populations-                                                                                                          Age, race, and sex had no impact on the steady state pharmacokinetics of inotersen or TTR reduction. Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal impairment

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary -

There are no data on the developmental risk associated with the use of TEGSEDI use in pregnant women. TEGSEDI treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking TEGSEDI.

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 TEGSEDI 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 2-4% and 15-20%, 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 TEGSEDI in human milk, the effects on the breast-fed infant, or the effects on milk production. A study in lactating mice has shown excretion of inotersen in milk.

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

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

4.Geriatric Use-                                                                                                                   Clinical studies of TEGSEDI included 69 patients (45%) aged 65 and over. No differences in pharmacokinetics or effectiveness were observed between these patients and younger patients. Patients 65 years and older may be at increased risk of certain adverse reactions, such as congestive heart failure, chills, myalgia, and extremity pain.

5.Renal Impairment-                                                                                                             No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate.

6.Hepatic Impairment-                                                                                                         No dose adjustment is necessary in patients with mild hepatic impairment.TEGSEDI has not been studied in patients with other degrees of hepatic impairment.