TEGSEDI

Clinical safety rating: caution

Comprehensive clinical and safety monograph for TEGSEDI (TEGSEDI).

How it works

TEGSEDI (inotersen) is an antisense oligonucleotide that binds to transthyretin (TTR) mRNA, reducing translation of both mutant and wild-type TTR protein, thereby decreasing amyloid deposition.

What the body does with it

Metabolism	Metabolized by exonucleases via hydrolysis to shorter oligonucleotides; not a substrate for CYP450 enzymes.
Excretion	Primarily metabolized by endonucleases and exonucleases with subsequent excretion; renal elimination of oligonucleotide metabolites is minor (<4% unchanged in urine). Biliary/fecal elimination is minimal.
Half-life	Terminal elimination half-life approximately 32 weeks (range 24-40 weeks) due to prolonged tissue retention in target organs (liver); supports monthly subcutaneous dosing.
Protein binding	Highly bound (>99%) to plasma proteins, predominantly albumin and low-density lipoproteins.
Volume of Distribution	Volume of distribution approximately 130 L/kg, indicating extensive tissue distribution (liver, pancreas, kidneys) with slow redistribution.
Bioavailability	Subcutaneous: approximately 70-80%.
Onset of Action	Subcutaneous: Reduction in serum transthyretin (TTR) levels observed within 4 weeks; maximal reduction achieved by 12-24 weeks.
Duration of Action	Duration of TTR suppression persists for several weeks after last dose; clinical effect (slowing neuropathy progression) is maintained with continuous monthly dosing.

Classification & Brands

Dosing & administration

284 mg subcutaneously once weekly on the same day of the week.

Dosage form	SOLUTION
Renal impairment	No dose adjustment recommended for mild to moderate renal impairment. Insufficient data for severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease.
Liver impairment	No dose adjustment recommended for mild hepatic impairment (Child-Pugh A). Not studied in moderate or severe hepatic impairment (Child-Pugh B or C).
Pediatric use	Safety and efficacy not established in pediatric patients.
Geriatric use	No specific dose adjustment recommended based on age; consider renal function and comorbidities.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for TEGSEDI (TEGSEDI).

Breastfeeding	No data on presence in human milk, effects on breastfed infant, or milk production; M/P ratio unknown. Consider developmental and health benefits of breastfeeding, mother's clinical need for TEGSEDI, and any potential adverse effects on breastfed infant.
Teratogenic Risk	No human data available; in animal studies, subcutaneous administration of inotersen during organogenesis at doses up to 13 times the human dose resulted in increased embryofetal mortality and malformations (cardiovascular, skeletal). Avoid use in pregnancy unless benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

WARNING: THROMBOCYTOPENIA and GLOMERULONEPHRITIS. Inotersen can cause severe thrombocytopenia and glomerulonephritis (including rapidly progressive glomerulonephritis), which may lead to renal failure. Monitoring is required; only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Platelet count less than 100 x 10^9/L at baseline","History of rapidly progressive glomerulonephritis or kidney transplant due to glomerulonephritis"]

Clinical Precautions

Precautions

["Thrombocytopenia: monitor platelet count every 2 weeks","Glomerulonephritis: monitor urine protein, serum creatinine, and urinalysis every 4 weeks","Hypersensitivity reactions","Vitamin A deficiency (TTR is a carrier for retinol-binding protein; supplementation may be needed)"]

Clinical Tips & Counseling

Drug interactions

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TEGSEDI

Clinical safety rating: caution

Comprehensive clinical and safety monograph for TEGSEDI (TEGSEDI).

How it works

TEGSEDI (inotersen) is an antisense oligonucleotide that binds to transthyretin (TTR) mRNA, reducing translation of both mutant and wild-type TTR protein, thereby decreasing amyloid deposition.

What the body does with it

Metabolism	Metabolized by exonucleases via hydrolysis to shorter oligonucleotides; not a substrate for CYP450 enzymes.
Excretion	Primarily metabolized by endonucleases and exonucleases with subsequent excretion; renal elimination of oligonucleotide metabolites is minor (<4% unchanged in urine). Biliary/fecal elimination is minimal.
Half-life	Terminal elimination half-life approximately 32 weeks (range 24-40 weeks) due to prolonged tissue retention in target organs (liver); supports monthly subcutaneous dosing.
Protein binding	Highly bound (>99%) to plasma proteins, predominantly albumin and low-density lipoproteins.
Volume of Distribution	Volume of distribution approximately 130 L/kg, indicating extensive tissue distribution (liver, pancreas, kidneys) with slow redistribution.
Bioavailability	Subcutaneous: approximately 70-80%.
Onset of Action	Subcutaneous: Reduction in serum transthyretin (TTR) levels observed within 4 weeks; maximal reduction achieved by 12-24 weeks.
Duration of Action	Duration of TTR suppression persists for several weeks after last dose; clinical effect (slowing neuropathy progression) is maintained with continuous monthly dosing.

Classification & Brands

Dosing & administration

284 mg subcutaneously once weekly on the same day of the week.

Dosage form	SOLUTION
Renal impairment	No dose adjustment recommended for mild to moderate renal impairment. Insufficient data for severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease.
Liver impairment	No dose adjustment recommended for mild hepatic impairment (Child-Pugh A). Not studied in moderate or severe hepatic impairment (Child-Pugh B or C).
Pediatric use	Safety and efficacy not established in pediatric patients.
Geriatric use	No specific dose adjustment recommended based on age; consider renal function and comorbidities.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for TEGSEDI (TEGSEDI).

Breastfeeding	No data on presence in human milk, effects on breastfed infant, or milk production; M/P ratio unknown. Consider developmental and health benefits of breastfeeding, mother's clinical need for TEGSEDI, and any potential adverse effects on breastfed infant.
Teratogenic Risk	No human data available; in animal studies, subcutaneous administration of inotersen during organogenesis at doses up to 13 times the human dose resulted in increased embryofetal mortality and malformations (cardiovascular, skeletal). Avoid use in pregnancy unless benefit outweighs risk.

Warnings & precautions

■ FDA Black Box Warning

Side Effect Profile

Serious Effects

Absolute Contraindications

["Platelet count less than 100 x 10^9/L at baseline","History of rapidly progressive glomerulonephritis or kidney transplant due to glomerulonephritis"]