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TEGSEDI (inotersen) injection

Inotersen is an antisense oligonucleotide (ASO) inhibitor of human transthyretin (TTR) protein synthesis. TEGSEDI contains inotersen sodium as the active ingredient. Inotersen sodium is a white to pale yellow solid and it is freely soluble in water and in phosphate buffer (pH 7.5 to 8.5). The chemical name of inotersen sodium is DNA, d(P-thio)([2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]rG-G-T-T-A-m5C-A-T-G-A-A-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rC). The molecular formula of inotersen sodium is C₂₃₀H₂₉9N₆₉ Na₁₉O₁₂₁P₁₉S₁₉and the molecular weight is 7600.73 Da.

The molecular formula of inotersen free base is C₂₃₀H₃₁₈N₆₉O₁₂₁P₁₉S₁₉ and its molecular weight is 7183.08.

TEGSEDI is a sterile, preservative-free, aqueous solution for subcutaneous injection. It is supplied in a prefilled syringe (PFS). Each PFS contains 1.5 mL of solution containing 284 mg inotersen (equivalent to 300 mg inotersen sodium salt) TEGSEDI is formulated in Water for Injection and may include hydrochloric acid and/or sodium hydroxide for pH adjustment to 7.5-8.5.

INDICATIONS AND USAGE

TEGSEDI is indicated for the treatment of the polyneuropathy of hereditary transthyretinmediated amyloidosis in adults.

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.

DOSAGE AND ADMINISTRATION

The recommended dose of TEGSEDI is 284 mg injected subcutaneously once weekly.

For consistency of dosing, patients should be instructed to give the injection on the same day every week.

If a dose is missed, patients should be instructed to take the missed dose as soon as possible, unless the next scheduled dose is within 2 days. In this situation, the patient should be directed to skip the missed dose and take the next scheduled dose on the scheduled day.

Administration

TEGSEDI is intended for subcutaneous use only.
The first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified healthcare professional. Patients and/or caregivers should be trained in the subcutaneous administration of TEGSEDI in accordance with the

Instructions for Use.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Sites for injection include the abdomen, upper thigh region, or outer area of the upper arm. It is important to rotate sites for injection.

– If injected in the upper arm, the injection should be administered by a person other than the patient.

– Injection should be avoided at the waistline and other sites where pressure or rubbing from clothing may occur.

– TEGSEDI should not be injected into areas of skin disease or injury.

– Tattoos and scars should also be avoided.

TEGSEDI prefilled syringe should be allowed to reach room temperature prior to injection.

– Remove from refrigerated storage at least 30 minutes prior to use.

– Other warming methods should not be used.

Use each prefilled syringe only once.

Assessment Prior to Initiating TEGSEDI

Measure platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and perform urinalysis prior to treatment with TEGSEDI and as directed following treatment initiation.

Laboratory Testing and Monitoring to Assess Safety after Initiating TEGSEDI

Monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during treatment with TEGSEDI, and for 8 weeks following discontinuation of treatment.

Platelet Count

Do not initiate TEGSEDI in patients with a platelet count less than 100 x 10⁹/L.

Recommendations for platelet monitoring frequency and TEGSEDI dosing are specified in Table 1. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable (e.g., clumped sample).

Table 1: TEGSEDI Monitoring and Treatment Recommendations for Platelet Count

Platelet count (x10⁹/L)	Monitoring Frequency	Dosing
At least 100	Weekly	Continue to dose weekly.
At least 75 to less than 100	Weekly	Stop treatment. Do not restart unless platelet count is greater than 100.
At least 50 to less than 75	Twice weekly until 3 successive values above 75; then weekly monitoring.	Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding.
At least 25 to less than 50*	Twice weekly until 3 successive values above 75; then weekly monitoring. Consider more frequent monitoring if additional risk factors for bleeding are present.#	Stop treatment. Do not restart TEGSEDI in patients with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of TEGSEDI outweighs the risk of thrombocytopenia and potential bleeding. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants.
Less than 25*†	Daily until 2 successive values above 25. Then monitor twice weekly until 3 successive values above 75. Then weekly monitoring until stable.	Stop TEGSEDI. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants.

* It is strongly recommended that, unless the patient has a medical contraindication to receiving glucocorticoids, the patient receive glucocorticoid therapy to reverse the platelet decline.

# Additional risk factors for bleeding include age >60 years, receiving anticoagulant or antiplatelet medicinal products, or prior history of major bleeding events.

†Patients who discontinue therapy with TEGSEDI because of platelet counts below 25 x109/L should not reinitiate therapy.

CONTRAINDICATIONS

TEGSEDI is contraindicated in patients with:

Platelet count below 100 x 10⁹/L.
History of acute glomerulonephritis caused by TEGSEDI
History of a hypersensitivity reaction to TEGSEDI

WARNINGS AND PRECAUTIONS

Thrombocytopenia: TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia that can be life-threatening.

Glomerulonephritis and Renal Toxicity: TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. Cases of glomerulonephritis were accompanied by nephrotic syndrome. Possible complications of nephrotic syndrome can include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection. TEGSEDI-treated patients who develop glomerulonephritis will require monitoring and treatment for nephrotic syndrome and its manifestations.

Stroke and Cervicocephalic Arterial Dissection: TEGSEDI may cause stroke and cervicocephalic arterial dissection.

Inflammatory and Immune Effects: Inflammatory and immune changes are an effect of some antisense oligonucleotide drugs, including TEGSEDI. In clinical studies, serious inflammatory and immune adverse reactions occurred in TEGSEDI-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis.

Liver Injury: The liver is a site of accumulation of antisense oligonucleotides. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin at baseline and every four months during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with TEGSEDI, as appropriate.

Hypersensitivity Reactions/Antibody Formation: TEGSEDI can cause hypersensitivity reactions. In clinical studies, 6 of 161 (4%) TEGSEDItreated patients stopped treatment because of a hypersensitivity reaction. Antibodies to TEGSEDI were present when the reactions occurred. These reactions generally occurred within 2 hours of administration of TEGSEDI and included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms.

If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI, and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reaction to TEGSEDI.

Reduced Serum Vitamin A Levels and Recommended Supplementation: TEGSEDI treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking TEGSEDI. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with TEGSEDI, as serum vitamin A levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

DRUG INTERACTIONS

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

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: There are no data on the developmental risk associated with the use of TEGSEDI 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.

Lactation: 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.

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

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.

Renal Impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m²). TEGSEDI has not been studied in patients with severe renal impairment or end-stage renal disease.

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.

TEGSEDI (inotersen) injection

TEGSEDI (inotersen) injection