A 2′-O-methoxyethyl modified antisense oligonucleotide called inotersen (Tegsedi) lowers transthyretin synthesis. In initial hereditary transthyretin amyloidosis polyneuropathy, it has recently been shown to lessen nerve degeneration and, as a result, enhance the quality of life.

Inotersen (Tegsedi) Uses:

• Amyloidosis-mediated polyneuropathy caused by inherited transthyretin: 

  • Treatment of hereditary Amyloi's polyneuropathy caused by transthyretin

Inotersen (Tegsedi) Use in Adults:

Treatment of polyneuropathy caused by familial transthyretin-mediated amyloidosis with inotersen (Tegsedi) dosage

• 284 mg once a week as a sub-Q

• Missed doses:

  • If you miss a dosage, take it as soon as you can.
  • Neglect the skipped dose and take the next dose on the planned day if the following dose is due in less than two days.

Use in children:

Not Indicated.

Pregnancy Risk Category: N (Not assigned)

• Certain adverse effects were observed in animal reproduction trials.
• Vitamin A concentrations must be high enough for embryonic development; inotersen reduces serum vitamin A levels.
• Effective contraception should be recommended for females with reproductive potential and males who have female partners. (Benson 2018, p.

Use of Inotersen during breastfeeding

• If inotersen is present in breast milk is unknown.
• The company advises balancing the advantages of treatment for the mother against the dangers of drug exposure for your child.

Inotersen (Tegsedi) Dose in Kidney Disease:

• Renal impairment prior to treatment initiation:

  • eGFR 30 mL/min/1.73 m2: No dose modification is required. 
  • There are no dosage changes specified in the manufacturer's labeling for eGFR less than 30 mL/minute/1.73 m2 (which has not been studied).

• Renal toxicity during treatment:

  • eGFR of 45 mL/min/1.73 m2 or urine protein to creatinine ratio (UPCR) of 1,000 mg/g
    • Delay starting therapy while the cause is being looked into.
    • Once the underlying cause is cured or eGFR reaches 45 mL/min/1.73 m2 and UPCR reaches 1,000 mg/g, 284 mg once a week can be restarted.

Note: If acute glomerulonephritis and a UPCR of less than 2,000 mg/g are verified, therapy should be completely stopped.

Inotersen (Tegsedi) Dose in Liver disease:

• Before treatment begins, hepatic impairment

  • Mild impairment
    • There is no need to change the dosage.
  • Moderate to severe impairment
    • The labeling provided by the manufacturer does not mention dose adjustments. There has been no testing.

• Treatment for Hepatotoxicity

  • Patients with signs or symptoms of hepatic impairment should have their serum transaminases or total bilirubin checked. If necessary, care should be stopped or interrupted.
  • Patients undergoing liver transplants should be treated for rejection immediately.

Common Side Effects of Inotersen (Tegsedi):

• Cardiovascular:

  • Peripheral Edema
  • Cardiac Arrhythmia
  • Presyncope
  • Syncope

• Central Nervous System:

  • Headache
  • Fatigue
  • Chills
  • Paresthesia

• Gastrointestinal:

  • Nausea

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Anemia

• Immunologic:

  • Antibody Development

• Local:

  • Injection Site Reaction

• Neuromuscular & Skeletal:

  • Myalgia
  • Arthralgia

• Renal:

  • Renal Insufficiency

• Miscellaneous:

  • Fever

Less Common Side Effects of Inotersen (Tegsedi):

• Cardiovascular:

  • Orthostatic hypotension

• Gastrointestinal:

  • Decreased appetite
  • Xerostomia

• Hematologic & oncologic:

  • Bruise
  • Eosinophilia

• Hepatic:

  • Increased liver enzymes

• Infection:

  • Increased serum alanine aminotransferase
  • Bacterial infection

• Renal:

  • Glomerulonephritis

• Respiratory:

  • Dyspnea
  • Flu-like symptoms

Frequency not defined:

• Endocrine & metabolic:

  • Vitamin A deficiency

Contraindications to Inotersen (Tegsedi):

• Intolerance of inotersen or any ingredient in the formulation
• Platelet count less than 100,000/mm3
• History of inotersen-related acute glomerulonephritis

Labeling in Canada: more signs against (not in US labeling) Before therapy:

• The ratio of creatinine to urine protein: 113 mg/mol (1 g/mol)

• eGFR 45mL/min/1.73m2

• Serious liver damage

Warnings and Precautions

• Cerebrovascular:

  • Within two days of the initial dose, stroke and cervicocephalic arterial dissection are possible side effects.
  • Patients should be instructed to notify their doctor if they notice any symptoms that could indicate a stroke or arterial dissection.

• Glomerulonephritis: [US Boxed Warning]:

  • It may develop glomerulonephritis, which may call for immunosuppressive treatment and result in renal failure requiring dialysis.
  • Patients who have a UPCR of 1,000 mg/g or above should not start using the medication.
  • Measure the serum creatinine, the eGFR, the UPCR, and the urinalysis results before you start.
  • Every two weeks, while you're receiving treatment, check your serum creatinine, eGFR, urinalysis, and UPCR levels.
  • Patients who develop a UPCR of 1,000 mg/g or more or an eGFR < 45 mL/minute/1.73 m2 should not be given Inotersen while the cause is still being looked into.
  • If a dose is held, weekly dosing may be resumed if the underlying cause of the reduction in renal function is treated, eGFR rises to 45 mL/minute/1.73 m2, and UPCR falls to below 1,000 mg/g, or both.
  • One clinical trial participant with glomerulonephritis who did not get immunosuppressive treatment continued to require dialysis.
  • Perform an additional evaluation for acute glomerulonephritis in individuals with UPCR of 2,000 mg/g or greater, as clinically warranted.
  • Immediately stop treatment if acute glomerulonephritis is identified.
  • In patients receiving nephrotoxic treatment and other medications that could harm renal function concurrently, exercise caution.
  • Nephrotic syndrome frequently accompanied cases of glomerulonephritis (may include edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection).
  • Since immunosuppressive medicine is often used to treat glomerulonephritis, it should be avoided in patients for whom it is not advised.

• Hepatic effects:

  • Abnormal LFTs, including increased ALT ≥3 times ULN, have been reported; liver laboratory anomalies can resolve with continued use.
  • It may also cause Immune-mediated biliary disease.
  • During treatment, check the grades of ALT, AST, and total bilirubin at baseline and then every 4 months after that.
  • If patients exhibit signs or symptoms of hepatic dysfunction, treatment should be stopped or discontinued, and serum transaminases and total bilirubin levels should be checked.

• Hypersensitivity reactions:

  • There have been hypersensitivity reactions.
  • Symptoms often appear within two hours of injection and may include flushing, chest discomfort, hypertension, chills, dysphagia, eosinophilia, choreiform involuntary movements, headache, arthralgia, myalgia, palmar erythema, and flu-like symptoms.
  • During clinical studies, patients who experienced hypersensitivity reactions also had anti-inotersen antibodies.
  • Stop using if a hypersensitivity reaction happens; patients who have experienced hypersensitivity reactions shouldn't receive further treatment.

• Inflammatory and immune effects:

  • There have been reports of severe immunological and inflammatory side effects, including as immune thrombocytopenia, glomerulonephritis, and antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis.
  • Rare but severe neurological adverse reactions, including paraparesis and impaired speech, have also occurred.

• Thrombocytopenia: [US Boxed Warning]:

  • It results in potentially fatal acute and unpredictable thrombocytopenia.
  • A cerebral hemorrhage caused the death of one clinical study participant.
  • Get a platelet count before starting treatment.
  • Patients with a platelet count under 100,000/mm3 should not take it.
  • If platelet counts are 75,000 or more/mm3, check them weekly; if they are less than 75,000/mm3, check them more regularly.
  • Get a platelet count as soon as you can if a patient shows symptoms or signs of thrombocytopenia; therapy shouldn't continue until the platelet count is satisfactory based on an interpretable blood sample.
  • For around 8 weeks after therapy ends, keep an eye on your platelet count to make sure it stays above 75,000/mm3.
  • Use with caution in patients receiving antiplatelet or anticoagulation therapy; if the platelet count falls below 50,000/mm3, consider stopping antiplatelet or anticoagulation therapy.
  • Avoid inotersen therapy in patients for whom corticosteroid medication is not recommended; corticosteroid therapy is advised in patients with a platelet count of 50,000/mm3 and in patients with probable immune-mediated thrombocytopenia.
  • If thrombocytopenia symptoms manifest, patients should be advised to contact their doctor.

• Vitamin A levels:

  • The amount of serum vitamin A may decline as a result of the medication.
  • During treatment, take vitamin A supplements at the recommended dietary amount (RDA).
  • Since serum vitamin A levels do not represent the overall amount of vitamin A in the body, do not administer amounts above the RDA.
  • It is advised to see an ophthalmologist if ocular symptoms like night blindness appear.

Inotersen: Drug Interaction

Monitoring parameters:

• Monitor platelet count at baseline and for eight weeks (or more if they remain below 100,000/mm3) after treatment is ended.
• Urinalysis:
  • After therapy has stopped, continue to be monitored every two weeks at baseline and for an additional eight weeks.
• AST, ALT, total Bilirubin
  • Every four months at baseline and for eight weeks following treatment cessation, observe. Monitor liver transplant patients at baseline every 4 months during treatment and for 8 weeks after discontinuation.

How to administer Inotersen (Tegsedi)?

SubQ

• It should be administered every week on the same date.
• Allow the prefilled syringes to reach room temperature for about 30 minutes before administering.
• You can inject it yourself in your upper thigh or abdomen. Only a caregiver should apply treatment to the upper arm.
• The waistline and other regions where clothing pressure or friction may occur should not be treated.
• After each surgery, switch up the injection sites.
• Do not apply anything to the skin that can lead to an infection or disease.

The way that Inotersen (Tegsedi) works is as follows:

Inotersen, an antisense oligonucleotide, binds to TTR mRNA and degrades both wild-type and mutant TTR DNA mRNAs. As a result, tissue TTR protein deposits form and serum TTR protein levels fall.

Absorption:

• Rapid

Protein binding:

• >94%

Metabolism:

• Metabolized by nucleases to nucleotides of various lengths

Half-life elimination:

• 32.3 days (range: 29.4 to 35.5 days)

Time to peak:

• 2 to 4 hours (median)

Excretion:

• Urine (<1% as unchanged drug)

International Brands of Inotersen:

• Tegsedi

Inotersen Brand Names in Pakistan:

No Brands Available in Pakistan.