inotersen

General

**REMS Drug**

Pronunciation:
in-oh-ter-sen

Trade Name(s)

Tegsedi

Ther. Class.

none assigned

Pharm. Class.

antisense oligonucleotides

Indications

Treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis.

Action

Acts as an antisense oligonucleotide that binds to and causes degradation of mutant and wild-type human transthyretin (TTR) mRNA, which subsequently results in a reduction of serum TTR protein and TTR protein deposits in tissues.

Therapeutic Effect(s):

Reduction in impairment from neuropathy and improved quality of life.

Pharmacokinetics

Absorption: Rapidly absorbed following SUBQ administration.

Distribution: Extensively distributed to tissues.

Protein Binding: >94%.

Metabolism and Excretion: Metabolized by nucleases to nucleotides of various lengths; primarily excreted in urine (<1% as unchanged drug).

Half-life: 32.3 days

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
SUBQ	unknown	2–4 hr	unknown

Contraindication/Precautions

Contraindicated in:

Hypersensitivity
Platelet count <100 × 10⁹ /L
History of acute glomerulonephritis due to inotersen
Severe proteinuria (urine protein to creatinine ratio >1000 mg/g)
Patients who are not candidates for immunosuppressive therapy
Liver transplant recipients (↑ risk of rejection)
Severe renal impairment or end-stage renal disease
Moderate or severe hepatic impairment.

Use Cautiously in:

OB: Safety not established in pregnancy
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant
Pedi: Safety and effectiveness not established in children
Geri: Older adults may be at ↑ risk of adverse reactions.

Adverse Reactions/Side Effects

CV: atrial fibrillation/flutter, bradycardia, peripheral edema, syncope, tachycardia

GI: nausea, vomiting, dry mouth, ↑ liver enzymes

GU: ↑ serum creatinine, proteinuria, glomerulonephritis, renal failure

Hemat: BLEEDING, THROMBOCYTOPENIA, anemia, eosinophilia

Local: injection site reactions

Metabolic: ↓ appetite

MS: arthralgia, myalgia

Neuro: paresthesia, CAROTID ARTERY DISSECTION, STROKE, fatigue, headache

Resp: dyspnea

Misc: chills, fever, hypersensitivity reactions, ↓ vitamin A concentrations

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

↑ risk of bleeding with antiplatelet agents (including aspirin, clopidogrel, prasugrel, or ticagrelor ), anticoagulants (including apixaban, dabigatran, edoxaban, heparin, rivaroxaban, or warfarin ), and NSAIDs ; consider discontinuing these medications if platelet count <50 × 10⁹ /L.
Concurrent use with nephrotoxic drugs may ↑ risk of nephrotoxicity.

Route/Dosage

SUBQ (Adults): 284 mg once weekly.

Availability

Solution for injection (prefilled syringes): 284 mg/1.5 mL

Assessment

Monitor for signs and symptoms of thrombocytopenia (unusual or prolonged bleeding, petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena, stiff neck, atypical severe headache) during therapy.
Monitor for signs and symptoms of liver dysfunction (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) periodically during therapy. If symptoms occur measure AST, ALT, and total bilirubin. Hold or discontinue therapy as needed.

Lab Test Considerations:

Assess platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), ALT, AST, total bilirubin, and urinalysis before starting, during therapy and for 8 wks after discontinuation.

Do not start therapy if platelet count <100 × 10⁹ /L. If platelet count ≥100 x 10⁹ /L, monitor weekly and continue weekly dose. If platelet count ≥75 to <100 × 10⁹ /L, monitor platelet count weekly. Hold inotersen. Do not resume until platelet count >100 × 10⁹ /L. If platelet count ≥50 to <75 × 10⁹ /L, monitor platelet count twice weekly until 3 successive values >75; then monitor weekly. Hold inotersen. Do not restart without 3 successive values >100 and benefit of inotersen outweighs risk of thrombocytopenia and potential bleeding. If platelet count ≥25 to <50 × 10⁹ /L, monitor platelet count twice weekly until 3 successive values >75; then monitor weekly. Consider monitoring more frequently if additional risk factors for bleeding are present. Hold inotersen. Do not restart without 3 successive values >100 and benefit of inotersen outweighs risk of thrombocytopenia and potential bleeding. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants. If platelet count <25 × 10⁹ /L, monitor platelet count daily until 2 successive values >25; then twice weekly until 3 successive values >75; then weekly until stable. Hold inotersen. Add corticosteroids. Consider discontinuation of any antiplatelet agents or anticoagulants. Following discontinuation for any reason, continue to monitor platelet count for 8 wks, or longer if platelet counts are <100 x 10⁹ /L, to verify platelet counts remain >75 × 10⁹ /L. If inotersen discontinued due to platelet count <25 x 10⁹ /L, do not restart therapy.
Do not start inotersen in patients with urine protein to creatinine ratio (UPCR) >1000 mg/g. Monitor serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, and UPCR every 2 weeks during therapy. If UPCR ≥1000 mg/g or eGFR <45 mL/min/1.73 m² , hold inotersen until cause determined. If a dose is held, once eGFR increases to ≥45 mL/min/1.73 m² , UPCR <1000 mg/g, or underlying cause corrected, resume weekly dosing. If UPCR ≥2000 mg/g, evaluate for acute glomerulonephritis. If acute glomerulonephritis confirmed, permanently discontinue inotersen.
Monitor ALT, AST, and total bilirubin every 4 mo during therapy; monitor monthly for patients who received a liver transplant.

Implementation

REMS: Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program, due to risks of serious bleeding caused by severe thrombocytopenia and risk for glomerulonephritis. Prescribers must be certified. Patients must enroll in program and comply with monitoring requirements. Pharmacies must be certified. Information is available at www.TEGSEDIREMS.com or 1-844-483-4736.
May cause decrease in serum Vitamin A. Supplement with RDA of Vitamin A; do not administer higher doses; serum Vitamin A levels do not reflect total Vitamin A in the body.
SUBQ Administer first injection by patient or caregiver under guidance of health care professional. Solution is pale yellow; do not administer solutions that are cloudy, discolored, or contain particulate matter. Inject into abdomen, upper thigh, or outer area of upper arm; rotate sites. Avoid areas of skin disease, injury, tattoos, or scars. Remove from refrigerator 30 min before use to allow solution to reach room temperature; avoid other warming methods.

Patient/Family Teaching

REMS: Instruct patient on proper technique for administration including equipment, storage, discarding of syringes. Explain REMS program requirements to patient. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
Advise patient to notify health care professional immediately if signs and symptoms of thrombocytopenia (unusual bruising or a rash of tiny reddish-purple spots, often on lower legs; bleeding from skin cuts that continue to ooze; bleeding from gums or nose; blood in urine or stools; bleeding into whites of eyes; sudden severe headache; neck stiffness; vomiting or coughing up blood; abnormal or heavy menstrual bleeding, kidney inflammation (puffiness or swelling in face, feet or hands; new onset or worsening shortness of breath; coughing; blood in urine or brown urine; foamy urine; passing less urine than usual), stroke (sudden numbness or weakness, especially on one side of body; severe headache or neck pain; confusion; problems with vision, speech, or balance; droopy eyelids), inflammatory and immune system problems (unexpected change in walking, weakness and spasms in legs; back pain; weight loss; headache; vomiting; problems with speech) liver injury (unexpected nausea and vomiting, stomach pain, being not hungry, yellowing of skin, having dark urine, or hypersensitivity reactions (joint pain, chills, redness on palms, muscle pain, chest pain, flushing, tremor, flu-like symptoms, high BP, difficulty swallowing) occur.
Instruct patients to take recommended daily allowance of vitamin A. Advise patients to contact health care professional ocular symptoms (night blindness).
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, herbal products, especially Vitamin A or beta-carotene supplements or blood thinners.
Rep: Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient of pregnancy exposure registry that monitors pregnancy outcomes in women exposed to inotersen during pregnancy. Register by calling: 1-877-465-7510, emailing: tegsedipregnancy@ubc.com, or visiting online at: www.tegsedipregnancystudy.com.
Emphasize importance of regular lab tests to monitor for side effects.

Evaluation/Desired Outcomes

Reduced impairment from neuropathy and improved quality of life.