Dosing & Uses
Dosage Forms & Strengths
injectable solution
- 284mg/1.5mL single-dose prefilled syringe
Hereditary Transthyretin Amyloidosis
Indicated for polyneuropathy of hereditary transthyretin amyloidosis (hATTR-PN) in adults
284 mg SC once weekly; administer on the same day each week
Dosage Modifications
Platelets
- Do not initiate if <100x 10^9/L
- If signs or symptoms of thrombocytopenia develop, obtain platelet count as soon as possible, and hold dosing until platelet count is confirmed; recheck platelet count as soon as possible if a platelet measurement is uninterpretable
Platelet count ≥100x 10^9/L
- Monitor weekly
- Continue to dose weekly
Platelet count ≥75 to <100 x 10^9/L
- Monitor weekly
- Stop treatment; may resume if platelet count >100
Platelet count ≥50 to <75x 10^9/L
- Monitor twice weekly until 3 successive values >75, then weekly
- Stop treatment; may resume after 3 successive values >100 and the benefit of inotersen outweighs thrombocytopenia risk
Platelet count ≥25 to <50x 10^9/L
- Monitor twice weekly until 3 successive values >75, then weekly
- Stop treatment; may resume after 3 successive values >100 and the benefit of inotersen outweighs thrombocytopenia risk
- Corticosteroids recommended
- Consider discontinuation of any antiplatelet agents or anticoagulants
Platelet count <25x 10^9/L
- Monitor daily until 2 successive values >25, then twice weekly until 3 successive values >75, then weekly until stable
- Stop treatment
- Corticosteroids recommended
- Consider discontinuation of any antiplatelet agents or anticoagulants
UPCR or eGFR
- Urine protein to creatinine ratio (UPCR) ≥1000 mg/g or eGFR <45 mL/min/1.73 m²: Hold dosing pending further evaluation
- Once eGFR ≥45 mL/minute/1.73 m², UPCR <1000 mg/g, or the underlying cause of the decline in renal function is corrected, may resume weekly dosing
- UPCR ≥2000 mg/g: Perform further evaluation for acute glomerulonephritis, as clinically indicated
- If acute glomerulonephritis confirmed, permanently discontinue
Renal impairment
- Mild-to-moderate (eGFR ≥30 to <90 mL/min/1.73 m²): No dose adjustment required
- Severe or end-stage renal disease: Not studied
Hepatic impairment
- Mild: No dose adjustment required
- Moderate-to-severe: Not studied
Dosing Considerations
Laboratory assessment
- Also see Black Box Warnings
- Before initiating: Measure platelet count, serum creatinine, eGFR, UPCR, ALT, AST, and total bilirubin, and perform urinalysis
- After initiating: Monitor platelet count, serum creatinine, eGFR, urinalysis, UPCR, ALT, AST, and total bilirubin during treatment and for 8 weeks after discontinuing
- Monitor ALT, AST, and total bilirubin q4months
- Monitor serum creatinine, eGFR, urinalysis, and UPCR q2weeks
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (2)
- voclosporin
voclosporin, inotersen. Either increases toxicity of the other by nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. Coadministration with drugs associated with nephrotoxicity may increase the risk for acute and/or chronic nephrotoxicity.
- warfarin
inotersen increases effects of warfarin by anticoagulation. Use Caution/Monitor.
Minor (0)
Adverse Effects
>10%
Injection site reactions (49%)
Nausea (31%)
Headache (26%)
Fatigue (25%)
Thrombocytopenia (24%)
Fever (20%)
Peripheral edema (19%)
Chills (18%)
Anemia (17%)
Vomiting (15%)
Myalgia (15%)
Decreased renal function (14%)
Arrhythmia (13%)
Arthralgia (13%)
Presyncope or syncope (13%)
1-10%
Decreased appetite (10%)
Paresthesia (10%)
Dyspnea (9%)
Elevated liver function test (9%)
Orthostasis (8%)
Influenzalike illness (8%)
Contusion (7%)
Bacterial infection (7%)
Eosinophilia (5%)
Dry mouth (5%)
Warnings
Black Box Warnings
Thrombocytopenia
- Reductions in platelet count may result in sudden and unpredictable thrombocytopenia, which can be life-threatening
- One clinical trial patient died from intracranial hemorrhage
- Contraindicated in patients with a platelet count <100x 10^9/L
- Obtain a platelet count before initiating drug
- During treatment, monitor platelet counts weekly if values are ≥75x 10^9/L, and more frequently if values are <75x 10^9/L
- If signs or symptoms of thrombocytopenia develop, obtain a platelet count as soon as possible; hold dosing until platelet count is determined to be interpretable and acceptable by a medical professional
- Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are <100x 10^9/L, to verify that platelet counts remain >75x 10^9/L
Glomerulonephritis
- Inotersen can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure
- One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis dependent
- In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection
- Should generally not be initiated in patients with UPCR ≥1000 mg/g
- Before initiating drug, measure serum creatinine, eGFR, UPCR, and perform urinalysis
- During treatment, monitor serum creatinine, eGFR, urinalysis, and UPCR q2weeks
- Do not administer to patients who develop UPCR ≥1000 mg/g or eGFR <45 mL/minute/1.73 m², pending further evaluation of the cause
- If dose held, may reinitiate weekly dosing once eGFR increases to ≥45 mL/minute/1.73 m², UPCR decreases to <1000 mg/g, or the underlying cause of the decline in renal function is corrected
- If UPCR ≥2000 mg/g, perform further evaluation for acute glomerulonephritis, as clinically indicated; if confirmed, permanently discontinue inotersen
REMS program
- Owing to risks of serious bleeding caused by severe thrombocytopenia and glomerulonephritis, both of which require frequent monitoring, inotersen is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS)
Contraindications
Platelet count <100x 10^9/L
History of acute glomerulonephritis caused by inotersen
Hypersensitivity
Cautions
Causes platelet count reduction that may result in sudden and unpredictable thrombocytopenia that can be life-threatening; monitoring required
Uninterpretable platelet counts may occur owing to platelet clumping that occurs between antiplatelet antibodies and EDTA; if EDTA-mediated platelet clumping suspected, repeat platelet count using a different anticoagulant (eg, sodium citrate, heparin) in the blood collection tube
Can cause glomerulonephritis that may result in dialysis-dependent renal failure; monitoring required; treatment for glomerulonephritis is immunosuppressive therapy; avoid use in patients for whom immunosuppressive treatment is not advised
Prescribers must be certified to prescribe inotersen by enrolling in and completing the REMS training program; patients must enroll in the program and comply with ongoing monitoring requirements
May cause stroke and cervicocephalic arterial dissection (rare) within 2 days of the first dose; patients may also have symptoms of cytokine release (eg, nausea, vomiting, muscular pain, weakness) and a high-sensitivity C-reactive protein level >100 mg/L during this time
Vitamin A levels may decrease; supplementation with recommended daily allowance advised; refer to ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occurs (eg, night blindness)
Inflammatory and immune effects
- May cause inflammatory and immune changes, including immune thrombocytopenia, glomerulonephritis, or rarely, antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis
- One patient developed gait changes that progressed over 6 months to paraparesis, in the absence of radiologic evidence of spinal cord compression
- Another patient developed progressive lumbar pain, weight loss, headache, vomiting, and impaired speech 7 months after starting inotersen; CSF analysis findings included elevated protein, lymphocyte-predominant pleocytosis, and testing that was negative for infection; recovery occurred after empiric therapy (ie, high-dose steroids, antibiotics) and the patient resumed inotersen without recurrence of symptoms
- The liver accumulates antisense oligonucleotides; monitor ALT, AST, and total bilirubin
- Cases of liver transplant rejection reported 2-4 months after starting therapy in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting therapy; patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of therapy; in patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly; discontinue therapy in patients who develop signs of liver transplant rejection
- Hypersensitivity may occur; discontinue treatment and do not reinitiate
Drug interaction overview
- Owing to thrombocytopenia risk, caution if inotersen is coadministered with antiplatelets or anticoagulants
- Caution if coadministered with other drugs that may impair renal function
Pregnancy
Pregnancy
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to drug during pregnancy; health care providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling: 1-877-465-7510, emailing: tegsedipregnancy@ubc.com, or visiting online at www.tegsedipregnancystudy.com
There are no available data regarding use in pregnant women
Inotersen treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking inotersen; vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects
Effects on the fetus of maternal serum transthyretin (TTR) reduction caused by inotersen and vitamin A supplementation are unknown
Animal studies
- In animal studies, SC administration of inotersen to pregnant rabbits resulted in premature delivery and reduced fetal body weight
Lactation
Unknown if distributed in human milk
The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin (TTR) mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues
In patients with ATTR, TTR builds up as fibrils in tissues (eg, peripheral nerves, heart, GI system, eyes, kidneys, CNS, thyroid, bone marrow); the presence of TTR fibrils interferes with the normal functions of these tissues
Absorption
Peak plasma time: 2-4 hr
Peak plasma concentration: 6.39 mcg/mL
Trough plasma concentration: 0.034 mcg/mL
AUC: 90 mcg·hr/mL
Distribution
Protein bound: >94%
Vd: 293 L
Metabolism
Metabolized by nucleases to nucleotides of various lengths
Elimination
Half-life: 32.3 days
Total body clearance: 3.18 L/hr
Excretion: Urine <1% (unchanged)
Administration
SC Preparation
Remove from refrigerator at least 30 minutes before administration to reach room temperature; do not use other warming methods (eg, water bath, microwave)
Inspect visually for particulate matter and discoloration before administration; solution should appear colorless to pale yellow
SC Administration
For SC injection only
Administer first injection by the patient or caregiver under the guidance of an appropriately qualified healthcare professional; train patients and/or caregivers SC administration
Injection SC in abdomen, upper thigh region, or outer area of upper arm; injection in upper arm should be administered by person other than the patient
Rotate injection sites
Avoid injection at the waistline and other sites where pressure or rubbing from clothing may occur
Do not inject into areas of skin disease or injury; also avoid tattoos and scars
Use each syringe only once
Missed dose
- Instruct patient to take missed dose as soon as possible, unless next scheduled dose is within 2 days
- If next dose within 2 days, direct patient to skip the missed dose and take the next scheduled dose on the scheduled day
Storage
Store refrigerated at 2-8°C (36-46°F) in the original container
Do not freeze
Can be kept at room temperature (not to exceed 30°C [86°F]) in the original container for up to 6 weeks; if not used within the 6 weeks, discard
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