Inotersen - Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Inotersen is indicated for the treatment of polyneuropathy in hereditary transthyretin amyloidosis (hATTR). It reduces transthyretin (TTR) protein production, which forms amyloid deposits in various tissues, including nerves. Approved by the US FDA (United States Food and Drug Administration) on October 5, 2018, Inotersen has demonstrated efficacy in improving neuropathy symptoms and quality of life in clinical trials. It is administered weekly through subcutaneous injection and is generally well-tolerated, although monitoring for potential side effects is recommended.

Drug Group

Inotersen belongs to a drug group known as antisense oligonucleotides (ASOs). These drugs work by targeting specific RNA sequences to interfere with protein production, in this case, targeting transthyretin (TTR) mRNA to reduce the production of abnormal transthyretin protein implicated in conditions like hereditary ATTR (transthyretin amyloidosis).

Indications

Inotersen is indicated for treating polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis.

Dosage Forms and Available Strengths

Injection: 284 mg (milligrams) per 1.5 mL (milliliter) clear, colorless to pale yellow solution in a single-dose prefilled syringe.

For Patients

What Is the Polyneuropathy of Hereditary ATTR Amyloidosis?

The polyneuropathy of hereditary ATTR amyloidosis involves nerve damage due to abnormal protein buildup from mutated transthyretin genes. This leads to symptoms like numbness, tingling, weakness, and pain in the limbs, which significantly impact daily life. Treatment focuses on stabilizing or reducing transthyretin levels to manage symptoms and slow disease progression.

How Does the Inotersen Work?

Inotersen works by binding to the transthyretin gene's messenger RNA (mRNA), reducing the production of abnormal transthyretin protein associated with hereditary transthyretin-mediated amyloidosis. This lowers disease progression.

What Are the Clinical Uses of the Inotersen?

Inotersen is specifically used for treating polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. This condition is characterized by the buildup of amyloid fibrils in different organs and tissues, leading to progressive nerve damage.

What Is the Dosage of the Inotersen?

The recommended dosage is 284 mg, given as a weekly subcutaneous (beneath the skin) injection. Laboratory tests like complete blood count (CBC), liver function tests (LFTs), renal function tests, and specific biomarkers relevant to the therapy must be measured before starting treatment, should continue to be monitored after starting treatment, and should be monitored for eight weeks following the discontinuation of therapy, as directed.

How Are Inotersen Administered?

Administration

• Inotersen is for subcutaneous use only.

• A medical practitioner should supervise the administration of the initial injection. Patients and caregivers should be trained in the subcutaneous administration of Inotersen.

• Inspect the drug for particles and discoloration before use.

• Rotate injection sites between the abdomen, upper thigh, and outer upper arm. Avoid injecting at the waistline, areas of skin disease or injury, tattoos, and scars. If injected in the upper arm, another person should administer it.

• Take the prefilled syringe out of the refrigerator at least half an hour before using it to allow it to get to room temperature. Do not use other warming methods.

• Use each prefilled syringe only once.

Pre-Treatment Assessment

• Before starting Inotersen, measure platelet count, serum creatinine, eGFR (estimated glomerular filtration rate), UPCR (urine protein-to-creatinine ratio), ALT (alanine aminotransferase), AST (aspartate aminotransferase), and total bilirubin, and perform urinalysis.

• Monitor platelet count, serum creatinine, eGFR, urinalysis, UPCR, ALT, AST, and total bilirubin during treatment and for eight weeks after stopping Inotersen.

Platelet Count Monitoring

• Do not start Inotersen if the platelet count is less than 100 x 10^9/L (liter).

• Follow specific monitoring and dosing recommendations based on platelet count.

Renal Monitoring

• Do not start Inotersen if UPCR is 1000 mg/g (milligrams per gram) or higher.

• Monitor serum creatinine, eGFR, urinalysis, and UPCR every two weeks.

• Hold Inotersen if UPCR is 1000 mg/g or higher or eGFR is below 45 mL/min/1.73 m² (milliliters per minute per square meter).

Liver Tests

• Monitor ALT, AST, and total bilirubin every four months during treatment.

What Are the Side Effects of Inotersen?

Inotersen can cause serious side effects, including:

1. Low Platelet Counts (Thrombocytopenia): Inotersen can lower the number of platelets in the blood, which can happen at any time during treatment. Platelets help blood clot, and if the count is too low, there could be severe bleeding that might be life-threatening, which can further result in:

• Unusual bruising or tiny reddish-purple spots, often on the lower legs.

• Bleeding from minor cuts that do not stop or keep oozing.

• Bleeding from the gums or nose.

• Blood in urine or stools.

• Bleeding in the whites of the eyes.

• Sudden, severe headaches or neck stiffness.

• Vomiting or coughing up blood.

• Abnormal or heavy menstrual periods.

2. Kidney Inflammation (Glomerulonephritis): Inotersen can cause the kidneys to stop working correctly, leading to severe kidney damage and possibly kidney failure that requires dialysis.

Contact the doctor immediately if one notices.

• Swelling in the face, feet, or hands.

• Development or worsening of shortness of breath and coughing.

• Blood in urine or brown-colored urine.

• Foamy urine.

• Passing less urine than usual.

Due to the risks of serious bleeding from low platelet counts and kidney problems, Inotersen is only available through a unique program called the Inotersen Risk Evaluation and Mitigation Strategy (REMS) Program. Healthcare providers should be consulted about enrolling in the REMS Program.

What Are the Things to Inform the Doctor Before Taking Inotersen?

Before starting Inotersen, inform the healthcare provider about all health issues, including:

• History of bleeding problems.

• History of kidney problems.

• History of liver transplants.

• Pregnancy or plans to become pregnant (unknown effects on unborn baby).

• Breastfeeding or plans to breastfeed (unknown effects on baby through breast milk).

• Also, disclose all medications taken, including prescriptions, over-the-counter (OTC) medicines, vitamins, and herbal supplements. Specifically, mention using vitamin A or beta-carotene supplements, blood thinners (anticoagulants), or medications affecting blood clotting.

Dietary Considerations

None, unless specified by the healthcare provider.

Missed Dose

In case of a missed dose of Inotersen:

• Take the dose as soon as one remembers unless the next scheduled dose is within two days.

• Ignore the dose one skipped and proceed with the regular dosing schedule.

• Contact a healthcare provider for guidance on managing missed doses and necessary adjustments to the treatment plan.

Overdose

In case of an overdose with Inotersen, immediate medical attention is crucial. Contact a healthcare provider or local poison control center right away.

Storage and Handling

Inotersen is a clear, colorless to pale yellow solution in a prefilled syringe with a safety needle shield device (SSD). It contains 284 mg of Inotersen (equivalent to 300 mg of Inotersen sodium salt) in 1.5 mL and comes in cartons of one or four syringes.

Storage: Keep refrigerated at two to eight degrees Celsius (36 to 46 degrees Fahrenheit) in the original container, shielded from light. Avoid freezing. It can be stored in the original container at room temperature (up to 30°C [86°F]) for up to six weeks. Let the syringe equilibrate to room temperature for 30 minutes before use, avoiding temperatures above 30°C (86°F).

Disposal: Inotersen should be disposed of carefully to prevent accidental ingestion and environmental harm. Unused or expired medication must not be flushed down the toilet. Instead, follow local guidelines for safe disposal, which might entail taking it back to the drugstore or using an FDA-drug take-back program. If disposing at home, secure the medication in a sealable bag and consider mixing it with an unappealing substance before placing it in the trash.

For Doctors

Chemical Taxonomy

Inotersen is an ASO antisense oligonucleotide that inhibits human transthyretin (TTR) protein synthesis. The Inotersen structure contains Inotersen sodium as its active ingredient. This white to pale yellow solid is freely soluble in water and phosphate buffer (pH 7.5 to 8.5).

• Chemical Name: Inotersen sodium.

• Molecular Formula: C₂₃₀H₂₉₉N₆₉Na₁₉O₁₂₁P₁₉S₁₉.

• Molecular Weight: 7600.73 Da (Dalton's).

Warnings and Precautions

1. Thrombocytopenia

• Inotersen and Platelet Count Reduction: Inotersen can significantly reduce platelet counts, potentially leading to sudden and life-threatening thrombocytopenia. In study 1, 25 percent of Inotersen-treated patients experienced platelet counts below 100 x 10^9/L, compared to two percent of placebo patients. Furthermore, 14 percent of Inotersen-treated patients had platelet counts below 75 x 10^9/L, whereas no placebo patients did. Among those with baseline platelet counts below 200 x 10^9/L, 39 percent experienced a nadir count below 75 x 10^9/L, compared to six percent with 200 x 10^9/L or higher baseline counts.

• Severe Thrombocytopenia Incidents: Three Inotersen-treated patients (three percent) developed severe thrombocytopenia (platelet count below 25 x 10^9/L), leading to potentially fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. One clinical trial patient succumbed to a fatal intracranial hemorrhage. All three patients with severe thrombocytopenia exhibited treatment-emergent antiplatelet IgG antibodies, with two experiencing platelet clumping that delayed diagnosis and treatment due to uninterpretable measurements.

• Monitoring and Dosing Guidelines: Inotersen should not be started in patients with platelet counts below 100 x 10^9/L. Following recommended monitoring and treatment protocols is crucial. If signs or symptoms of thrombocytopenia arise, promptly obtain a platelet count and suspend Inotersen until an acceptable count is verified.

• Concurrent Medications: When Inotersen uses antiplatelet drugs or anticoagulants, be aware of increased bleeding risk from thrombocytopenia. Consider discontinuing these drugs if the platelet count drops below 50 x 10^9/L.

• Symptoms of Thrombocytopenia: Symptoms include unusual or prolonged bleeding, petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, abnormal menstrual bleeding, hematemesis, hematuria, hematochezia, melena, neck stiffness, and severe headaches.

• Severe Thrombocytopenia Treatment: Glucocorticoid therapy is strongly recommended for individuals with platelet counts below 50 x 10^9/L or suspected immune-mediated thrombocytopenia. Avoid Inotersen if glucocorticoid treatment is contraindicated.

2. Glomerulonephritis and Renal Toxicity

• Renal Complications: Inotersen can induce glomerulonephritis, potentially leading to dialysis-dependent renal failure. In study 1, three percent of Inotersen-treated patients developed glomerulonephritis versus none on placebo. Immunosuppressive treatment was necessary, and one untreated patient remained dialysis-dependent.

• Nephrotic Syndrome: Glomerulonephritis cases were often accompanied by nephrotic syndrome, leading to complications like edema, hypercoagulability, and infection susceptibility. Monitor and treat Inotersen-treated patients who develop nephrotic syndrome.

• Monitoring Renal Parameters: Follow recommended guidelines for monitoring renal parameters. Inotersen should generally not be started in patients with a UPCR of 1000 mg/g or greater. If acute glomerulonephritis is confirmed, stop Inotersen.

3. Stroke and Cervicocephalic Arterial Dissection

• Inotersen may cause stroke and cervicocephalic arterial dissection. In clinical studies, one Inotersen-treated patient experienced carotid artery dissection and stroke. Educate patients about the symptoms of these conditions and instruct them to seek help immediately if they occur.

4. Inflammatory and Immune Effects

• Inotersen can cause serious inflammatory and immune adverse reactions, including immune thrombocytopenia, glomerulonephritis, and ANCA-positive systemic vasculitis. Neurologic adverse severe reactions have also been reported.

5. Liver Effects

• Inotersen treatment can lead to increased alanine aminotransferase (ALT) levels. Monitor ALT, aspartate aminotransferase (AST), and total bilirubin at baseline and during treatment. Interrupt or discontinue Inotersen if signs of hepatic dysfunction appear.

6. Hypersensitivity Reactions

• Inotersen can cause hypersensitivity reactions, including headache, chest pain, hypertension, chills, flushing, and flu-like symptoms. If a hypersensitivity reaction occurs, stop using Inotersen immediately and begin appropriate treatment. Do not use Inotersen in patients with hypersensitivity to the drug.

7. Uninterpretable Platelet Counts

• EDTA Reaction: Platelet clumping, caused by a reaction between antiplatelet antibodies and EDTA (ethylenediaminetetraacetic acid), can result in uninterpretable platelet counts. If EDTA-mediated platelet clumping is suspected, perform a repeat platelet count using a different anticoagulant.

• Reduced Serum Vitamin A Levels

• Supplementation: Inotersen treatment reduces serum vitamin A levels. Patients should take vitamin A at the recommended daily allowance. Higher doses are not advised, as they do not reflect the total body vitamin A levels.

8. Inotersen REMS Program

• Restricted Access: Due to serious bleeding risks from severe thrombocytopenia and glomerulonephritis, Inotersen is available only through the Inotersen REMS Program. Requirements include prescriber certification, patient enrollment and monitoring, and pharmacy certification.

What Are the Pharmacological Actions of Inotersen?

• Pharmacodynamics: The pharmacodynamic effects of Inotersen were studied in hATTR amyloidosis patients receiving 284 mg weekly via subcutaneous injection. Over 65 weeks of treatment, serum TTR levels decreased by 68 to 74 percent (median: 75 to 79 percent), independent of TTR mutation, sex, age, or race. Reductions in serum retinol-binding protein and vitamin A were also noted, with mean decreases of 71 and 63 percent, respectively, at Week 65. Studies on cardiac electrophysiology showed no significant QTc prolongation in healthy volunteers, but 5.4 percent of Inotersen-treated patients experienced QRS prolongation (more than 160 ms and more than 25 percent above baseline) compared to 1.7 percent on placebo in a 66-week trial.

• Mechanism of Action: Inotersen, an antisense oligonucleotide, binds to TTR mRNA, leading to mutant and wild-type TTR mRNA degradation. The Inotersen mechanism of action reduces serum TTR protein levels and diminishes TTR protein deposits in tissues.

• Pharmacokinetics: Inotersen's systemic exposure increases dose-proportionally from 150 to 400 mg of Inotersen sodium salt. At the recommended weekly dose of 284 mg, a steady state is reached in about three months. Steady-state peak concentrations (Cmax), trough concentrations (Ctrough), and area under the curve (AUCτ) are 6.39 (5.65, 7.20) µg/mL, 0.034 (0.031, 0.038) µg/mL, and 90 (82.4, 97.4) µg·h/mL, respectively. It is rapidly absorbed, highly bound to plasma proteins (more than 94 percent), and primarily metabolized with a half-life of 32.3 (29.4, 35.5) days. Inotersen's pharmacokinetics are not affected by age, race, sex, mild or moderate renal impairment, or mild hepatic impairment.

Toxicity:

In carcinogenicity studies with Inotersen, no increase in tumors was observed in transgenic mice after 26 weeks of weekly subcutaneous administration at varying doses (0, 10, 30, or 80 mg/kg). In genotoxicity tests, Inotersen showed no mutagenic effects in bacterial assays or chromosomal aberrations in Chinese hamster lung cells, and it did not induce micronuclei in mouse bone marrow. In fertility studies, Inotersen administration did not adversely affect fertility in male and female mice given doses (0, 3, 15, or 25 mg/kg) every other day before mating and during organogenesis.

What Are the Contraindications of Inotersen?

Inotersen is contraindicated in patients with:

• A platelet count of less than 100 x 10^9/L.

• A history of acute glomerulonephritis caused by Inotersen.

• A history of a hypersensitivity reaction.

Drug Interactions of Inotersen:

Caution is advised when using antiplatelet drugs (for example, Adenosine, Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine), anticoagulants (for example, Heparin, Warfarin), or medications that affect platelets (for example, Aspirin, NSAIDs) with Inotersen due to the risk of thrombocytopenia. Similarly, nephrotoxic drugs and those that may impair renal function should be used cautiously with Inotersen to avoid potential complications such as glomerulonephritis and renal toxicity.

Clinical Studies

Inotersen's efficacy was proven in a 65-week clinical trial involving adult patients with polyneuropathy due to hATTR amyloidosis. Patients received either Inotersen (284 mg Inotersen) or placebo weekly subcutaneous injections. Seventy-seven percent of Inotersen-treated patients and 87 percent of placebo patients completed the trial. The neurological symptoms improved by evaluating the disease progression parameters through standardized and quantitative assessments (mNIS+7 and QoL-DN). These improvements were consistent across all patient subgroups.

Use in Specific Populations

• Use in Pregnancy: Developmental risks in pregnancy are unknown. It decreases serum vitamin A levels, requiring supplementation. Excessive vitamin A is linked to adverse effects, but there are no adverse effects in mice, premature delivery, and reduced fetal weight in high-dose rabbits.

• Lactation: The presence of human milk and its effects on infants are unknown. Excretion is observed in lactating mice (animal studies).

• Pediatric Use: The use of the drug in children needs to be established.

• Geriatric Use: No differences in pharmacokinetics or effectiveness were noted in patients aged 65 and over, but an increased risk of specific adverse reactions is possible.

• Renal Impairment: No dose adjustment is needed for mild to moderate impairment (eGFR ≥30 to <90 mL/min/1.73m²). Data are lacking for severe impairment.

• Hepatic Impairment: No dose adjustment is needed for mild impairment. Data for other degrees of hepatic impairment needs to be included.