Tegsedi (inotersen sodium)

Dosage of inotersen sodium is expressed in terms of inotersen.

Inotersen is administered by subcutaneous injection only. The injection is administered once weekly (preferably on the same day each week for consistency of dosing).

Inotersen sodium injection is commercially available in single-use prefilled syringes. The prefilled syringes should be stored at 2-8degreesC in the original carton and protected from light until time of use; the drug should not be frozen. If necessary, the prefilled syringes may be stored at room temperature (up to 30degreesC) in the original container for up to 6 weeks; the drug should be discarded if it is not used within this time period. Exposure of inotersen to temperatures above 30degreesC should be avoided.

Inotersen may be self-administered after the patient and/or their caregiver have received appropriate training. The first self-administered injection should be performed under the guidance of an appropriately qualified healthcare professional.

Prior to administration, the prefilled syringe should be allowed to reach room temperature for at least 30 minutes; other warming methods (e.g., microwave, hot water, placement near other heat sources) should not be used. The needle cap should not be removed from the syringe until immediately prior to injection. The solution should be inspected visually prior to administration, and should not be used if any cloudiness, particulate matter, or discoloration is present.

Subcutaneous injections of inotersen should be made into the abdomen (except within 2 inches of the navel), upper thigh, or outer area of the upper arm (by a caregiver). Injection sites should be rotated. Injections should not be made into the waistline or other areas where pressure or rubbing from clothing may occur; injections into areas where the skin is tender, bruised, red, damaged, tattooed, or scarred also should be avoided.

No dosing information is available for this tab.

Formal drug interaction studies have not been conducted to date with inotersen. Inotersen is not a substrate for major cytochrome P-450 (CYP) isoenzymes or transporters. Inotersen also is not an inhibitor or inducer of major CYP isoenzymes and is not an inhibitor of major transporters.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Inotersen/Anticoagulants; Antiplatelets

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with anticoagulants and/or antiplatelet agents may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may also be greater in patients greater than 60 years or have a prior history of major bleeding events. Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving anticoagulants and/or antiplatelet agents.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Monitor platelet count frequently. If platelet count is less than 50, stop inotersen treatment and consider discontinuation of any anticoagulant and/or antiplatelet agents. Monitor for signs and symptoms of thrombocytopenia; such as, 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), neck stiffness, or atypical severe headache.

DISCUSSION: In a clinical study, platelet counts below 100 occurred in 25% of inotersen-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In study 1 and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 had a nadir platelet count below 75, compared to 6% of patients with baseline platelet counts 200 or higher. Three inotersen-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25). One patient experienced a fatal intracranial hemorrhage.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)

Inotersen/Non-Steroidal Anti-Inflammatory Drugs

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia. Inotersen can also cause glomerulonephritis and renal toxicity. NSAIDs can impair thromboxane-dependent platelet aggregation by blocking the formation of thromboxane A2. Concurrent administration with NSAIDs may also result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with NSAIDs may result in additive or synergistic effects, including fatal and non-fatal intracranial hemorrhage, or renal toxicity.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may also be greater in patients greater than 60 years or have a prior history of major bleeding events. Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding. Patients with pre-existing renal impairment.

PATIENT MANAGEMENT: Inotersen should be administered with caution in patients receiving NSAIDs. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Monitor platelet count frequently. If platelet count is less than 50, stop inotersen treatment and consider discontinuation of NSAID. Monitor for signs and symptoms of thrombocytopenia; such as, 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), neck stiffness, or atypical severe headache. Monitor renal function closely.

DISCUSSION: In a clinical study, platelet counts below 100 occurred in 25% of inotersen-treated patients, compared with 2% of patients on placebo. Platelet counts below 75 occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In study 1 and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 had a nadir platelet count below 75, compared to 6% of patients with baseline platelet counts 200 or higher. Three inotersen-treated patients (3%) had sudden severe thrombocytopenia (platelet count below 25). One patient experienced a fatal intracranial hemorrhage.(1) The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents.(1) Inotersen is only available through a Tegsedi REMS program because of the risk of severe thrombocytopenia and the risk of glomerulonephritis.(1)

Inotersen/Selected Nephrotoxic Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen can cause glomerulonephritis and renal toxicity. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment.

PATIENT MANAGEMENT: The US manufacturer of inotersen state that caution should be used when administered concurrently with potentially nephrotoxic agents or agents that impair renal function.(1) If concurrent therapy is warranted, monitor renal function closely.(1)

DISCUSSION: The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents. Inotersen is only available through a Tegsedi REMS program because of the risk of glomerulonephritis and severe thrombocytopenia.(1)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

There are no moderate interactions for this drug.

*Platelet counts <100,000/mm3.

*History of acute glomerulonephritis attributed to inotersen.

*History of hypersensitivity to inotersen or any ingredient in formulation.

• Liver transplant rejection

• Glomerulonephritis
• Thrombocytopenic disorder

There are no moderate contraindications for this drug.

Adverse effects reported in >=20% of patients receiving inotersen and more frequently than with placebo in clinical studies include injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever.

More Frequent

• Hyperbilirubinemia
• Thrombocytopenic disorder

Less Frequent

• Abnormal hepatic function tests
• Anemia
• Bacterial infection
• Cardiac arrhythmia
• Chorea
• Eosinophilia
• Glomerulonephritis
• Hypersensitivity drug reaction
• Hypertension
• Increased alanine transaminase
• Increased aspartate transaminase
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Nephrotic syndrome
• Orthostatic hypotension

Rare or Very Rare

• ANCa-positive vasculitis
• Cerebrovascular accident
• Cervicocephalic arterial dissection
• Clostridioides difficile infection
• Paraplegia

More Frequent

• Fatigue
• Fever
• Headache disorder
• Injection site sequelae
• Nausea
• Vitamin A deficiency

Less Frequent

• Anorexia
• Arthralgia
• Bruising
• Cachexia
• Chest pain
• Chills
• Dysphagia
• Dyspnea
• Flu-like symptoms
• Flushing
• Myalgia
• Palmar rash
• Paresthesia
• Peripheral edema
• Syncope
• Vomiting
• Xerostomia

Rare or Very Rare

• Gait abnormality

No enhanced messaging available.

Safety and efficacy of inotersen have not been established in pediatric patients.

There are no available data on the developmental risks associated with the use of inotersen in pregnant women.

Administration of high doses of inotersen to pregnant rabbits every other day during the period of organogenesis resulted in premature births and reduced fetal body weights at doses associated with maternal toxicity. No adverse developmental effects or effects on fertility were noted when inotersen (or a rodent-specific pharmacologically active surrogate) was administered every other day to male and female mice prior to and during mating and continuing in female mice throughout the period of organogenesis.

A pregnancy registry has been established; encourage patients to enroll by calling 1-877-465-7510, emailing tegsedipregnancy@ubc.com or visiting www.tegsedipregnancystudy.com.

It is not known whether inotersen is distributed into human milk; the drug has been detected in the milk of lactating mice. The effects of inotersen on the breast-fed infant or on milk production are not known. Consider the benefits of breast-feeding and the woman's clinical need for inotersen along with any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

In clinical trials of inotersen, 45% of patients were >=65 years of age. Although no overall differences in efficacy or pharmacokinetics have been observed between geriatric patients and younger adults, the risk of certain adverse effects (e.g., heart failure, chills, myalgia, extremity pain) may be increased in patients >=65 years of age.