Applies to inotersen: subcutaneous solution.

Serious side effects of Inotersen

Along with its needed effects, inotersen may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking inotersen:

More common

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• bruise
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chills
• cough
• decreased frequency or amount of urine
• diarrhea
• difficulty in moving
• dizziness or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, slow, or irregular heartbeat
• fever
• general feeling of discomfort or illness
• headache
• hoarseness
• increased blood pressure
• increased thirst
• joint pain
• loss of appetite
• lower back or side pain
• muscle pain or stiffness
• nausea
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• runny nose
• shivering
• sore throat
• sweating
• swelling of the face, fingers, arms, or lower legs
• tightness of the chest
• trouble breathing
• trouble sleeping
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• weight gain

Less common

• Chest pain
• sores, ulcers, or white spots on the lips or in the mouth
• swollen glands

Other side effects of Inotersen

Some side effects of inotersen may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• swollen joints

Less common

• Dry mouth

For Healthcare Professionals

Applies to inotersen: subcutaneous solution.

General

The more commonly reported adverse reactions have included injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever.^[Ref]

Hematologic

Sudden and unpredictable platelet count reductions have been reported. Three clinical trial patients had sudden and severe thrombocytopenia with platelet counts below 25 x 10(9)/L. One patient died of a fatal intracranial hemorrhage. All 3 of these patients had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. For 2 of these patients, platelet clumping cause by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA) caused a delay in interpretable platelet measurements which delayed diagnosis and treatment.

Very common (10% or more): Thrombocytopenia (24%), anemia (17%)

Common (1% to 10%): Eosinophilia

Renal

Very common (10% or more): Decreased renal function (14%), increased urine protein to creatinine ratio (UPCR; 15%); increased serum creatinine (11%)

Common (1% to 10%): Glomerulonephritis

Frequency not reported: Nephrotic syndrome, tubular proteinuria

Glomerulonephritis was reported in 3 treated patients during clinical trials; glomerulonephritis did not resolve with discontinuation and immunosuppressive therapy was necessary. One patient did not receive immunosuppressive treatment and remained dialysis-dependent.

Nephrotic syndrome was reported as accompanying cases of glomerulonephritis. Tubular proteinuria was reported and attributed to the accumulation of antisense oligonucleotides in the proximal tubule cells of the kidney. UPCR elevations to greater than 5 times the upper limit of normal (5xULN) occurred in 15% of drug treated patients compared to 8% in placebo patients.

Hypersensitivity

Common (1% to 10%): Hypersensitivity reactions

Hypersensitivity reactions have been reported and generally occurred within 2 hours of receiving the drug. Reactions have included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms. Drug antibodies were present when the reactions occurred.

Hepatic

Common (1% to 10%): ALT elevations

Uncommon (0.1% to 1%): Autoimmune hepatitis with primary biliary cirrhosis; biliary obstruction of unclear etiology

Frequency not reported: Immune-mediated biliary disease

ALT elevations to at least 3 times the upper limit of normal (3 x ULN) occurred in 8% of drug-treated patients compare to 3% of placebo patients; 3% of drug-treated patients had an ALT of 8 x ULN compared to 0% of placebo patients. Some patients had resolution of these ALT elevations with continued therapy.

One case of immune-mediated biliary disease was reported and a single case of autoimmune hepatitis with primary biliary cirrhosis in a patient with a family history of primary biliary cirrhosis.

Nervous system

Very common (10% or more): Headache (26%)

Common (1% to 10%): Paresthesia

Uncommon (0.1% to 1%): Carotid artery dissection and stroke; serious neurologic adverse reaction

Neurologic serious reactions consistent with inflammatory and immune effects have occurred. One patient developed a change in gait 2 months after the first dose, it progressed to paraparesis over 6 months. No radiologic evidence of spinal cord compression was found. Another patient developed progressive lumbar pain, weight loss, headache, vomiting, and impaired speech 7 months after starting therapy. Cerebrospinal fluid analysis showed elevated protein, and a lymphocyte-predominant pleocytosis that was negative for infection. This patient recovered after high-dose steroids and antibiotics and resumed therapy.

Immunologic

Bacterial infection includes bacteremia, cellulitis staphylococcal, clostridium difficile infection, conjunctivitis bacterial, cystitis Escherichia, Helicobacter gastritis, Helicobacter infection, Staphylococcal infection.

Anti-drug antibodies were present in 30% of patients after 65 weeks of receiving this drug. As with other measures of anti-drug antibodies, the detection is highly dependent on the sensitivity and specificity of the assay. The assay used measured IgG isotypes only; other isotypes may be possible. Anti-drug antibodies were present in many case of adverse reactions, although the data was too limited to make definitive conclusions about the relationship.

Very common (10% or more): Anti-drug antibodies

Common (1% to 10%): Influenza-like illness, bacterial infection

Frequency not reported: Immune thrombocytopenia, antineutrophil cytoplasmic autoantibody (ANCA) positive systemic vasculitis

Local

Very common (10% or more): Injection site reactions (49%)

Injection site reactions included bruising, erythema, hematoma, hemorrhage, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria. Injection site reactions occurred in 49% of patients receiving this drug compared with 10% of placebo patients.

Musculoskeletal

Very common (10% or more): Myalgia (15%), arthralgia (13%)

Metabolic

Common (1% to 10%): Decreased appetite

Respiratory

Common (1% to 10%): Dyspnea

Other

Very common (10% or more): Fatigue (25%), fever (20%), chills (18%)

Cardiovascular

Very common (10% or more): Peripheral edema (19%), arrhythmia (13%), pre-syncope or syncope (13%)

Common (1% to 10%): Orthostasis

Arrhythmia included arrhythmia, atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, tachycardia, and ventricular extrasystoles.

Dermatologic

Common (1% to 10%): Contusion

Gastrointestinal

Very common (10% or more): Nausea (31%), vomiting (15%)

Common (1% to 10%): Dry mouth