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Mipomersen

Pronunciation

(mi poe MER sen)

Index Terms

  • ISIS 301012
  • Mipomersen Sodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Subcutaneous, as sodium [preservative free]:

Kynamro: 200 mg/mL (1 mL)

Brand Names: U.S.

  • Kynamro

Pharmacologic Category

  • Antihyperlipidemic Agent, Apolipoprotein B Antisense Oligonucleotide

Pharmacology

Mipomersen is an oligonucleotide inhibitor of apo B-100 synthesis. ApoB is the main component of LDL-C and very low density lipoprotein (VLDL), which is the precursor to LDL-C. Mipomersen binds to the messenger ribonucleic acid (mRNA) of apoB in a sequence-specific manner which results in degradation (RNase H-mediated) or disruption of the mRNA thereby reducing formation of apoB.

Metabolism

Metabolized in tissues by endonucleases to form shorter oligonucleotides available for further metabolism by exonucleases

Excretion

Urine <4% (24 hours postdose)

Time to Peak

~3 to 4 hours

Half-Life Elimination

~1 to 2 months

Protein Binding

≥90%

Use: Labeled Indications

Homozygous familial hypercholesterolemia: Adjunct to dietary therapy and other lipid-lowering treatments to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH)

Contraindications

Hypersensitivity to mipomersen or any component of the formulation; moderate or severe hepatic impairment (Child-Pugh class B or C); active liver disease; unexplained persistent elevations of hepatic transaminases

Dosing: Adult

Homozygous familial hypercholesterolemia (HoFH): SubQ: 200 mg once weekly. Note: Maximal LDL-C reduction seen after ~6 months.

Missed dose: If dose is missed, administer at least 3 days before the next weekly dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is not recommended in patients with severe renal impairment, clinically significant proteinuria, or receiving hemodialysis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), active liver disease, or unexplained persistent elevations of hepatic transaminases.

Dosing: Adjustment for Toxicity

ALT or AST ≥3 x and <5 x ULN: First, repeat measurement within 1 week to confirm elevation. Once confirmed, withhold mipomersen and obtain additional liver function tests (eg, total bilirubin, alkaline phosphatase, and INR); investigate for probable cause. If resumed when AST or ALT <3 x ULN, monitor liver function tests more frequently.

ALT or AST ≥5 x ULN: Withhold mipomersen and obtain additional liver function tests (eg, total bilirubin, alkaline phosphatase, and INR); investigate for probable cause. If resumed when AST or ALT <3 x ULN, monitor liver function tests more frequently.

Clinical symptoms of liver injury (eg, nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), bilirubin increase ≥2 x ULN, or active liver disease: Discontinue mipomersen; investigate for probable cause.

Administration

For subQ administration only. Do not administer IM or IV. Remove syringe from refrigerator, allow to reach room temperature (≥30 minutes prior to administration), and visually inspect prior to administration; do not mix or coadminister with other products or administer if solution is cloudy or contains visible particulate matter. Administer SubQ into the abdomen, thigh region, or outer area of upper arm; do not administer where there is active skin disease or injury (eg, sunburns, skin rash, inflammation/infection, areas of psoriasis) or into tattooed skin or scar. Administer on the same day every week.

Dietary Considerations

Limit alcohol consumption during treatment to ≤1 drink/day.

Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F) or when refrigeration is not available, may store at ≤30°C (86°F) (away from heat sources) for up to 14 days. Protect from light. Keep in original container until time of use. For single use only; discard any unused drug after removal of dose.

Drug Interactions

Acetaminophen: May enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Alcohol (Ethyl): May enhance the hepatotoxic effect of Mipomersen. Management: Patients being treated with mipomersen should limit their consumption of alcohol to a maximum of 1 drink (or equivalent) per day. Consider therapy modification

Amiodarone: May enhance the hepatotoxic effect of Mipomersen. Monitor therapy

ISOtretinoin: May enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Lomitapide: May enhance the hepatotoxic effect of Mipomersen. Specifically, the risk of steatosis may be increased with this combination. Avoid combination

Methotrexate: Mipomersen may enhance the hepatotoxic effect of Methotrexate. Monitor therapy

Propacetamol: Mipomersen may enhance the hepatotoxic effect of Propacetamol. Monitor therapy

Tamoxifen: May enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Tetracycline Derivatives: May enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Fatigue (15%), headache (12%)

Gastrointestinal: Nausea (14%)

Hepatic: Increased serum ALT (≥3 x ULN to <5 x ULN: 12%; ≥5 x ULN to <10 x ULN: 3%; ≥10 x ULN: 1%)

Immunologic: Antibody development (38% to 72%)

Local: Erythema at injection site (59%), pain at injection site (56%), hematoma at injection site (32%), itching at injection site (29%), swelling at injection site (18%), skin discoloration at injection site (17%)

Respiratory: Flu-like symptoms (13% to 66%)

1% to 10%:

Cardiovascular: Hypertension (7%), peripheral edema (5%), angina pectoris (4%), palpitations (3%)

Central nervous system: Chills (6%), insomnia (3%)

Gastrointestinal: Vomiting (4%), abdominal pain (3%)

Genitourinary: Proteinuria (9%)

Hematologic & oncologic: Neoplasms (4%, benign and malignant)

Hepatic: Liver steatosis (7%), increased serum AST (≥3 x ULN to <5 x ULN: 7%; ≥5 x ULN to <10 x ULN: 3%), abnormal hepatic function tests (5%), increased liver enzymes (3%)

Hypersensitivity: Recall skin sensitization (8%, including local erythema, tenderness, and/or pruritus at previous injection sites)

Neuromuscular & skeletal: Limb pain (7%), musculoskeletal pain (4%)

Miscellaneous: Fever (8%)

<1% (Limited to important or life-threatening): Glomerulonephritis, hypersensitivity reactions, immune thrombocytopenia

ALERT: U.S. Boxed Warning

Risk of hepatotoxicity:

Mipomersen can cause elevations in transaminases. In the mipomersen clinical trial in patients with homozygous familial hypercholesterolemia, 12% of patients treated with mipomersen compared with 0% of patients treated with placebo had at least 1 elevation in ALT at least 3 times the upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or partial thromboplastin time (PTT).

Mipomersen also increases hepatic fat, with or without concomitant increases in transaminases. In the trials in patients with heterozygous familial hypercholesterolemia and hyperlipidemia, the median absolute increase in hepatic fat was 10% after 26 weeks of treatment, from 0% at baseline, measured by magnetic resonance imaging (MRI). Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis.

Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT and AST regularly as recommended. During treatment, withhold the dose of mipomersen if the ALT or AST are at least 3 times the ULN. Discontinue mipomersen for clinically significant liver toxicity.

Because of the risk of hepatotoxicity, mipomersen is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Kynamro REMS. Prescribe mipomersen only to patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia (HoFH). The safety and effectiveness of mipomersen have not been established in patients with hypercholesterolemia who do not have HoFH.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: [US Boxed Warning]: May cause transaminase elevation; elevations in ALT ≥3 times upper limit of normal (ULN) occurred during clinical trials (no clinically meaningful concomitant bilirubin, INR, or PTT elevation was observed). Mipomersen also increases hepatic fat, with or without concomitant transaminase elevations. Hepatic steatosis associated with mipomersen may be a risk factor for progressive liver disease including steatohepatitis and cirrhosis. Monitor hepatic function (ALT, AST, alkaline phosphatase, and total bilirubin) prior to treatment; monitor ALT and AST regularly as recommended during treatment; withhold dose if ALT or AST are ≥3 times ULN. Discontinue mipomersen if clinically significant hepatotoxicity occurs. Alcohol consumption during treatment should be limited to ≤1 drink/day due to potential to increase levels of hepatic fat and induce or exacerbate liver injury. Use caution when used concomitantly with other medications known to cause hepatotoxicity (eg, isotretinoin, amiodarone, acetaminophen [>4 g/day for ≥3 days/week]). Concomitant administration with other LDL-lowering agents that also have the potential to increase hepatic fat is not recommended (has not been studied).

• Influenza-like symptoms: Within 2 days after an injection, influenza-like symptoms (eg, fever, chills, myalgia, arthralgia, malaise, or fatigue) have been reported in 30% of patients.

• Injection site reactions: Injection site reactions (eg, erythema, pain, tenderness, pruritus, and local swelling) were common in patients receiving mipomersen; minimize injection site reactions by using proper subcutaneous administration technique.

Disease-related concerns:

• Hepatic impairment: Use caution in patients with hepatic impairment (has not been studied); use is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C), active liver disease, or unexplained persistent elevations of hepatic transaminases.

• Renal impairment: Use caution in patients with renal impairment, including those who undergo hemodialysis (has not been studied); use is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on hemodialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: A higher incidence of hepatic steatosis, hypertension, and peripheral edema were reported in the elderly; use with caution.

Other warnings/precautions:

• Appropriate use: The use of mipomersen as an adjunct to LDL-C apheresis is not recommended (use not established).

• Limitations of use: [US Boxed Warning]: Prescribe mipomersen only to patients with a clinical or laboratory diagnosis consistent with HoFH. Safety and effectiveness have not been established in patients with hypercholesterolemia who do not have HoFH, including those with HeFH.

• REMS program: [US Boxed Warning]: Due to the risk for hepatotoxicity, access is restricted through a REMS program (Kynamro REMS program). Only certified health care providers and pharmacies may prescribe and dispense mipomersen.

Monitoring Parameters

Measure ALT, AST, total bilirubin, and alkaline phosphatase before initiating therapy, then monthly for the first year of treatment, followed by every 3 months (or more frequently if clinically indicated) after the first year; lipid levels (total cholesterol [C], LDL-C, HDL-C, triglycerides) at least every 3 months for the first year

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Females of reproductive potential should use effective contraception during therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, flu-like symptoms, or loss of strength and energy. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, arrhythmia, swelling of arms or legs, severe headache, or severe irritation at injection site (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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