Mipomersen

Mipomersen
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

WARNING: RISK OF HEPATOTOXICITY See full prescribing information for complete Boxed Warning. * KYNAMRO can cause elevations in transaminases. In the KYNAMRO clinical trial in patients with HoFH, 4 (12%) of the 34 patients treated with KYNAMRO compared with 0% of the 17 patients treated with placebo had at least one elevation in alanine aminotransferase (ALT) ≥ 3x upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR) or partial thromboplastin time (PTT). KYNAMRO also increases hepatic fat, with or without concomitant increases in transaminases. In the trials in patients with heterozygous familial hypercholesterolemia (HeFH) 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, AST regularly as recommended. During treatment, withhold the dose of KYNAMRO if the ALT or AST are ≥ 3x ULN. Discontinue KYNAMRO for clinically significant liver toxicity. Because of the risk of hepatotoxicity, KYNAMRO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYNAMRO REMS.

Overview

Mipomersen is a lipid-lowering medication that is FDA approved for the {{{indicationType}}} of hypercholesterolemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases, specifically ALT.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Homozygous Familial Hypercholesterolemia (HoFH)

• KYNAMROTM is indicated as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

• Limitations of Use

• The safety and effectiveness of KYNAMRO have not been established in patients with hypercholesterolemia who do not have HoFH.
• The effect of KYNAMRO on cardiovascular morbidity and mortality has not been determined.
• The safety and effectiveness of KYNAMRO as an adjunct to LDL apheresis have not been established; therefore, the use of KYNAMRO as an adjunct to LDL apheresis is not recommended.

• Dosing Information

• Before beginning treatment with KYNAMRO, measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin.
• The recommended dose of KYNAMRO is 200 milligrams (mg) once weekly as a subcutaneous injection.
• KYNAMRO is intended for subcutaneous use only. Do not administer intramuscularly or intravenously.
• The injection should be given on the same day every week, but if a dose is missed, the injection should be given at least 3 days from the next weekly dose.
• After initiation of KYNAMRO therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen with KYNAMRO therapy after approximately 6 months (based on the time to steady state seen in clinical studies). Health care providers should assess the patient’s LDL-C level after 6 months to determine if the LDL-C reduction achieved with KYNAMRO is sufficiently robust to warrant the potential risk of liver toxicity.

• Administration

• Each vial or pre-filled syringe of KYNAMRO provides 200 mg of mipomersen sodium in a deliverable volume of 1 milliliter (mL) of solution and is intended for single-use only.
• The KYNAMRO vial or pre-filled syringe should be removed from 2-8°C (36-46°F) refrigerated storage and allowed to reach room temperature for at least 30 minutes prior to administration.
• Parenteral drug products should be inspected visually prior to administration. If the solution is cloudy or contains visible particulate matter, the contents must not be injected and the product should be returned to the pharmacy.
• The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional.
• KYNAMRO should be injected into the abdomen, thigh region, or outer area of the upper arm. KYNAMRO should not be injected in areas of active skin disease or injury such as sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis, etc. Areas of tattooed skin and scarring should also be avoided.

• Adjustments for Patients Developing Transaminase Elevations

• Table 1 summarizes recommendations for monitoring for patients who develop elevated transaminases during therapy with KYNAMRO.

This image is provided by the National Library of Medicine.

• If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with KYNAMRO and investigate to identify the probable cause.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Mipomersen in adult patients.

Non–Guideline-Supported Use

Hypercholesterolemia

• Dosing Information

• Mipomersen 200 mg subQ once weekly.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• Safety and effectiveness have not been established in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Mipomersen in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Mipomersen in pediatric patients.

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent elevations of serum transaminases.
• Patients with a known hypersensitivity to any component of this product.

Warnings

WARNING: RISK OF HEPATOTOXICITY See full prescribing information for complete Boxed Warning. * KYNAMRO can cause elevations in transaminases. In the KYNAMRO clinical trial in patients with HoFH, 4 (12%) of the 34 patients treated with KYNAMRO compared with 0% of the 17 patients treated with placebo had at least one elevation in alanine aminotransferase (ALT) ≥ 3x upper limit of normal (ULN). There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR) or partial thromboplastin time (PTT). KYNAMRO also increases hepatic fat, with or without concomitant increases in transaminases. In the trials in patients with heterozygous familial hypercholesterolemia (HeFH) 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, AST regularly as recommended. During treatment, withhold the dose of KYNAMRO if the ALT or AST are ≥ 3x ULN. Discontinue KYNAMRO for clinically significant liver toxicity. Because of the risk of hepatotoxicity, KYNAMRO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYNAMRO REMS.

Risk of Hepatotoxicity

• KYNAMRO can cause elevations in transaminases and hepatic steatosis, as described below. To what extent KYNAMRO-associated hepatic steatosis promotes the elevations in transaminases is unknown. There is concern that KYNAMRO could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of KYNAMRO in HoFH would have been unlikely to detect this adverse outcome given their size and duration.

Elevation of Transaminases

• KYNAMRO can cause increases in serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In the clinical trial, 4 (12%) of the 34 subjects with HoFH treated with KYNAMRO compared to 0% of the 17 subjects treated with placebo had an elevation in ALT ≥ 3x ULN, and 3 (9%) of those treated with KYNAMRO compared to 0% treated with placebo had at least one elevation in ALT ≥ 5x ULN.
• Measure a full liver panel to include ALT, AST, total bilirubin, and alkaline phosphatase before initiation of treatment with KYNAMRO. KYNAMRO is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevations of serum transaminases. If the baseline liver-related tests are abnormal, consider initiating KYNAMRO after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, conduct liver-related tests monthly (ALT and AST, at a minimum). After the first year, conduct these tests at least every 3 months. Discontinue KYNAMRO for persistent or clinically significant elevations.
• If transaminase elevations are accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥ 2x ULN, or active liver disease, discontinue treatment with KYNAMRO and identify the probable cause.

Hepatic Steatosis

• KYNAMRO increases hepatic fat (steatosis) with or without concomitant increases in transaminases. Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with KYNAMRO therapy are unknown. During the clinical trials in patients with heterozygous familial hypercholesterolemia (HeFH) 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).
• Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking KYNAMRO should consume no more than one alcoholic drink per day.
• Caution should be exercised when KYNAMRO is used with other medications known to have potential for hepatotoxicity, for example isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥ 3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of KYNAMRO with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
• Mipomersen has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.

KYNAMRO REMS

• Because of the risk of hepatotoxicity, KYNAMRO is available only through a limited program under the REMS. Under the KYNAMRO REMS, only certified healthcare providers and pharmacies may prescribe and distribute KYNAMRO. Further information is available at www.KynamroREMS.com or by telephone at 1-877-KYNAMRO (1-877-596-2676).

Injection Site Reactions

• Injection site reactions have been reported in 84% of patients receiving KYNAMRO therapy. These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling. Injection site reactions do not occur with all injections but resulted in discontinuation of therapy in 5% of patients in pooled Phase 3 trials. To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed.

Flu-Like Symptoms

• Flu-like symptoms have been reported in 30% of patients receiving KYNAMRO therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue. Flu-like symptoms, which typically occur within 2 days after an injection, do not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled Phase 3 trials.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Mipomersen in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Mipomersen in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

• Drug

• Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mipomersen in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Mipomersen during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Mipomersen with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Mipomersen with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Mipomersen with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Mipomersen with respect to specific gender populations.

Race

There is no FDA guidance on the use of Mipomersen with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Mipomersen in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Mipomersen in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Mipomersen in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Mipomersen in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Mipomersen in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Mipomersen in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Mipomersen in the drug label.

Pharmacology

Mipomersen
Systematic (IUPAC) name
2'-O-(2-methoxyethyl)-P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioadenylyl-(3'→5')-2'-deoxy-Pthioguanylyl-(3'→5')P-thiothymidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-Pthioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methylcytidine nonadecasodiumsalt
Identifiers
CAS number	629167-92-6
ATC code	C10AX11
PubChem	44564107
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	7594.80 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	Injection

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Mipomersen in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Mipomersen in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Mipomersen in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Mipomersen in the drug label.

How Supplied

Storage

There is limited information regarding Mipomersen Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Mipomersen in the drug label.

Precautions with Alcohol

• Alcohol-Mipomersen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Kynamro®

Look-Alike Drug Names

• N/A

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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