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  • CLASSES

    Other Cholesterol and Triglyceride Regulating Agents

    BOXED WARNING

    Ethanol ingestion, hepatic disease, hepatotoxicity

    Mipomersen is contraindicated in patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) or active hepatic disease, including unexplained persistent elevations of serum transaminases. Mipomersen may cause elevations in serum transaminases and hepatic steatosis. Measure ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation of mipomersen therapy. If the baseline liver-related tests are abnormal, initiation of mipomersen may be considered after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, measure liver-related tests (ALT and AST, at a minimum) monthly. After the first year, conduct these tests at least every 3 months. Increased monitoring and temporary cessation of therapy may be required for elevated transaminases. Discontinue mipomersen for persistent or clinically significant elevations. If transaminase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin 2 times the upper limit of normal or greater, or active liver disease, discontinue treatment with mipomersen and identify the probable cause. Ethanol ingestion may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking mipomersen should not consume more than one alcoholic drink per day.[53015]

    DEA CLASS

    Rx

    DESCRIPTION

    Apolipoprotein B synthesis inhibitor administered as a once weekly injection
    Decreases LDL, total, and non-HDL cholesterols and apo B in patients with homozygous familial hypercholesterolemia (HoFH)
    Most common ADRs are injection site reactions, flu-like symptoms, nausea, headache and elevations in liver enzymes

    COMMON BRAND NAMES

    Kynamro

    HOW SUPPLIED

    Kynamro Subcutaneous Inj Sol: 1mL, 200mg

    DOSAGE & INDICATIONS

    For the reduction of 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).
    NOTE: Mipomersen is indicated for use as an adjunct to a low-fat diet and in combination with other lipid-lowering medications. The safety and efficacy of mipomersen as an adjunct to LDL apheresis has not been established and is therefore not recommended.
    Subcutaneous dosage
    Adults

    200 mg subcutaneously once weekly. Administer the injection on the same day every week. If a dose is missed, the injection should be given at least 3 days from the next weekly dose. Measure transaminases (ALT, AST), alkaline phosphatase, and total bilirubin prior to initiation of and during therapy. Monitor lipid levels at least every 3 months for the first year. Maximal reduction of LDL-C may be seen after approximately 6 months. Assess the patient's LDL-C level after 6 months to determine if the LDL-C reduction achieved is sufficient to warrant the potential risk of liver toxicity. Geriatric patients are at increased risk for hypertension, peripheral edema, and hepatic steatosis compared to younger patients during mipomersen therapy and should be closely monitored.

    MAXIMUM DOSAGE

    Adults

    200 mg SC once weekly.

    Geriatric

    200 mg SC once weekly.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Safety and efficacy in patients with known hepatic impairment have not been established. Further, use is contraindicated in patients with clinically significant hepatic dysfunction, which may include persistent elevations of transaminases.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. Due to the lack of clinical data and the renal safety profile of mipomersen, the drug is not recommended in patients with severe renal impairment or clinically significant proteinuria.
     
    Intermittent hemodialysis
    Mipomersen is not recommended in patients on renal dialysis due to a lack of clinical data and the renal safety profile of mipomersen.
     
    Peritoneal dialysis
    Mipomersen is not recommended in patients on renal dialysis due to a lack of clinical data and the renal safety profile of mipomersen.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    The first injection administered by the patient or caregiver should be performed under the guidance and supervision of an appropriately qualified health care professional.
    Remove the mipomersen vial or pre-filled syringe from refrigerated storage and allow to reach room temperature for at least 30 minutes prior to administration.
    Inject mipomersen into the abdomen, thigh region, or outer area of the upper arm. Do not inject 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.

    STORAGE

    Kynamro:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store at or below 86 degrees F, away from heat sources, for up to 14 days if refrigeration is not available
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Ethanol ingestion, hepatic disease, hepatotoxicity

    Mipomersen is contraindicated in patients with moderate or severe hepatic impairment (based on Child-Pugh category B or C) or active hepatic disease, including unexplained persistent elevations of serum transaminases. Mipomersen may cause elevations in serum transaminases and hepatic steatosis. Measure ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation of mipomersen therapy. If the baseline liver-related tests are abnormal, initiation of mipomersen may be considered after an appropriate work-up and the baseline abnormalities are explained or resolved. During the first year, measure liver-related tests (ALT and AST, at a minimum) monthly. After the first year, conduct these tests at least every 3 months. Increased monitoring and temporary cessation of therapy may be required for elevated transaminases. Discontinue mipomersen for persistent or clinically significant elevations. If transaminase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin 2 times the upper limit of normal or greater, or active liver disease, discontinue treatment with mipomersen and identify the probable cause. Ethanol ingestion may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking mipomersen should not consume more than one alcoholic drink per day.[53015]

    Geriatric

    A higher incidence of hypertension and peripheral edema was reported in patients 65 years and older treated with mipomersen compared to patients in this age group receiving placebo and also to the younger mipomersen-treated age group. Hepatic steatosis was also reported with greater frequency in the 65 years and older group compared to patients less than 65 years. Closely monitor geriatric patients during mipomersen therapy.

    Dialysis, proteinuria, renal impairment

    The safety and efficacy of mipomersen have not been established in patients with known renal impairment or in patients undergoing renal dialysis. Therefore, the drug is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.

    Low-density lipoprotein apheresis

    Because the safety and efficacy of mipomersen as an adjunct to low-density lipoprotein apheresis have not been established, such use is not recommended.

    Pregnancy

    Mipomersen is classified in FDA pregnancy category B. There are no adequate and well-controlled studies in pregnant women. Females of reproductive potential should use effective contraception during mipomersen therapy. According to the manufacturer, the drug should be used during pregnancy only if clearly needed and females who become pregnant during mipomersen therapy should be instructed to notify their healthcare provider. No evidence of fetal harm was demonstrated in mice or rabbits administered doses resulting in 2 to 5 times clinical exposure at a 200 mg per week therapeutic dose. Decreased rat pup survival was observed with subcutaneous administration of mipomersen at 3 times the clinical exposure at a 200 mg per week when given from gestation day 6 through weaning on lactation day 20. Dose-related decreases in pup body weights, impaired reflexes, and grip strength were observed after administration of 2 times the anticipated human dose to pregnant rats.[53015]

    Breast-feeding

    It is not known whether mipomersen is excreted in human milk; however, bioavailability of mipomersen after oral administration is expected to be low. According to the manufacturer, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The oral bioavailability of mipomersen from breast milk is expected to be less than 10%; however, a risk to the nursing infant cannot be excluded.[53015] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Contraception requirements, reproductive risk

    Mipomersen may cause fetal harm if taken during pregnancy. Due to the potential for reproductive risk, discuss contraception requirements, including the use of effective contraception during mipomersen therapy, in females of child-bearing potential.[53015] 

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 3.0-9.0
    new primary malignancy / Delayed / 4.0-4.0
    glomerulonephritis / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 38.0-72.0
    erythema / Early / 59.0-59.0
    hematoma / Early / 32.0-32.0
    steatosis / Delayed / 7.0-25.0
    proteinuria / Delayed / 9.0-9.0
    hypertension / Early / 7.0-7.0
    peripheral edema / Delayed / 5.0-5.0
    angina / Early / 4.0-4.0
    palpitations / Early / 3.0-3.0
    thrombocytopenia / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 84.0-84.0
    influenza / Delayed / 30.0-66.0
    pruritus / Rapid / 29.0-29.0
    skin discoloration / Delayed / 17.0-17.0
    fatigue / Early / 15.0-15.0
    nausea / Early / 14.0-14.0
    headache / Early / 12.0-12.0
    fever / Early / 8.0-8.0
    chills / Rapid / 6.0-6.0
    vomiting / Early / 4.0-4.0
    musculoskeletal pain / Early / 4.0-4.0
    abdominal pain / Early / 3.0-3.0
    insomnia / Early / 3.0-3.0
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Caffeine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Chlorpheniramine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Codeine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dextromethorphan: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Diphenhydramine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Hydrocodone: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Oxycodone: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Pentazocine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Propoxyphene: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Acetaminophen; Pseudoephedrine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Amiodarone: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as amiodarone. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Benzhydrocodone; Acetaminophen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Butalbital; Acetaminophen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Demeclocycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Doxycycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Ethanol: (Moderate) Patients taking mipomersen should not consume more than one alcoholic drink per day. Ethanol may increase levels of hepatic fat and induce or exacerbate liver injury.
    Isotretinoin: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Lomitapide: (Major) Mipomersen has not been studied in combination with other LDL-lowering agents that can also increase hepatic fat, such as lomitapide. Therefore, the combined use of mipomersen and lomitapide is not recommended.
    Methotrexate: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as methotrexate. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Minocycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Omadacycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Sarecycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Tetracycline: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Tetracyclines: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tetracyclines. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Tramadol; Acetaminophen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.

    PREGNANCY AND LACTATION

    Pregnancy

    Mipomersen is classified in FDA pregnancy category B. There are no adequate and well-controlled studies in pregnant women. Females of reproductive potential should use effective contraception during mipomersen therapy. According to the manufacturer, the drug should be used during pregnancy only if clearly needed and females who become pregnant during mipomersen therapy should be instructed to notify their healthcare provider. No evidence of fetal harm was demonstrated in mice or rabbits administered doses resulting in 2 to 5 times clinical exposure at a 200 mg per week therapeutic dose. Decreased rat pup survival was observed with subcutaneous administration of mipomersen at 3 times the clinical exposure at a 200 mg per week when given from gestation day 6 through weaning on lactation day 20. Dose-related decreases in pup body weights, impaired reflexes, and grip strength were observed after administration of 2 times the anticipated human dose to pregnant rats.[53015]

    It is not known whether mipomersen is excreted in human milk; however, bioavailability of mipomersen after oral administration is expected to be low. According to the manufacturer, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. The oral bioavailability of mipomersen from breast milk is expected to be less than 10%; however, a risk to the nursing infant cannot be excluded.[53015] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mipomersen is an antisense oligonucleotide. It inhibits the synthesis of apo B-100, the principal apolipoprotein of LDL and VLDL. Mipomersen inhibits synthesis of apo B by sequence-specific binding to its messenger ribonucleic acid (mRNA), resulting in degradation of the mRNA through enzyme-mediated pathways or disruption of mRNA function through binding alone.

    PHARMACOKINETICS

    Mipomersen is administered subcutaneously. The drug is >= 90% plasma-protein bound. Mipomersen is not a substrate for CYP450 metabolism, and is metabolized in tissues by endonucleases to form shorter oligonucleotides which are further metabolized by exonucleases. The elimination of mipomersen involves both metabolism in tissues and excretion, primarily in urine. Less than 4% of the drug is recovered in the urine within 24 hours after a dose. The elimination half-life for mipomersen is approximately 1—2 months.

    Subcutaneous Route

    The pharmacokinetics of mipomersen are approximately dose-proportional for subcutaneous doses from 30—400 mg. After subcutaneous injection, peak plasma concentrations are reached in about 3—4 hours. The estimated plasma bioavailability of mipomersen ranged from 54% to 78%, relative to intravenous administration, following subcutaneous administration over a dose range of 50—400 mg. With once weekly dosing, steady-state plasma trough levels are reached in approximately 6 months.