CLASSES

Other Cholesterol and Triglyceride Regulating Agents

BOXED WARNING

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

MAXIMUM DOSAGE

200 mg SC once weekly.

200 mg SC once weekly.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

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.

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

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

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

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]

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.

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.

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

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.

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

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

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

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; Butalbital: (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; Butalbital; 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; Butalbital; 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.
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; 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; 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; 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; 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.
Acetaminophen; Tramadol: (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.
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.

PREGNANCY AND LACTATION

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.