Usual Adult Dose for Hyperlipidemia

200 mg subcutaneously once weekly on the same day each week

Indication: An adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and non-high density lipoprotein-cholesterol (nonHDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Renal Dose Adjustments

Mild to moderate renal dysfunction: No data

Severe renal dysfunction, significant proteinuria, or on renal dialysis: Not recommended

Liver Dose Adjustments

Mild to moderate liver dysfunction: No data

Significant liver dysfunction (which may include persistent elevations of transaminases): Contraindicated

Dose Adjustments

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.

Patients with elevated transaminases:
For transaminases 3 times ULN or greater but less than 5 times ULN:

• Confirm elevation with a repeat measurement within one week.
• If confirmed, withhold dosing, obtain additional liver tests if not already measured (such as total bilirubin, alkaline phosphatase and INR) and investigate to identify the cause.
• If mipomersen therapy is resumed after transaminases resolve to less than 3 times ULN, liver tests may need to be conducted more frequently.

For transaminases 5 times ULN or greater:

• Withhold dosing and conduct additional liver tests if not already measured (such as total bilirubin, alkaline phosphatase and INR) and investigate to identify the cause.
• If mipomersen therapy is resumed after transaminases resolve to less than 3 times ULN, liver tests may need to be conducted more frequently.

If transaminase elevations are accompanied by liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin 2 times ULN or greater, or active liver disease, treatment should be discontinued to identify the cause.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for mipomersen. It includes a medication guide, elements to assure safe use, and implementation system. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:

• RISK OF HEPATOTOXICITY: This drug can cause elevations in transaminases. At least 1 elevation in ALT of 3 times the upper limit of normal (3 x ULN) or greater was reported in clinical trials. This drug also increases hepatic fat, with or without concomitant increases in transaminases. In 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 and AST as recommended. During treatment, withhold the dose of this drug if the ALT or AST are 3 x ULN or greater. Discontinue this drug for clinically significant liver toxicity.
• Due to the risk of hepatotoxicity, this drug is only available through the REMS program; this drug should be prescribed only to patients with a clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia (HoFH). Safety and effectiveness have not been established in patients with hypercholesterolemia who do not have HoFH.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Renal dialysis: Not recommended

Other Comments

Mipomersen is intended for subcutaneous use only.

Transaminases (ALT, AST), alkaline phosphatase, and total bilirubin should be measured before beginning treatment with mipomersen.

After initiation of therapy lipid levels should be monitored at least every 3 months for the first year. Maximal reduction of LDL-C may be seen after approximately 6 months. The patient's LDL-C level should be assessed after 6 months to determine if the LDL-C reduction achieved is sufficient robust to warrant the potential risk of liver toxicity.

Mipomersen vials or syringes should be stored in the refrigerator and removed at least 30 minutes prior to administration.

The first injection administered by the patient or caregiver should be performed under the supervision of a healthcare provider.

Mipomersen should be injected into the abdomen, thigh region, or outer area of the upper arm. It should not be injected in areas of active skin disease or injury (e.g., sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis). Areas of tattooed skin and scarring should also be avoided.