Dosing and uses of Kynamro (mipomersen)
Adult dosage forms and strengths
subcutaneous injection
- 200mg/mL
Homozygous Familial Hypercholesterolemia
Indicated as an adjunct to lipid-lowering medications and diet to reduce LDL-C, apoB, TC, and non-HDL-C in patients with homozygous familial hypercholesterolemia (HoFH)
200 mg SC once weekly
Dosage modifications
Elevated transaminases
- ≥3x and <5x ULN: Confirm by repeating measurement within 1 week; if confirmed withhold dosing
- ≥5x ULN: Withhold dosing
- Obtain additional liver-related tests if not already measured (eg, total bilirubin, alkaline phosphatase, INR) and investigate to identify the probable cause
- Recommendations are based on ULN of ~ 30-40 IU/L
- If transaminase elevations accompanied by clinical symptoms of liver injury (eg, nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment and investigate to identify the probable cause
- If resuming mipomersen after transaminases resolve to <3x ULN consider monitoring liver-related tests more frequently
Dosing Considerations
Measure baseline transaminases (ALT, AST), alkaline phosphatase, and total bilirubin
Safety and effectiveness not been established in patients with hypercholesterolemia who do not have HoFH
Effect on cardiovascular morbidity and mortality undetermined
Safety and effectiveness of mipomersen as an adjunct to LDL apheresis have not been established; therefore, the use as an adjunct to LDL apheresis is not recommended
Monitor lipid levels at least q3months during the first year of treatment to determine if the LDL-C reduction achieved is sufficiently robust to warrant the potential risk of liver toxicity; maximal LDL-C reduction observed after ~6 months
Administration
For subcutaneous use only; do not administer IM or IV
Administer on the same day each week; if a dose is missed, the injection should be given at least 3 days from the next weekly dose
Inject SC into abdomen, thigh region, or outer area of the upper arm
Do not inject in areas of active skin disease or injury (eg, sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis)
Avoid areas of tattooed skin and scarring
Storage
- Vials or syringes: Store refrigerated between 2-8°C (36-46°F)
- Allowed to reach room temperature for at least 30 minutes prior to administration
- Do not use if solution is cloudy or contains visible particulate matter
Pediatric dosage forms and strengths
Safety and efficacy not established
Kynamro (mipomersen) adverse (side) effects
>10%
Injection site reactions (84%)
Increased hepatic fat >5% (62%)
Fatigue (15%)
Nausea (14%)
Influenza-like illness (13%)
Headache (12%)
1-10%
ALT increased (10%)
Pyrexia (8%)
Hypertension (7%)
Hepatic steatosis (7%)
Extremity pain (7%)
AST increased (6%)
Chills (6%)
Abnormal LFTs (5%)
Edema (5%)
Musculoskeletal pain (4%)
Vomiting (4%)
Angina (4%)
Hepatic enzyme increased (3%)
Abdominal pain (3%)
Palpitations (3%)
Insomnia (3%)
Postmarketing Reports
Idiopathic thrombocytopenic purpura
Warnings
Black box warnings
In the clinical trial, 4 of 34 (12%) patients treated with mipomersen had at least 1 elevation in ALT ≥3x ULN compared with 0% of the 17 patients treated with placebo
Measure ALT, AST, alkaline phosphatase, and total bilirubin before initiating treatment and then ALT, AST regularly as recommended
During treatment, withhold dosing if ALT or AST are ≥3 x ULn
Discontinue clinically significant liver toxicity
Increases hepatic steatosis with or without concomitant increases in transaminases
Hepatic steatosis associated with therapy; may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis
Because of risk of hepatotoxicity, therapy is available only through a restricted REMS program; should only be prescribed to patients with a clinical or laboratory diagnosis consistent with HoFH; safety and efficacy in patients with hypercholesterolemia who do not have HoFH not established
Contraindications
Hypersensitivity
Moderate-to-severe hepatic impairment (Child-Pugh B or C) or active liver disease, including unexplained persistent increased serum transaminases
Cautions
May cause elevations in transaminases and hepatic steatosis (see Black box warnings, Dosage modifications); concern exists that these increases could induce steatohepatitis, which can progress to cirrhosis over several years
Infection site reactions reported
Women of reproductive potential should use effective contraception during mipomersen therapy
Not recommended with severe renal impairment, clinically significant proteinuria, or on renal dialysis (lack of clinical data)
Site reactions, including erythema, pain, tenderness, pruritus and local swelling reported
Flu-like symptoms, occurring within 2 days after injection reported; symptoms may include influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue
Pregnancy and lactation
Pregnancy category: B
Lactation: Unknown whether distributed in breast milk
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Kynamro (mipomersen)
Mechanism of action
Antisense oligonucleotide inhibitor that targets messenger RNA for apolipoprotein B-100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL
Absorption
Bioavailability: 54-78%
Peak plasma time: 3-4 hr
Distribution
Protein bound: ≥90%
Distribution half-life: 2-5 hr
Steady-state typically reached within 6 months
Metabolism
Metabolized in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases
Elimination
Half-life: 1-2 months
Excretion: <4% urine over 24 hr
