Kynamro

Mipomersen is a cholesterol-lowering medication. It reduces blood levels of "bad" cholesterol, such as low-density lipoprotein (LDL), apolipoprotein-B (apo-B), or non-high-density lipoprotein (non-HDL).

Mipomersen is used together with a low-fat diet and other treatments to lower total cholesterol in people with homozygous familial hypercholesterolemia (an inherited type of high cholesterol).

It is not known whether mipomersen will lower your risk of heart disease.

Mipomersen is available only from a certified pharmacy under a special program called Kynamro REMS. Your doctor must be registered in the program in order to prescribe mipomersen for you.

Mipomersen may also be used for purposes not listed in this medication guide.

Mipomersen is available only from a certified pharmacy under a special program called Kynamro REMS. Your doctor must be registered in the program in order to prescribe mipomersen for you.

You should not use mipomersen if you have active liver disease or abnormal liver function tests.

Mipomersen can cause your liver enzymes to get too high. Your blood will need to be tested often. Your treatments may be delayed based on the results of these tests.

You should not use mipomersen if you are allergic to it, or if you have:

• active liver disease; or
• abnormal liver function tests.

To make sure mipomersen is safe for you, tell your doctor if you have:

• cirrhosis or other liver disease;
• kidney disease (or if you are on dialysis); or
• if you drink alcohol.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using mipomersen.

Do not use if you are pregnant. Use effective birth control during treatment. Stop using mipomersen and tell your doctor right away if you become pregnant.

It is not known whether mipomersen passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Kynamro is a prescription medication used to lower cholesterol in people with homozygous familial hypercholesterolemia (HoFH, a hereditary disorder that causes high cholesterol levels). Kynamro belongs to a group of drugs called antisense oligonucleotides. This drug lowers cholesterol levels by removing a main part of "bad" cholesterol.

This medication comes in an injectable form to be given just under the skin, once a week. Kynamro comes in single-use (1 time) vials, or as single-use pre-filled syringes.

Common side effects include skin reactions at the injection site, fever, chills, and headache.

You should not use mipomersen if you are allergic to it, or if you have:

• active liver disease; or

• abnormal liver function tests.

To make sure mipomersen is safe for you, tell your doctor if you have:

• cirrhosis or other liver disease;

• kidney disease (or if you are on dialysis); or

• if you drink alcohol.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using mipomersen.

Using mipomersen during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or if you become pregnant while using this medicine. Use effective birth control during treatment.

It is not known whether mipomersen passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Antilipemic agent; synthetic antisense oligonucleotide inhibitor of human apolipoprotein B (apo B)-100 synthesis.1 4 5 6 7 8 11 12 14 15

General

• Obtain liver-related tests (i.e., ALT, AST, alkaline phosphatase, and total bilirubin concentrations) prior to initiation of therapy and at recommended intervals during therapy.1 (See Hepatotoxicity under Cautions.)

• Determine lipoprotein concentrations at least every 3 months during first year of therapy.1 Assess LDL-cholesterol concentration after 6 months of therapy to determine whether reductions in LDL-cholesterol concentrations are sufficient to justify risks (e.g., hepatotoxicity) of continued therapy.1

Restricted Distribution Program

• Mipomersen can only be prescribed by and obtained through a limited network of certified prescribers and pharmacies enrolled in the Kynamro REMS program.1 3 9

• Additional information available at 877-596-2676 or at .1 3

Administration

Administer by sub-Q injection; do not administer IV or IM.1

Sub-Q Administration

Administer once weekly on the same day of the week and at the same time of day.1 9

Patient may self-administer drug after receiving appropriate training; self-administer first injection under the guidance and supervision of an appropriately qualified healthcare professional.1 9 10

Prior to administration, allow refrigerated vial or prefilled syringe to reach room temperature for ≥30 minutes (see Storage under Stability); do not remove needle cover from the prefilled syringe while allowing the drug to reach room temperature.1

If mipomersen sodium injection appears cloudy or if particulate matter is present, return drug to the pharmacy.1

Inject sub-Q slowly (over ≥10 seconds) and steadily into abdomen, thighs, or outer area of upper arms; rotate sites.1 Do not inject into areas of active skin disease or injury (e.g., sunburns, rashes, inflammation, infections, active psoriasis); avoid tattooed and scarred skin.1

If a dose is missed and remembered ≥3 days before next scheduled weekly dose, administer dose as soon as it is remembered.1 9 If missed dose is remembered <3 days before next dose is due, skip the dose and resume regular dosing schedule; do not administer 2 doses within a 3-day period.1 9

Contains no preservatives; discard unused portions after initial entry into vial.1

Dosage

Available as mipomersen sodium; dosage expressed in terms of the salt.1

Adults

200 mg once weekly.1

If hepatotoxicity occurs, interrupt or permanently discontinue therapy and investigate probable cause.1 (See Table 1.)

Special Populations

No special population dosage recommendations at this time.1

• Importance of educating patients regarding the Kynamro REMS restricted distribution program for obtaining mipomersen.1 4 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

• Importance of advising patients to read the manufacturer's medication guide and instructions for use carefully prior to initiating therapy and each time the prescription is refilled.1 9 10

• Risk of hepatotoxicity; importance of obtaining liver-related laboratory tests prior to initiation of therapy and at recommended intervals during therapy.1 Importance of limiting alcohol consumption to ≤1 alcohol-containing drink per day.1 9 Importance of immediately reporting symptoms suggestive of liver injury (e.g., nausea, vomiting, fever, anorexia, unusual fatigue, jaundice, dark urine, pruritus, abdominal pain).1 9

• Importance of advising patients of the possibility of injection site reactions (e.g., erythema, pain, tenderness, itching, local swelling) and flu-like symptoms (e.g., fever, chills, muscle or joint aches, malaise or fatigue).1 9

• If the drug is being self-administered, importance of instructing patient and/or caregiver regarding proper dosage, preparation, and administration of mipomersen, including use of aseptic technique and safe disposal of needles and syringes.1

• If a dose is missed, importance of administering the missed dose as soon as it is remembered, but only if it can be administered ≥3 days before the next scheduled weekly dose.1 9 If there are <3 days until the next scheduled weekly dose, skip the dose and resume regular dosing schedule.1 9

• Importance of women using effective methods of contraception during mipomersen therapy.1 9 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 9

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., liver disease, kidney disease).1 9

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

In the U.S.

• Kynamro

Available Dosage Forms:

• Solution

Therapeutic Class: Antihyperlipidemic

Pharmacologic Class: Mipomersen

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly to lower your cholesterol levels and to decide if you should continue to use it. Blood tests may be needed to check for unwanted effects.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a liver injury.

Tell your doctor if you have redness, pain, tenderness, itching, or swelling at the injection site. Also, tell your doctor if you have flu-like symptoms (eg, fever, chills, joint or muscle pain, unusual tiredness or weakness) after receiving this medicine.

Drinking alcohol while using this medicine may increase your risk of liver injury. It is recommended that you drink no more than one alcoholic drink per day while using this medicine.

Make sure your doctor knows if you are pregnant or planning to become pregnant. You must use an effective form of birth control to keep from getting pregnant. Talk to your doctor about effective birth control.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• It is used to lower cholesterol.

Kynamro® 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

Kynamro is contraindicated in the following conditions:

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Reproduction and embryofetal development studies performed in mice at doses up to 87.5 mg/kg/wk given by subcutaneous administration from mating through organogenesis and in pregnant rabbits given 52.5 mg/kg/wk, show no evidence of impaired fertility or harm to the fetus at 2 (mice) to 5 (rabbits) times clinical exposure at a 200 mg/wk therapeutic dose.

Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Pregnant rats given subcutaneous doses of 7, 35, 70 mg/kg/wk mipomersen sodium from gestation day 6 through weaning on lactation day 20, resulted in decreased rat pup survival at 70 mg/kg/wk, 3-times clinical exposure at a 200 mg/wk therapeutic dose based on body surface area comparisons across species. Dose related decreases in pup body weights, impaired reflexes and grip strength were observed at 35 mg/kg/wk (2-times the anticipated human dose. Levels of mipomersen in rat milk were very low (≤0.92 µg/mL at subcutaneous doses up to 70 mg/kg/wk). Due to the poor oral bioavailability of mipomersen sodium, it was considered unlikely that these low milk exposure levels adversely affected the pups during lactation.

Nursing Mothers

It is not known whether Kynamro is excreted in human milk.  Because many drugs are excreted in human milk a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 

Levels of mipomersen present in rat milk were low (≤ 0.92 µg/mL) given subcutaneous doses up to 70 mg/kg/wk. Oral bioavailability is expected to be less than 10%.  However a risk to newborns/infants cannot be excluded, therefore caution should be used when Kynamro is administered to a nursing woman.

Lactating rats administered mipomersen sodium at doses up to 70 mg/kg/wk (3-times the anticipated systemic exposure from a 200 mg/wk dose, based on body surface area comparison) consumed less food while nursing.  This correlated with reduced weight gain in the rat pups, and decreased pup survival in litters of dams given 70 mg/kg/wk.

Pediatric Use

Safety and effectiveness have not been established in pediatric patients. 

A juvenile toxicity study was conducted in rats at doses up to 50 mg/kg/wk (2-times the systemic exposure from a 200 mg/wk clinical dose based on body surface area comparisons).  Doses > 10 mg/kg/wk were associated with reduced body weight gain in young rats, but had no effect on long bone growth or sexual development.

Geriatric Use

Clinical studies of Kynamro did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.  Of the 51 patients enrolled in the Phase 3 trial in HoFH, the mean age was 31 years and the oldest patient in the trial was 53 years.  Of the 261 patients who received Kynamro in the pooled Phase 3 trials, 59 (22.6%) were ≥ 65 years old and 10 (3.8%) were ≥ 75 years old. In the pooled Phase 3 trials, patients ≥ 65 years of age treated with Kynamro had a higher incidence of hypertension and peripheral edema compared to placebo patients in this age group, as well as compared to the younger Kynamro-treated age group. Hepatic steatosis was also reported with greater frequency in the ≥ 65 group (13.6%) compared to the <65 group (10.4%).

Females of Reproductive Potential

Kynamro may cause fetal harm [see Use in Specific Populations (8.1)].  Females who become pregnant during Kynamro therapy should notify their healthcare provider.

Contraception

Females of reproductive potential should use effective contraception during Kynamro therapy.

Renal Impairment

The safety and efficacy of Kynamro treatment in patients with known renal impairment or in patients undergoing renal dialysis have not been established.  Due to the lack of clinical data and Kynamro’s renal safety profile, Kynamro is not recommended in patients with severe renal impairment, clinically significant proteinuria, or on renal dialysis.

Hepatic Impairment

The safety and efficacy of Kynamro treatment in patients with known hepatic impairment have not been established.  Kynamro is contraindicated in patients with clinically significant hepatic dysfunction, which may include persistent elevations of transaminases.  [seeContraindications (4) and Warnings and Precautions (5.1)]

Mechanism of Action

Mipomersen is an antisense oligonucleotide targeted to human messenger ribonucleic acid (mRNA) for apo B-100, the principal apolipoprotein of LDL and its metabolic precursor, VLDL.  Mipomersen is complementary to the coding region of the mRNA for apo B-100, and binds by Watson and Crick base pairing.  The hybridization of mipomersen to the cognate mRNA results in RNase H-mediated degradation of the cognate mRNA thus inhibiting translation of the apo B-100 protein.

The in vitro pharmacologic activity of mipomersen was characterized in human hepatoma cell lines (HepG2, Hep3B) and in human and cynomolgus monkey primary hepatocytes.  In these experiments, mipomersen selectively reduced apo B mRNA, protein and secreted protein in a concentration- and time-dependent manner.  The effects of mipomersen were shown to be highly sequence-specific.  The binding site for mipomersen lies within the coding region of the apo B mRNA at the position 3249-3268 relative to the published sequence GenBank accession number NM_000384.1.

Pharmacodynamics

Cardiac ECG Effects

At a concentration of 3.8 times the Cmax of the maximum recommended dose (200 mg subcutaneous injection), mipomersen does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

Single- and multiple-dose pharmacokinetics of mipomersen in healthy volunteers and in patients with FH and non-FH has shown that mipomersen plasma exposure increases with increasing dose in the range of 30 mg to 400 mg. 

Absorption

Following subcutaneous injection, peak concentrations of mipomersen are typically reached in 3 to 4 hours.  The estimated plasma bioavailability of mipomersen following subcutaneous administration over a dose range of 50 mg to 400 mg, relative to intravenous administration, ranged from 54% to 78%. 

Distribution

Mipomersen is highly bound to human plasma proteins (≥ 90%) at clinically relevant concentrations (1-8 µg/mL).  Mipomersen has a distribution plasma half-life of approximately 2 to 5 hours.

With once weekly dosing, plasma trough levels increase over time and approach steady-state, typically within 6 months. 

Metabolism

Mipomersen is not a substrate for CYP450 metabolism, and is metabolized in tissues by endonucleases to form shorter oligonucleotides that are then substrates for additional metabolism by exonucleases.

Excretion

The elimination of mipomersen involves both metabolism in tissues and excretion, primarily in urine.  Both mipomersen and putative shorter oligonucleotide metabolites were identified in human urine.  Urinary recovery was limited in humans with less than 4% within the 24 hours post dose.  Following subcutaneous administration, elimination half-life for mipomersen is approximately 1 to 2 months.

Drug Interactions

No clinically relevant pharmacokinetic interactions were reported between mipomersen and warfarin, or between mipomersen and simvastatin or ezetimibe.  The results of these studies are summarized in Figures 1 and 2.

Figure 1: Impact of Other Drugs on Mipomersen Pharmacokinetics

Figure 2: Impact of Mipomersen on the Pharmacokinetics of Other Drugs

Specific Populations

Renal Impairment

Pharmacokinetics of Kynamro in patients with renal impairment has not been established [see Use in Specific Populations (8.7)].

Hepatic Impairment

Pharmacokinetics of Kynamro in patients with hepatic impairment has not been established [see Use in Specific Populations (8.8)]. 

You should not use Kynamro if you are allergic to mipomersen, or if you have:

• active liver disease; or

• abnormal liver function tests.

To make sure this medicine is safe for you, tell your doctor if you have:

• cirrhosis or other liver disease;

• kidney disease (or if you are on dialysis); or

• if you drink alcohol.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using Kynamro.

Using Kynamro during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or if you become pregnant while using this medicine. Use effective birth control during treatment.

It is not known whether mipomersen passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.