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Kynamro

Generic Name: Mipomersen Sodium
Class: Antilipemic Agents, Miscellaneous
Chemical Name: d(P - thio)([2′ - O - (2 - methoxyethyl)]rG - [2′ - O - (2 - methoxyethyl)]m5rC - [2′ - O - (2 - methoxyethyl)]m5rC - [2′ - O - (2 - methoxyethyl)]m5rU - [2′ - O - (2 - methoxyethyl)]m5rC - A - G - T - m5C - T - G - m5C - T - T - m5C - [2′ - O - (2 - methoxyethyl)]rG - [2′ - O - (2 - methoxyethyl)]m5rC - [2′ - O - (2 - methoxyethyl)]rA - [2′ - O - (2 - methoxyethyl)]m5rC - [2′ - O - (2 - methoxyethyl)]m5rC), DNA sodium salt
Molecular Formula: C230H305N67Na19O122P19S19
CAS Number: 629167-92-6

Warning(s)

  • Hepatotoxicity
  • Increases in serum aminotransferase (ALT and/or AST) concentrations and/or hepatic steatosis reported; hepatic steatosis is a risk factor for progressive liver disease, including steatohepatitis and cirrhosis.1 (See Hepatotoxicity under Cautions.)

  • Monitor liver-related laboratory tests prior to initiation of therapy and at recommended intervals during therapy.1 If hepatotoxicity occurs, interrupt or discontinue therapy depending on severity and persistence of toxicity.1 (See Hepatotoxicity under Dosage and Administration.)

  • Restricted Distribution Program
  • Available only through the Kynamro REMS program.1 3 9 (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for mipomersen to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of mipomersen and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). Also see Restricted Distribution Program under Dosage and Administration.

Introduction

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

Uses for Kynamro

Homozygous Familial Hypercholesterolemia

Adjunct to other antilipemic agents and diet to reduce LDL-cholesterol, apolipoprotein B (apo B), total cholesterol, and non-HDL-cholesterol concentrations in the management of homozygous familial hypercholesterolemia (designated an orphan drug by US FDA for use in this condition).1 2 4

Safety and efficacy not established in patients with hypercholesterolemia who do not have homozygous familial hypercholesterolemia.1

Safety and efficacy as an adjunct to LDL apheresis not established; use in combination with LDL apheresis not recommended.1

Effects on cardiovascular morbidity and mortality not established.1

Kynamro Dosage and Administration

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

Dyslipidemias
Homozygous Familial Hypercholesterolemia
Sub-Q

200 mg once weekly.1

Dosage Modification
Hepatotoxicity
Sub-Q

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

Table 1. Recommended Dosage Modifications for Hepatotoxicity.1

ALT or AST Concentration

Treatment and Monitoring Recommendations

3 to <5 times the ULN

Repeat ALT and AST measurement within 1 week; if ALT or AST concentration remains elevated, withhold mipomersen, obtain additional liver-related tests (e.g., alkaline phosphatase, total bilirubin, INR) if not already measured, and investigate probable cause1

 

If therapy is resumed (after ALT or AST concentrations have decreased to <3 times the ULN), consider monitoring liver-related tests more frequently1

≥5 times the ULN

Withhold mipomersen, obtain additional liver-related tests (e.g., alkaline phosphatase, total bilirubin, INR) if not already measured, and investigate probable cause1

 

If therapy is resumed (after ALT or AST concentrations have decreased to <3 times the ULN), monitor liver-related tests more frequently1

Serum ALT or AST elevations accompanied by clinical symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), bilirubin concentration ≥2 times the ULN, or active liver disease

Discontinue mipomersen and investigate probable cause1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Kynamro

Contraindications

  • Moderate or severe hepatic impairment (Child-Pugh class B or C).1

  • Active liver disease, including unexplained, persistent elevations in hepatic aminotransferase concentrations.1

  • Known hypersensitivity to mipomersen or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hepatotoxicity

Increases in serum aminotransferase (ALT and/or AST) concentrations reported; severe (≥3 or ≥5 times the ULN) elevations also reported.1 4 Elevations in ALT generally accompanied by lesser elevations in AST and not associated with increases in total bilirubin, changes in INR or PTT, or decreases in albumin concentration.1 4 Serum aminotransferase concentrations declined toward baseline within weeks to months following discontinuance of mipomersen.1

Hepatic steatosis, with or without concomitant increases in serum aminotransferase concentrations, reported.1 Decreases in hepatic fat fraction noted by MRI assessment at 24 weeks following discontinuance of mipomersen.1 Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis.1 Long-term consequences of hepatic steatosis associated with mipomersen therapy unknown.1 However, there is concern that mipomersen-induced hepatic steatosis could result in steatohepatitis, which can progress to cirrhosis over several years.1

Obtain liver function tests (i.e., ALT, AST, alkaline phosphatase, total bilirubin concentrations) prior to initiation of therapy; evaluate and manage abnormal concentrations before initiating therapy.1 During first year of therapy, perform liver function tests (or, at a minimum, ALT and AST concentrations) monthly; thereafter, perform liver-related tests at least every 3 months.1 If persistent or clinically relevant elevations in aminotransferase concentrations occur, interrupt or permanently discontinue mipomersen therapy and investigate probable cause.1 (See Hepatotoxicity under Dosage and Administration.)

Exercise caution when used concomitantly with other potentially hepatotoxic drugs.1 Concomitant use with other LDL-lowering agents known to increase hepatic fat not recommended.1 (See Hepatotoxic Drugs under Interactions.)

Sensitivity Reactions

Hypersensitivity Reactions

Angioedema reported.1

Other Warnings and Precautions

Injection Site Reactions

Local injection site reactions (i.e., erythema, pain, hematoma, tenderness, pruritus, local swelling, discoloration) reported frequently.1 Recall reactions (recurrence of skin reactions at previous injection sites when subsequent injections are administered), including local erythema, tenderness, and/or pruritus, also reported.1 Use proper sub-Q technique to minimize potential for injection site reactions.1

Flu-like Symptoms

Flu-like symptoms (i.e., influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise, fatigue) reported; typically occurred within 2 days of mipomersen injection.1

If flu-like symptoms are accompanied by elevations in hepatic aminotransferase concentrations, suggesting liver injury, discontinue mipomersen and investigate probable cause.1 (See Hepatotoxicity under Dosage and Administration.)

Immunogenicity

Development of anti-mipomersen antibodies reported.1 No effect on efficacy, but antibody-positive patients had higher trough mipomersen concentrations and higher incidences of flu-like symptoms and drug discontinuance.1

Specific Populations

Pregnancy

Category B.1

Women of childbearing potential should use effective contraception during therapy.1 (See Advice to Patients.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 However, patients ≥65 years of age reportedly had higher incidences of hypertension, peripheral edema, and hepatic steatosis compared with younger patients.1

Hepatic Impairment

Safety and efficacy not established in patients with known hepatic impairment.1

Contraindicated in patients with clinically relevant hepatic impairment.1 (See Contraindications under Cautions.)

Renal Impairment

Safety and efficacy not established in patients with known renal impairment or in patients undergoing dialysis.1

Not recommended in patients with severe renal impairment or clinically relevant proteinuria, or in patients undergoing dialysis.1

Common Adverse Effects

Injection site reactions,1 4 fatigue,1 nausea,1 4 influenza-like illness,1 4 headache,1 4 increased serum aminotransferase (ALT, AST) concentrations,1 4 8 pyrexia,1 hepatic steatosis,1 8 extremity pain,1 hypertension,1 chills,1 peripheral edema,1 abnormal liver function test,1 angina pectoris,1 vomiting,1 musculoskeletal pain,1 palpitations,1 abdominal pain,1 increased hepatic enzyme,1 insomnia.1

Interactions for Kynamro

Not a substrate of CYP isoenzymes.1 5 6 7

Hepatotoxic Drugs

Possible increased risk of hepatotoxicity.1 Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted.1 (See Specific Drugs and Foods under Interactions.)

Concomitant use with other LDL-lowering agents known to increase hepatic fat not studied; concomitant use not recommended.1

Protein-bound Drugs

Interactions with other highly protein-bound drugs generally not expected because binding of oligonucleotides to plasma proteins is relatively weak.7 (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug

Interaction

Comments

Acetaminophen (>4 g daily for ≥3 days per week)

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Alcohol

Possible increased levels of hepatic fat; may induce or exacerbate liver injury1

Limit alcohol consumption to ≤1 alcohol-containing drink per day1

Amiodarone

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Ezetimibe

No clinically relevant pharmacokinetic interactions observed1 7

No dosage adjustment of mipomersen or ezetimibe required1

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) (atorvastatin, simvastatin)

No displacement of mipomersen or statin from protein-binding sites7

Simvastatin: No clinically relevant pharmacokinetic interactions observed1 7

Simvastatin: No dosage adjustment of mipomersen or simvastatin required1

Isotretinoin

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Methotrexate

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Tamoxifen

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Tetracyclines

Possible increased risk of hepatotoxicity1

Use concomitantly with caution; more frequent monitoring of liver-related tests may be warranted1

Warfarin

No clinically relevant pharmacokinetic or pharmacodynamic interactions (as determined by INR, aPTT, or PT)1 11

Kynamro Pharmacokinetics

Absorption

Bioavailability

Rapidly and extensively absorbed following sub-Q injection.6 15

Absolute bioavailability following sub-Q injection is approximately 54–78%.1 6

Peak plasma concentrations attained within 3–4 hours following sub-Q injection.1 5 6

Steady-state concentrations achieved approximately 6 months following once-weekly dosing.1 6

Mipomersen exposure increases with increasing dose over range of 30–400 mg.1

Special Populations

Pharmacokinetics not established in patients with hepatic or renal impairment.1 (See Hepatic Impairmentand also Renal Impairment under Cautions.)

Distribution

Extent

Widely distributed into most tissues.6 7 12 15

Distributed into milk in rats; not known whether distributed into human milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

≥90% (mainly albumin).1 6

Elimination

Metabolism

Metabolized by endonucleases to shorter oligonucleotides, which are further metabolized by exonucleases.1 5 6

Not a substrate for CYP metabolism.1 5 6 7

Elimination Route

Excreted principally in urine as unchanged drug and oligonucleotide metabolites; following administration of a single 200-mg IV dose, <4% recovered in urine within 24 hours.1 5 6 12 15

Half-life

Approximately 1–2 months.1 5 6 12 15

Stability

Storage

Parenteral

Injection

2–8°C.1 Store in original carton and protect from light.1

If refrigeration is not available, may store at ≤30°C (away from heat sources) for up to 14 days.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility

Do not mix or administer concomitantly with other drugs.1

Actions

  • Selectively binds to complementary messenger RNA (mRNA) sequence encoding apo B-100 and prevents translation of apo B-100 protein.1 4 7 12 14

  • Produces dose-dependent reductions in concentrations of apo B-100 and apo B-100-containing atherogenic lipids (e.g., LDL-cholesterol, non-HDL-cholesterol, triglycerides) independent of LDL-receptor activity.4 6 12 14

  • No clinically important prolongation of QTc interval.1

Advice to Patients

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of mipomersen is restricted.1 3 9 (See Restricted Distribution Program under Dosage and Administration.)

Mipomersen Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

200 mg/mL

Kynamro (available in 1-mL single-use prefilled syringes and 1-mL single-use vials)

Hospira

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Genzyme Corporation. Kynamro (mipomersen sodium) injection solution for subcutaneous injection prescribing information. Cambridge, MA; 2013 Jan.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed [2014 01 10].

3. Kynamro (mipomersen sodium) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2014 Jun 26.

4. Raal FJ, Santos RD, Blom DJ et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010; 375:998-1006. [PubMed 20227758]

5. . Two new drugs for homozygous familial hypercholesterolemia. Med Lett Drugs Ther. 2013; 55:25-7. [PubMed 23545581]

6. Crooke ST, Geary RS. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br J Clin Pharmacol. 2013; 76:269-76. [PubMed 23013161]

7. Yu RZ, Geary RS, Flaim JD et al. Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2'-O-methoxyethyl modified antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clin Pharmacokinet. 2009; 48:39-50. [PubMed 19071883]

8. Duell PB, Santos RD, East C et al. Long-term safety and efficacy of mipomersen in patients with familial hypercholesterolemia uncontrolled by maximally tolerated lipid lowering therapy. J Clin Lipidol. 2012; 6:291.

9. Genzyme Corporation. Kynamro (mipomersen sodium) injection medication guide. Cambridge, MA: 2013 Jan.

10. Genzyme Corporation. Kynamro (mipomersen sodium) injection instructions for use. Cambridge, MA: 2013 Jan.

11. Li Z, Hard ML, Grundy JS et al. Lack of Clinical Pharmacodynamic and Pharmacokinetic Drug-Drug Interactions between Warfarin and the Antisense Oligonucleotide Mipomersen. J Cardiovasc Pharmacol. 2014; :. [PubMed 24691275]

12. Ito MK. ISIS 301012 gene therapy for hypercholesterolemia: sense, antisense, or nonsense?. Ann Pharmacother. 2007; 41:1669-78. [PubMed 17848425]

13. Ito MK, McGowan MP, Moriarty PM et al. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(3 Suppl):S38-45. [PubMed 21600528]

14. Marais AD, Blom DJ. Recent advances in the treatment of homozygous familial hypercholesterolaemia. Curr Opin Lipidol. 2013; 24:288-94. [PubMed 23839331]

15. Bell DA, Hooper AJ, Watts GF et al. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia. Vasc Health Risk Manag. 2012; 8:651-9. [PubMed 23226021]

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