Included as part of the "PRECAUTIONS" Section
Risk Of Hepatotoxicity
KYNAMRO can cause elevations in transaminases and hepatic steatosis, as described below. To what extent KYNAMRO-associated hepatic steatosis promotes the elevations in transaminases is unknown. There is concern that KYNAMRO could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of KYNAMRO in HoFH would have been unlikely to detect this adverse outcome given their size and duration [see Clinical Studies].
Elevation Of Transaminases
KYNAMRO can cause increases in serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In the clinical trial, 4 (12%) of the 34 subjects with HoFH treated with KYNAMRO compared to 0% of the 17 subjects treated with placebo had an elevation in ALT ≥ 3x ULN, and 3 (9%) of those treated with KYNAMRO compared to 0% treated with placebo had at least one elevation in ALT ≥ 5x ULN.
Monitoring Of Transaminases
Before initiating KYNAMRO and during treatment, monitor transaminases as recommended in Table 2.
Table 2. Recommendations for Monitoring Transaminases
|Before initiating treatment
- Measure ALT, AST, alkaline phosphatase , and total bilirubin
- If abnormal, consider initiating KYNAMRO only after an appropriate work-up and the baseline abnormalities have been explained or resolved.
- KYNAMRO is contraindicated in patients with moderate or severe hepatic impairment, or active liver disease, including unexplained persistent elevation of serum transaminases [see CONTRAINDICATIONS].
|During the first year
- Measure liver-related tests (ALT and AST, at a minimum) monthly.
|After the first year
- Measure liver-related tests (ALT and AST, at a minimum) at least every 3 months.
|At any time during treatment
- If transaminases are abnormal, withhold dose of KYNAMRO and monitor as recommended [see DOSAGE AND ADMINISTRATION].
- Discontinue KYNAMRO for persistent or clinically significant elevations.
- If transaminase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin >2x ULN, or active liver disease, discontinue treatment with KYNAMRO and identify the probable cause.
KYNAMRO increases hepatic fat (steatosis) with or without concomitant increases in transaminases [see ADVERSE REACTIONS]. Hepatic steatosis is a risk factor for advanced liver disease, including steatohepatitis and cirrhosis. The long-term consequences of hepatic steatosis associated with KYNAMRO therapy are unknown. During the clinical 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).
Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. It is recommended that patients taking KYNAMRO should consume no more than one alcoholic drink per day.
Caution should be exercised when KYNAMRO is used with other medications known to have potential for hepatotoxicity, for example isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of KYNAMRO with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Mipomersen has not been studied concomitantly with other LDL-lowering agents that can also increase hepatic fat. Therefore, the combined use of such agents is not recommended.
Because of the risk of hepatotoxicity, KYNAMRO is available only through a limited program under the REMS. Under the KYNAMRO REMS, only certified healthcare providers and pharmacies may prescribe and distribute KYNAMRO. Further information is available at www.KynamroREMS.com or by telephone at 1-877-KYNAMRO (1-877596-2676).
Injection Site Reactions
Injection site reactions have been reported in 84% of patients receiving KYNAMRO therapy. These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling. Injection site reactions do not occur with all injections but resulted in discontinuation of therapy in 5% of patients in pooled Phase 3 trials. [see ADVERSE REACTIONS] To minimize the potential for injection site reactions, proper technique for subcutaneous administration should be followed. [see PATIENT INFORMATION]
Flu-like symptoms have been reported in 30% of patients receiving KYNAMRO therapy and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue. Flu-like symptoms, which typically occur within 2 days after an injection, do not occur with all injections but resulted in discontinuation of therapy in 3% of patients in pooled Phase 3 trials. [see ADVERSE REACTIONS]
There have been reports of generalized hypersensitivity (e.g. angioedema, urticaria, or generalized rash) in patients taking KYNAMRO. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of KYNAMRO. [see CONTRAINDICATIONS and ADVERSE REACTIONS.
Patient Counseling Information
See FDA-approved labeling (PATIENT INFORMATION)
Advise patients of the following:
Risk Of Hepatotoxicity [See WARNINGS AND PRECAUTIONS]
- KYNAMRO can cause elevations in transaminases and hepatic steatosis. Discuss with the patient the importance of monitoring liver-related laboratory tests before taking KYNAMRO and periodically thereafter.
- Patients should be advised of the potential for increased risk of liver injury if alcohol is consumed while taking KYNAMRO. It is recommended that patients taking KYNAMRO should consume no more than one alcoholic drink per day.
- Advise patients to promptly report symptoms of possible liver injury, such as nausea, vomiting, fever, anorexia, fatigue, jaundice, dark urine, pruritus, or abdominal pain.
KYNAMRO REMS [See WARNINGS AND PRECAUTIONS]
- KYNAMRO is only available through a restricted program called KYNAMRO REMS and therefore, KYNAMRO is only available from certified pharmacies that are enrolled in the program. Additional information may be obtained at 1-877KYNAMRO (1-877-596-2676).
Injection Site Reactions [See WARNINGS AND PRECAUTIONS]
- Injection site reactions have been reported frequently in patients receiving KYNAMRO.
- These local reactions typically consist of one or more of the following: erythema, pain, tenderness, pruritus and local swelling.
Flu-Like Symptoms [See WARNINGS AND PRECAUTIONS]
- Flu-like symptoms have been reported in patients receiving KYNAMRO.
- Flu-like symptoms typically occur within 2 days after an injection and include one or more of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue.
Hypersensitivity Reactions (See WARNINGS AND PRECAUTIONS)
- Inform patients that hypersensitivity reactions (e.g., angioedema, urticaria, or generalized rash) have occurred in patients taking KYNAMRO.
- Instruct patients to promptly seek medical attention if a hypersensitivity reaction occurs.
[See DOSAGE AND ADMINISTRATION]
- The patient or caregiver should be instructed to review the KYNAMRO Medication Guide and Instructions for Use carefully.
- KYNAMRO is administered as a subcutaneous injection given once a week.
- Do not remove the needle cover from the pre-filled syringe while allowing the syringe to reach room temperature.
- The patient or caregiver should be instructed by a physician or an appropriately qualified healthcare professional in the proper technique for administering subcutaneous injections, including the use of aseptic technique.
- The patient and caregiver should be cautioned that needles or syringes must not be reused and instructed in safe disposal procedures. A puncture-resistant container for disposal of used needles and syringes should be supplied to the patient along with instructions for safe disposal of the full container.
- KYNAMRO should be injected into the abdomen, thigh region, or outer area of the upper arm. Patients and caregivers should be advised to alternate sites for subcutaneous injections. KYNAMRO should not be injected in areas of active skin disease or injury such as sunburns, skin rashes, inflammation, skin infections, active areas of psoriasis, or areas of tattooed skin and scarring.
- Patients and caregivers should be advised to alternate sites for subcutaneous injection. The injection should be performed slowly and steadily and the needle should not be withdrawn until the injection is complete.
- Protect from light. Do not mix or co-administer KYNAMRO with other products.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a subcutaneous carcinogenicity study in mice, mipomersen sodium was administered for up to 104 weeks at doses of 5, 20, 60 mg/kg/week. There were statistically significant increases in the incidences of hepatocellular adenoma and combined adenoma and carcinoma in female mice at 60 mg/kg/wk (2-times the systemic clinical exposure at 200 mg/wk, based on a body surface area comparison) for both mipomersen sodium and the mouse-specific analog. This dose also resulted in statistically significant increases in the incidence of hemangiosarcomas in female mice and fibrosarcomas of the skin/subcutis in male mice.
In a subcutaneous carcinogenicity study in rats, mipomersen sodium was administered for up to 104 weeks at doses of 3, 10, 20 mg/kg/wk. The incidence of fibrosarcomas of the skin/subcutis and the combination of fibroma, fibrosarcomas and malignant fibrous histiocytoma of the skin/subcutis was statistically significantly increased in female rats at 10 mg/kg/wk, at less than clinical exposure at the 200 mg/wk dose based on body surface area comparisons. Both sexes of rats also had statistically significant increases in the incidence of malignant fibrous histiocytoma of the skin/subcutis at 20 mg/kg/wk (at clinical exposure at the 200 mg/wk dose based on body surface area comparisons.
Mipomersen did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using a mouse lymphoma cell line, and an in vivo micronucleus assay in mice.
Mipomersen sodium had no effect on fertility in mice at doses up to 87.5 mg/kg/wk (2times clinical exposure at the 200 mg/wk dose based on body surface area comparisons).
Use In Specific Populations
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 (2times 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.
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.
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.
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 Pregnancy]. Females who become pregnant during KYNAMRO therapy should notify their healthcare provider.
Females of reproductive potential should use effective contraception during KYNAMRO therapy.
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.
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. [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]