Get Email Alerts |
Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
JADELLE (NDA-020544)
(LEVONORGESTREL)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/20/2016 (SUPPL-10)
4 Contraindications
(Additions and/or revisions are underlined)
JADELLE is contraindicated in patients who have:
- Current thrombophlebitis or thromboembolic disorders
- Undiagnosed abnormal uterine bleeding
- Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past
5 Warnings and Precautions
5.1 Insertion and Removal Complications(Additions and/or revisions are underlined)
…In clinical trials, removal complications and difficulties, including damage to the implants, were reported in 7.5% of the more than 1,100 JADELLE removals. Complications of insertion or removal included deep placement, multiple or long incisions, bruising, displacement, pain, prolonged removal, incomplete removal requiring an additional visit or visits, broken implants, and fibrous pericapsular tissue.
Infection (including cellulitis), ulcerations, excessive scarring/keloid, phlebitis and hyperpigmentation have been reported with JADELLE implants. During clinical trials of JADELLE implants, infection at the insertion site occurred in 0.4% of women. Attention to aseptic technique and proper insertion and removal of JADELLE implants reduces the likelihood of infection. If infection occurs, initiate suitable treatment. If infection persists, remove the implants.
…Nerve injury, most commonly associated with deep placement and removal, may also occur…Replace an expelled implant with a new sterile implant. If infection is present, ensure that it is resolved before another implant is inserted. Protection against pregnancy is likely to be inadequate if only a single implant is in place.
Implant displacement (i.e., movement) has been reported with JADELLE implants. While displacement most commonly involves minor changes in the position of the implants, reports of significant displacement (up to several inches) have been received. Some instances of displacement have been associated with pain or discomfort…
Advise women that JADELLE implants can be removed for any reason whenever the woman wishes, and must be removed by the end of five years.
(Revised subheading)
(Additions and/or revisions are underlined)
Follow women who are being treated for hyperlipidemias closely if they elect to use JADELLE implants, as serum lipoprotein levels may be altered.
…Consider more frequent blood glucose monitoring in diabetic patients who use JADELLE implants.
(Newly added subsection)
Sex hormone-binding globulin and thyroid-binding globulin concentrations are decreased by JADELLE use. Thyroxine concentrations may be slightly decreased and triiodothyronine uptake increased. The dose of replacement thyroid hormone therapy may need to be decreased.
(Additions and/or revisions are underlined)
Consider the possibility of an ectopic pregnancy among women using JADELLE implants…In clinical studies on JADELLE used for up to 5 years with more than 4,100 woman-years of exposure, 8 pregnancies occurred, one of which was ectopic…In case of contraceptive failure with JADELLE, exclude ectopic pregnancy.
(Additions and/or revisions are underlined)
If thromboembolic disorders or cardiovascular problems occur in JADELLE users, remove the implants. Consider removal in women who will be subjected to prolonged immobilization because of surgery or other illnesses. Use of JADELLE in women with active thrombophlebitis or thromboembolic disorders is contraindicated.
Evaluate patients for retinal thrombosis immediately if there is an unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
(Additions and/or revisions are underlined)
Discourage women with a history of hypertension-related diseases or renal disease from using hormonal contraception.
For women with well-controlled hypertension, use of JADELLE can be considered. Closely monitor women with hypertension who use JADELLE. If sustained hypertension develops during the use of JADELLE, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, remove JADELLE.
(Additions and/or revisions are underlined)
…In some cases, they may twist or rupture, sometimes causing abdominal pain, and surgical intervention may be required.
(Additions and/or revisions are underlined)
In case of abnormal bleeding, conduct appropriate diagnostic testing to rule out malignancy and pregnancy. If pregnancy occurs, remove JADELLE implants.
During clinical trials, JADELLE implants were used by 1,393 subjects, including 1,243 subjects at fully compliant sites. Table 2 displays menstrual complaints reported by more than 1.0% of the 1,243 subjects at compliant sites in the first year of JADELLE use, and the percent of patients with those events in Years 1 to 5 of use. About 14% of subjects discontinued the trial prematurely because of unacceptable menstrual bleeding patterns.
(Additions and/or revisions are underlined)
…Use of JADELLE in women with acute liver disease is contraindicated.
If jaundice develops in any woman using JADELLE implants, consider removing the implants.
(Revised subheading)
(Additions and/or revisions are underlined)
Carefully observe women with a history of depression and consider removal of JADELLE if depression recurs to a serious degree. Consider removing JADELLE implants in women who become significantly depressed, because depression may be drug-related.
(Additions and/or revisions are underlined)
Idiopathic intracranial hypertension has been reported on rare occasions in users of levonorgestrel implants. Consider this diagnosis if persistent headache and/or visual disturbances occur in a woman with JADELLE, particularly if the patient is obese or has recently gained weight. Remove JADELLE if idiopathic intracranial hypertension is diagnosed.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following adverse reactions reported with the use of progestin-only contraception are discussed elsewhere in the labeling:
- Ectopic pregnancies
- Menstrual changes
(Newly added subheading; Additions and/or revisions are underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
JADELLE was evaluated in three clinical trials. Two of these trials were randomized, multi-center comparisons of JADELLE and another levonorgestrel implant that were conducted at sites in and outside of the US. The third trial was an open-label, multi-center study conducted primarily at sites in the US. A total of 1,393 women used JADELLE in these studies, including 1,243 women who participated at fully compliant study sites.
Of the 1,243 women treated with JADELLE at compliant sites, 460 women completed 5 years of JADELLE use. The total experience with JADELLE in Years 1 through 5 was 4,138 woman-years. The mean experience with JADELLE per woman was 3.3 years.
Subjects in the clinical studies of JADELLE were healthy women between 18 and 40 years of age who were at risk of becoming pregnant. Exclusion criteria included major diseases (e.g., diabetes mellitus, cancer, severe cardiovascular disease, thromboembolism), receipt of injectable contraceptives within the previous year, receipt of oral contraceptives within the previous month, and being less than 6 weeks postpartum.
In the clinical trials of JADELLE, the average weight change over 5 years of use was a gain of about 9 pounds. Approximately 20% of women gained at least 10 pounds in the first year, and 50% gained at least 10 pounds by the end of the fifth year of use.
Adverse reactions reported by greater than or equal to 5% of subjects during 5 years of JADELLE use in clinical trials are listed in Table 3.
Table 3: Adverse Reactions Reported in Greater than or Equal to 5% of Subjects during 5 Years of JADELLE Use in Clinical Trials (Table has been added; please refer to label)
Non-menstrual adverse reactions that led to discontinuation in greater than or equal to 1% were recorded for the 1,393 subjects with JADELLE implants at all study sites in the clinical studies during Years 1 through 5, and are shown in Table 4.
Table 4: Adverse Reactions that Led to Discontinuation in Greater than or Equal to 1% of Subjects During 5 Years of JADELLE Use in Clinical Trials (Table has been added; please refer to label)
The most common serious adverse reactions (leading to hospitalization) in subjects using JADELLE were gallbladder or biliary disorders (cholecystitis, cholelithiasis, biliary lithiasis; 7 subjects), ovarian disorders (cyst, mass, enlargement; 6 subjects), cervical disorders (cervicitis, dysplasia, biopsy, polyp; 4 subjects), breast cancer (2 subjects), other breast disorders and surgeries (4 subjects), uterine disorders (fibroid, prolapse, adenomyosis; 4 subjects), and depression (2 subjects).
(Newly added subsection)
The following adverse reactions have been identified during post-approval use of JADELLE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: anemia, coagulopathy, hemoconcentration, leukocytosis, hemoglobin decreased
Endocrine disorders: increased serum prolactin, thyroid disorder
Eye disorders: blurred vision, ocular icterus, papilledema, visual impairment
Gastrointestinal disorders: abdominal discomfort, distension or pain, constipation, diarrhea, flatulence, gastritis, pancreatic cyst, vomiting
Hepatobiliary disorders: cholelithiasis, cholestatic jaundice
Immune system disorders: Anaphylactic shock, hypersensitivity, mouth swelling
Implant site skin disorders: abscess, bruising, cellulitis, discharge, discoloration, discomfort, edema, erosion, erythema, fibrosis, furuncle, hematoma, hemorrhage, hypersensitivity, hypoesthesia, impaired healing, induration, infection, inflammation, irritation, pain, pruritus, rash, swelling, urticaria, vesicles, warmth
Infections: bronchitis, cystitis, fungal infection, influenza, pharyngitis, pneumonia, urinary tract infection, vaginal infection, vulvovaginal mycotic infection
Metabolism and nutrition disorders: changes in weight and appetite, changes in glucose, hypoglycemia, increased body temperature, pyrexia
Musculoskeletal and connective tissue disorders: arthralgia, arthropathy, asthenia, joint swelling, limb discomfort, muscle atrophy, spasms, tightness or weakness, musculoskeletal pain, musculoskeletal stiffness, systemic lupus erythematosus
Nervous system disorders: benign intracranial hypertension, brain edema, burning sensation, cerebrovascular stenosis, dysesthesia, hypersomnia, hypoesthesia, loss of consciousness, migraine, monoplegia, peripheral neuropathy, paresthesia, peripheral nerve lesion, somnolence, syncope
Neoplasms benign, malignant and unspecified: fibroadenoma of breast, melanocytic nevus
Psychiatric disorders: anxiety, apathy, depressed mood, fear of eating, hallucination, insomnia, irritability, libido decrease or loss, altered mood, mood swings, nervousness, panic attack, personality change, stress, tearfulness, tension
Renal and urinary disorders: dysuria, urine abnormality, urine output decreased
Reproductive system and breast disorders: alterations in bleeding and menstrual patterns, adnexa uteri pain, breast discharge, engorgement, enlargement, swelling or mass, cervical dysplasia, dyspareunia, endometriosis, galactorrhea, genital discharge, nipple pain, genital pruritus, suppressed lactation, uterine cyst, vaginal discharge or odor
Respiratory: dyspnea
Skin and subcutaneous tissue disorders: chloasma, dermatitis ecchymosis, eczema, erythema, abnormal hair growth, hirsuitism, nail discoloration, night sweats, pain, palmar-plantar erythema, pruritus, rash, scarring, seborrheic dermatitis, discoloration, discomfort, striae, ulcer, urticaria
Vascular disorders: deep vein thrombosis, pulmonary embolism, intracranial venous sinus thrombosis, hot flush, hypertension, hypotension, peripheral coldness, varicose vein, thrombosis, vasodilation
7 Drug Interactions
(Additions and/or revisions are underlined)
Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
(Newly added subheading; Additions and/or revisions are underlined)
Substances decreasing the plasma concentrations of hormonal contraceptives (HCs) and potentially diminishing the efficacy of HCs:
Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of HCs and potentially diminish the effectiveness of HCs or increase breakthrough bleeding.
Some drugs or herbal products that may decrease the effectiveness of HCs include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between HCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with HCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of HCs:
Co-administration of certain HCs and strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase the serum concentrations of progestins, including levonorgestrel.
Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV)Antiretrovirals
When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos) amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir, nevirapine, efavirenz] or increase [e.g., indinavir and atazanavir/ritonavir, etravirene]). These changes may be clinically relevant in some cases.
Efavirenz, a moderate CYP3A4 inducer, significantly decreased systemic exposure to levonorgestrel. Postmarketing reports of contraceptive failure with JADELLE in efavirenz-exposed patients have been received.
Consult the prescribing information of anti-viral and anti-retroviral concomitant medications to identify potential interactions.(Newly added subsection)
Hormonal contraceptives may affect the metabolism of other drugs. Consequently, plasma concentrations may either increase (for example, cyclosporine) or decrease (for example, lamotrigine). Consult the labelling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
(Revised subheading)
(Additions and/or revisions are underlined)
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
JADELLE is contraindicated for use in pregnant women because there is no need for pregnancy prevention in a woman who is already pregnant. Published studies report no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins, including levonorgestrel, in pregnant women. Remove JADELLE if a woman wishes to continue her pregnancy.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Levonorgestrel is present in breast milk. Available data show no adverse effects on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for JADELLE and any potential adverse effects on the breastfed infant from JADELLE or from the underlying maternal condition.
(Additions and/or revisions are underlined)
Safety and efficacy of JADELLE implants have been established in women of reproductive age. Efficacy is expected to be the same for postmenarcheal adolescents under the age of 18 years and for patients 18 years and older…
(Additions and/or revisions are underlined)
This product has not been studied in postmenopausal women and is not indicated in this population.
(Additions and/or revisions are underlined)
Serum levonorgestrel concentrations were found to be inversely related to body weight. Serum levonorgestrel concentrations in women weighing more than 70 kg were approximately half of those in women weighing less than 50 kg…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Insertion Site Instructions:
Advise the patient to keep the insertion area dry and avoid heavy lifting for 2 to 3 days. The gauze may be removed after 1 day, and the skin closure may be removed as soon as the insertion area has healed, typically in 3 days.
Symptoms Related to Insertion and Infection
Advise patients to report symptoms related to insertion such as pain, edema and bruising. Advise patients to report symptoms of infection (including cellulitis and abscess formation) including blistering, ulcerations, sloughing, excessive scarring, phlebitis and hyperpigmentation.
Removal of JADELLE
Advise the patient that JADELLE can be removed for any reason whenever she wishes and must be removed by the end of 5 years. Removal may cause more discomfort and scarring than the insertion procedure .
Changes in Normal Menses
Advise the patient that the use of JADELLE may be associated with changes in their normal menstrual bleeding pattern .
Sexually Transmitted Infections
Advise the patient that JADELLE does not protect against HIV infection or other sexually transmitted infections.
(Extensive changes; please refer to label)
Other
(Physician Labeling Rule (PLR) conversion; please refer to label)