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warnings and cautions
5 WARNINGS AND PRECAUTIONS CNS Depressant Effect and Daytime Impairment: Advise patients about the potential for somnolence and other nervous system effects. Advise patients who experience these effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved ( 5.1 ) Hepatic Transaminase Elevations: Perform bloodwork prior to initiation of LYNKUET to evaluate for hepatic function and injury. Do not start therapy if serum transaminase concentration is equal to or exceeds two times the upper limit of normal (ULN) or if the total bilirubin is equal to or exceeds two times the ULN. Perform follow-up evaluations of hepatic transaminase concentration 3 months after initiation. Advise patients to discontinue LYNKUET immediately in case of signs or symptoms suggesting liver injury. ( 5.2 ) Risk of pregnancy loss: May cause pregnancy loss or stillbirth when administered during pregnancy. Exclude pregnancy in females of reproductive potential prior to initiating LYNKUET. Discontinue if pregnancy is confirmed ( 5.3 ) Risk of seizure ( 5.4 ) 5.1 Central Nervous System (CNS) Depressant Effect and Daytime Impairment In the three OASIS trials, nervous system effects (including somnolence, fatigue, vertigo, dizziness and presyncope) occurred in 11.9% of patients on LYNKUET compared to 3.5% on placebo. [see also Adverse Reactions (6.1) ]. Advise patients about the potential for somnolence and other nervous system effects. Advise patients who experience these effects to refrain from driving or engaging in hazardous occupations or activities until the effects have resolved [see Clinical Studies (14.3) ]. 5.2 Hepatic Transaminase Elevations Elevations in serum transaminase (ALT and/or AST) concentrations equal to or greater than three times the ULN occurred in 0.6% of patients receiving LYNKUET and 0.4% of patients receiving placebo up to 12 weeks in three clinical trials. Perform baseline bloodwork (including ALT, AST, alkaline phosphatase, and total and direct bilirubin) prior to initiation of LYNKUET to evaluate for hepatic function and injury. Do not start therapy if serum transaminase concentration is equal to or exceeds two times the ULN or if the total bilirubin is equal to or exceeds two times the ULN. Perform follow-up evaluations of hepatic transaminase concentration 3 months after initiation of therapy. Advise patients to discontinue LYNKUET immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain). Discontinue LYNKUET if transaminase elevations exceed five times the ULN or if transaminase elevations exceed three times the ULN and total bilirubin exceeds two times the ULN. Exclude alternative causes of hepatic laboratory test elevations. 5.3 Risk of Pregnancy Loss LYNKUET is contraindicated for use in pregnancy [see Contraindications (4) ]. Findings from animal studies suggest that LYNKUET can cause pregnancy loss or stillbirth. Exclude pregnancy in females of reproductive potential prior to initiating LYNKUET. Advise females of reproductive potential to use effective contraception during treatment with LYNKUET and for 2 weeks after stopping LYNKUET [see Use in Specific Populations (8.1 , 8.3) ] . 5.4 Risk of Seizure Seizure was reported in patients taking LYNKUET [ see Adverse Reactions (6.1 , 6.2) ]. In addition, convulsions were observed in studies conducted in male and female rats [see Nonclinical Toxicology (13.2) ]. Advise patients about the potential risk of seizure. Use LYNKUET with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Central Nervous System (CNS) Depressant Effect and Daytime Impairment [see Warnings and Precautions (5.1) ] Hepatic Transaminase Elevations [see Warnings and Precautions (5.2) ] Risk of Seizure [ see Warnings and Precautions (5.4) ] The most frequently reported (≥5%) adverse reactions were headache, fatigue, dizziness and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 clinical practice. The safety of LYNKUET was evaluated in three randomized, double-blind, placebo-controlled, multicenter clinical trials (OASIS 1, OASIS 2, OASIS 3 ) in 1420 women . In OASIS 1 and OASIS 2 combined, 793 women received LYNKUET or placebo for 12 weeks. After the first 12 weeks, 341 women randomized to LYNKUET continued to receive LYNKUET for another 14 weeks, with a total treatment duration of up to 26 weeks. In OASIS 1 and OASIS 2 combined, 349 women received placebo for the first 12 weeks and 348 women switched to LYNKUET for the next 14 weeks. In OASIS 3, 627 women received LYNKUET or placebo for up to 52 weeks to evaluate long-term safety [see Clinical Studies (14) ] . Common Adverse Reactions In OASIS 1 and 2 combined, through the first 12 weeks, commonly reported adverse reactions in the LYNKUET group (≥2% and greater than in placebo) were headache, fatigue, gastroesophageal reflux disease, dizziness, nausea, and somnolence. Similar adverse reactions were seen in OASIS 3. Table 2 shows adverse reactions reported in at least 2% of women and more commonly in women taking LYNKUET than placebo in OASIS 3. Table 2: Common Adverse Reactions Reported in ≥ 2% in LYNKUET and Greater than Placebo, Weeks 1-52 (OASIS 3) Adverse Reaction LYNKUET N=313 n (%) Placebo N=314 n (%) Headache 30 (9.6) 22 (7.0) Fatigue Includes asthenia. 23 (7.3) 9 (2.9) Dizziness Includes balance disorder, presyncope, vertigo, vertigo CNS origin, vertigo positional, and vestibular neuronitis. 19 (6.1) 6 (1.9) Somnolence Includes lethargy. 16 (5.1) 4 (1.3) Abdominal pain Includes abdominal discomfort, abdominal pain lower/upper. 14 (4.5) 8 (2.5) Rash Includes dermatitis, urticaria. 13 (4.2) 5 (1.6) Diarrhea 12 (3.8) 3 (1.0) Muscle spasms Includes muscle tightness. 10 (3.2) 2 (0.6) Other clinically important adverse reactions: Seizure was reported in one patient (<0.1%) with a history of seizures in the clinical trials of LYNKUET. Adverse Reactions Leading to Discontinuation In OASIS 3, adverse reactions leading to treatment discontinuation (≥1% in LYNKUET and greater than placebo) were abdominal pain (1.6%), fatigue (1.6%), depression (1.6%) and headache (1.3%). Photosensitivity In the OASIS trials, mild to moderate events of photosensitivity occurred in 0.5% of patients receiving LYNKUET and 0.1% of patients receiving placebo. Onset of photosensitivity reactions ranged from day 1 to day 290. While discontinuation occurred in one patient, photosensitivity events in other patients resolved under continued treatment with LYNKUET [see Nonclinical Toxicology (13.2) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of LYNKUET. 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. Postmarketing cases of seizure have been reported in patients treated with LYNKUET.